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Natural Products with Potential to Treat RNA Virus Pathogens Including SARS-CoV-2

Mitchell P. Christy
Mitchell P. Christy
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, United States
More by Mitchell P. Christy

Yoshinori Uekusa
Yoshinori Uekusa
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, United States
Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
More by Yoshinori Uekusa

Lena Gerwick*
Lena Gerwick
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, United States
*Phone: 858-534-0566. Email: [email protected]
More by Lena Gerwick
http://orcid.org/0000-0001-6108-9000

, and

William H. Gerwick*
William H. Gerwick
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, United States
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093, United States
*Phone: 858-534-0578. Email: [email protected]
More by William H. Gerwick
http://orcid.org/0000-0003-1403-4458

Cite this: J. Nat. Prod. 2021, 84, 1, 161–182

Publication Date (Web):December 22, 2020

https://doi.org/10.1021/acs.jnatprod.0c00968

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Abstract

Three families of RNA viruses, the Coronaviridae, Flaviviridae, and Filoviridae, collectively have great potential to cause epidemic disease in human populations. The current SARS-CoV-2 (Coronaviridae) responsible for the COVID-19 pandemic underscores the lack of effective medications currently available to treat these classes of viral pathogens. Similarly, the Flaviviridae, which includes such viruses as Dengue, West Nile, and Zika, and the Filoviridae, with the Ebola-type viruses, as examples, all lack effective therapeutics. In this review, we present fundamental information concerning the biology of these three virus families, including their genomic makeup, mode of infection of human cells, and key proteins that may offer targeted therapies. Further, we present the natural products and their derivatives that have documented activities to these viral and host proteins, offering hope for future mechanism-based antiviral therapeutics. By arranging these potential protein targets and their natural product inhibitors by target type across these three families of virus, new insights are developed, and crossover treatment strategies are suggested. Hence, natural products, as is the case for other therapeutic areas, continue to be a promising source of structurally diverse new anti-RNA virus therapeutics.

Note

This article is made available via the ACS COVID-19 subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

Introduction

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Deadly outbreaks caused by viruses have occurred periodically throughout human history. Several endemic infections evolved into pandemics that threatened the entire global population. The last pandemic of the 19th century, known as La Grippe or the Russian Flu, occurred between 1889 and 1890 and caused approximately one million deaths.(1) This outbreak was caused by an influenza A virus, subtype H2N2.(2) The 1918 Spanish flu epidemic arrived on the heels of World War I and killed mainly small children, young adults, and the elderly.(3) It is generally felt that this was the deadliest pandemic ever recorded, with an estimated 50 million fatalities. The Spanish flu epidemic was also caused by an influenza virus, subtype H1N1. Other notable pandemics are the 1957 and 1968 influenza infections. These were widespread, and the 1957 influenza epidemic killed roughly one million people. Thanks to extensive research and development spanning decades, pandemics caused by influenza viruses are now able to be abated and at times prevented by vaccines, although few truly effective drug treatments are available.

For decades, natural products (NPs) have been an inspiration for the development of new pharmaceuticals; approximately 50% of all small-molecule drugs have an NP derivation or inspiration.(4) Due to the vast diversity of natural products in nature made by microbes, plants, and fungi, these compounds have been a useful reservoir of structural information from which to draw in drug discovery campaigns. As Frank Lovering laid out in his treatise on stereochemical complexity in drug development, the complexity that natural products tend to possess is a testament to their usefulness in this area.(5,6) As we search for new answers to the threat of global pandemics, where better to begin looking than to nature?

The human immunodeficiency virus (HIV) has been endemic for the last 40 years. It was present in human populations at a low rate since the 1950s, but in the late 1970s and early 1980s, more cases of immunodeficiency occurred with an unknown cause. The human immunodeficiency virus was identified in 1983 by Luc Montagnier (Pasteur Institute, Paris, France) and Robert Gallo (NIH, Bethesda, Maryland, USA).(7−11) HIV infections led to the acquired immune deficiency syndrome (AIDS) epidemic that claimed approximately 30 million lives worldwide.(12) There is currently no cure for AIDS, but disease progression can be mitigated with a variety of antiviral treatments, where roughly 23 million treatments are prescribed each year. The most common of these treatments are integrase inhibitors such as dolutegravir and raltegravir. Another common drug class is the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). The combination of dolutegravir/rilpivirine, a non-nucleoside reverse transcriptase inhibitor, can be given as a once-daily tablet, which improves compliance.(13) One reason why it has been so difficult to make an AIDS vaccine is that the virus infects the very cells of the immune system that a vaccine should induce; hence, HIV is a good example of why vaccines cannot always be developed, and thus antiviral treatments are needed.

The term hepatitis is used to describe the infection of the liver by any of the hepatitis A through E viruses. However, hepatitis viruses are fairly heterogeneous; hepatitis (Hep) A is an unenveloped symmetrical RNA virus, whereas Hep B is a double-stranded DNA virus. The most common strategy for controlling different hepatitis viruses has been through the development of vaccines (e.g., to Hep A and B), though there are some drug treatments as well. Vaccines are under development for Hep C and Hep E, and Hep D occurs only as a co-infectant with Hep B. Hence, immunization against Hep B also provides protection against Hep D.(14) Antiviral therapeutics have also been developed for treating Hep C(15) and are highly effective such that the virus can be completely eradicated.(16)

In this review, we focus on three virus families, the Coronaviridae, Flaviviridae, and Filoviridae, because these three families have been responsible for causing a number of endemic and pandemic outbreaks, including the current COVID-19 pandemic (Table 1). Examples belonging to the Coronaviridae are SARS-CoV-1, SARS-CoV-2, and MERS-CoV. The family Flaviviridae contains the Dengue, Yellow fever, Japanese encephalitis virus, Zika, and tick-borne encephalitis (TBV) viruses. Lastly, the filoviruses considered in this review include those causing Ebola and Marburg diseases. Unfortunately, many of these viruses have inadequate or completely absent treatment options. Because of this deficiency, we have focused this review on identifying potential druggable protein targets that have been or could be used in the development of small-molecule treatments, with an emphasis on natural products and their derivatives.

Table 1. Viruses Discussed in This Review and Associated Information

virus	taxonomy	emergence	source/transmission	type	genome size	treatments
SARS-CoV	order: Nidovirales, family: Coronaviridae, genus: Betacoronavirus	Foshan, China 2002	bats → intermediate mammal host → human	positive-sense RNA virus	∼30 kb	no
SARS-CoV-2	order: Nidovirales, family: Coronaviridae, genus: Betacoronavirus	Wuhan, China 2019	bats → intermediate mammal host → human	positive-sense RNA virus	∼30 kb	no
MERS-CoV	order: Nidovirales, family: Coronaviridae, genus: Betacoronavirus	Jeddah, Saudi Arabia 2012	bats → intermediate mammal host → human	positive-sense RNA virus	∼30 kb	no
Ebola virus	order: Mononegavirales, family: Filoviridae, genus: Ebolavirus	Sudan and Zaire 1976	bats → humans; mammal hosts → humans; humans → humans	negative-sense RNA virus	19 kb	vaccine: rVSV-ZEBOV
Marburg virus	order: Mononegavirales, family: Filoviridae, genus: Marburgvirus	Marburg, Germany 1967	bats → humans; mammal hosts → humans; humans → humans	negative-sense RNA virus	19 kb	no
Dengue	order: Amarillovirales, family: Flaviviridae, genus: Flavivirus	endemic since WWII, subtropics and tropics where the aedes sp mosquito exist	primates → mosquito vector → humans	positive-sense RNA virus	10.7 kb	no
West Nile	order: Amarillovirales, family: Flaviviridae, genus: Flavivirus	Africa 1937, United States 1999	birds → mosquito vector → human	positive-sense RNA virus	11 kb	no
Zika	order: Amarillovirales, family: Flaviviridae, genus: Flavivirus		unknown → mosquito vector → humans	positive-sense RNA virus	11 kb	vaccines in development, no other treatments available
tick-borne encephalitis virus	order: Amarillovirales, family: Flaviviridae, genus: Flavivirus	virus isolated in 1937, endemic in Russia, Europe	ticks → humans	positive-sense RNA virus	11 kb	vaccine available, but not outside of endemic areas
Japanese encephilitis virus	order: Amarillovirales, family: Flaviviridae, genus: Flavivirus	Southeast Asia 1930s	unknown → mosquito vector → humans	positive-sense RNA virus	10.9 kb	vaccine available, but no other pharmaeutical treatments available

Viral Life Cycles

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Coronaviridae

The current outbreak of SARS-CoV-2 represents the third documented spillover of an animal coronavirus to humans in the last 20 years that has resulted in a major epidemic of global proportions.(17) As of this writing, the virus has infected worldwide almost 65 million people and claimed over 1.5 million lives.(18) The Coronaviridae Study Group of the International Committee on Taxonomy of Viruses has assessed the placement of this current human pathogen within the Coronaviridae family. They have recognized this virus as forming a sister clade to the prototype human and bat severe acute respiratory syndrome coronaviruses (SARS-CoVs) and designated it as SARS-CoV-2.(19) Coronaviruses are enveloped, positive-sense RNA viruses that are distributed broadly among humans, other mammals, and birds and are known to cause respiratory, enteric, hepatic, and neurologic diseases.(20,21) The Coronaviridae family of viruses contains the largest known RNA genomes, 30–32 kb,(22) and is divided into four genera (alpha, beta, gamma, and delta coronaviruses). While most coronavirus infections cause common cold symptoms in humans, SARS-CoV, MERS-CoV, and SARS-CoV-2, the three coronaviruses covered in this review, have the potential to cause more serious disease, including death. These three viruses have emerged relatively recently, all in the 21st century, and have been the focus of extensive research in an urgent response to their global occurrence and impact. SARS-CoV appeared first in late 2002 and was characterized by rapid human-to-human transmission with various degrees of morbidity and mortality ranging from moderate to high. The zoonotic origin of these outbreaks was linked to bat coronaviruses (>90% sequence identity) with possible intermediate transmission through other mammals such as civets(20) or pangolins.(23) These infections tended to disproportionately affect older populations, with SARS mortality reaching 50% of those infected over 60 years of age.(20) To date there are no clinically approved treatments for these viruses, and therefore we provide this review with the goal of providing insight into these viruses, their vulnerabilities, and past and ongoing natural product-based drug discovery efforts to curb these deadly pathogens.

Coronaviruses infect their hosts through a number of pathways, exploiting host receptors and transmembrane proteases to facilitate their entry into cells and delivery of viral RNA into the cytoplasm (Figure 1, Table 2). In overview, the viral spike glycoprotein (S) facilitates entry into target cells by binding to cellular receptors and is subsequently primed by host cellular proteases that promote fusion of viral and cellular membranes and internalization. Trimers of the S protein form peplomers embedded in the viral envelope, giving the virus its characteristic crown-like morphology. Due to their highly homologous S proteins (96% sequence identity), both SARS-CoV and SARS-CoV-2 make use of the mammalian angiotensin converting enzyme 2 (ACE2) as a means of initial contact.(20,24,25) The MERS-CoV and SARS-CoV-1/2 spike proteins share a high degree of structural similarity in their core subdomains, but are notably divergent in the receptor-binding subdomain. For this reason, MERS-CoV utilizes a different surface protein for entry, namely, the dipeptidyl peptidase 4 receptor (DPP-4 or CD26).(26) It has been posited that the more widespread distribution of SARS-CoV-2 is facilitated by a stronger binding affinity to the ACE2 receptor.(27) Once contact is made, host proteases TMPRSS2/4 (colocalized with ACE2 or DPP-4 on the cell surface) or endosomal cathepsin L cleaves at two or more sites on the S protein to facilitate a conformational rearrangement and fusion with the host membrane, releasing viral RNA into the host cytoplasm.(24,28−30) Mechanistically, it appears that the coronavirus S protein undergoes a receptor-mediated conformational change that reveals cryptic cleavage sites within the viral envelope glycoprotein.(31) Proteolysis by host proteases is then necessary to fully activate the viral glycoprotein’s membrane-fusion potential. Inhibiting activity of either host protease partially blocks infection, and inhibiting both efficiently prevents cell entry and replication in vitro.(29,32) Temporary blockage of these host proteases by small molecules is nonlethal to mammalian cells, and thus they are active targets of investigation for prophylactic treatment. Following entry, the replicase gene is translated by host machinery and cotranslationally processed by the Mpro and PLpro into 16 nonstructural proteins encoded in orf1a/1ab. These proteins are assembled into the replicase–transcriptase complex to create an environment suitable for viral RNA synthesis and are responsible for RNA replication and transcription of the genomic and subgenomic RNAs. A comprehensive list of these proteins and their known functions has been assembled by Fehr and Perlman.(33) Viral RNA synthesis by the replicase complex produces RNAs that serve as mRNAs for production of the structural and accessory proteins. This process is currently the focus of active drug discovery efforts to prevent viral replication. For example, remdesivir (1) (Gilead Sciences;

Figure 7) is a promising candidate targeting the RNA-dependent RNA polymerase (RdRp).(34,35)

Figure 1. Life cycle of coronaviruses as represented by the SARS-CoV-1/2 and MERS-CoV viruses. The Roman numerals in the figure refer to entries in Table 2. The “T” symbol indicates a target with potential for developing an inhibitor.

Table 2. Validated and Potential Drug Targets and Known NP Inhibitors against Coronaviridaea

	number	target protein	function	natural product inhibitors	NP-inspired inhibitors
viral proteins	1	spike glycoprotein	host cell recognition	griffithsin (2), emodin (3)	EK1 and other spike fragments
	II	main protease (Mpro/3CLpro)	viral protein mauration	herbacetin (13), rhoifolin (15), and other flavonoids	peptidomimetics
	III	papain-like protease (PLpro)	viral protein mauration	tomentin B (16), hirsutenone (17), tanshinones (19), psoralidin (18), and others	inhibitors needed
	IV	RNA-dependent RNA polymerase (RdRp)	viral RNA replication	inhibitors needed	favipiravir (22), remdesivir (1), ribavirin (23), galidesivir (24), β-d-N4-hydroxycytidine (25)
	V	NSP1	obstructs host cell protein synthesis and innate immune response	inhibitors needed	inhibitors needed
	VI	NSP13	viral helicase	myricetin (26), scutellarein (27)	inhibitors needed
	VII	Orf8b	obstructs innate immune response	inhibitors needed	inhibitors needed
host proteins	VIII	TMPRSS2	cell membrane protease, cleaves viral spike protein facilitating membrane fusion and entry	aprotinin (34)	inhibitors needed
host proteins	IX	cathepsin L	endosomal protease, cleaves spike protein facilitating membrane fusion	gallinamide A (35), nicolaidesin C (36), grassypeptolide (37), E-64, leupeptin (38)	other reviews

^{^a}

Roman numbering corresponds to numbering in Figure 1. Numbers in parentheses correspond to structures in Figures 5–11.

Figure 2. Life cycle of *Flaviviridae* as represented by the dengue virus. The Roman numerals in the figure refer to entries in Table 3. The “T” symbol indicates a target with potential for developing an inhibitor.

Figure 3. Life cycle of filoviruses as represented by the Ebola virus. The Roman numerals in the figure refer to the entries in Table 4. The “T” symbol indicates a target with potential for developing an inhibitor.

Figure 4. Schematic diagrams for the genomes of coronavirus SARS-CoV-2 (*Coronaviridae*), Dengue virus (*Flaviviridae*), and Ebola virus (*Filoviridae*). The genomes of *Coronaviridae* and *Flaviviridae* are composed of single-strand positive-sense RNA, whereas those of the *Filoviridae* are composed of a single strand of negative-sense RNA. Genes labeled by Roman numerals encode potential druggable protein targets mentioned in this review and accord with the same Roman numerals used in Figures 1–3 and Tables 2–4. Capsid protein (pink), spike protein (red), polymerase (brown), enzyme (orange), structural protein (green), envelope protein (yellow), cofactor/activator (blue), others/undefined protein (gray).

Figure 5. Inhibitors of viral structural proteins of (A) *Coronaviridae*, (B) *Flaviviridae*, or (C) *Filoviridae*. The following are natural products: griffithsin (PDB: 2GTY), emodin, nordihydroguaiaretic acid, ellagic acid, gallic acid, cyanovirin-N (11, PDB: 2EZM), and natural product derivatives: PG545, 8, 9, 10.

Figure 6. Inhibitors of viral proteases 3CLpro (A), PLpro (B), or NS3 (C). The following are natural products: herbacetin, pectolinarin, rhoifolin, tomentin B, hirsutenone, cryptotanshinone, psoralidin, ganodermanotriol, ivermectin, and natural product derivatives: rupintrivir.

The main pillars of drug discovery against these recently emergent coronaviruses have been inhibition of viral entry or prevention of replication once infection has occurred. There are several routes by which the virus can escape the cell, including exocytosis or by inducing apoptosis, and this makes the targeting of packaging or export mechanisms much more challenging drug targets. However, by targeting the spike glycoprotein, host recognition by the virus is prevented and entry nullified. Alternatively, inhibition of polyprotein processing by the viral proteases or targeting the RdRp can partly or wholly prevent replication. A list of repurposed or investigational agents against SARS-CoV-2 was recently reported,(36) and several studies have been published identifying new inhibitors of SARS-CoV and MERS-CoV.(37,38)

Flaviviridae

Several well-known endemics are caused by flaviviruses, for example, West Nile, Dengue, Zika, Japanese encephalitis (JEV), and tick-borne encephalitis virus (TBV). Most Flaviviridae infections involve an intermediate host before transmission to humans. West Nile, Zika, Dengue, and JEV viruses are all transmitted by mosquitoes, whereas TBV involves spread by ticks; humans are typically the end host. Intermediate animal hosts include monkeys, birds, and pigs, with transfers to mosquitoes, which pass the infection to humans (Figure 2, Table 3). However, Dengue is common in human populations around the world, with around 4.2 million cases reported to WHO in 2019; however the true number of infections is estimated to be much higher. Because of its prevalence, human to mosquito to human transmission of Dengue is the most common route (Figure 2).(39) The tick-borne flaviviruses are commonly transmitted from deer and sheep to ticks and then to humans.(40) Because there are many different flaviviruses that can cause potential pandemics, after a brief review of the diversity of disease-causing Flaviviridae, this review focuses on Dengue virus. This is appropriate and representative, as all flaviviruses have similar genome sizes (10–11 kb) as well as similar gene organization in their positive RNA strand genomes.

Table 3. Validated and Potential Drug Targets in Flaviviridae and NP Inhibitors (Dengue Virus Shown as Example)a

	number	target protein	function	natural product inhibitors	NP-inspired inhibitors
viral proteins	I	capsid protein	binds to viral nucleotide strand, forms viral capsid	nordihydroguaiaretic acid (NDGA) (4)	inhibitors needed
	II	prM/M protein	membrane protein	inhibitors needed	ectodomain of M protein, decanoyl-Arg-Val-Lys-Arg-CMK
	III	E protein	envelope protein	inhibitors needed	heparan sulfate mimic PG545 (5)
	IV	NS1	Antihost factor glycoprotein	Castanospermine (32)	Heparan sulfate mimic PG545, Celgosivir (33)
	Va	NS2A	membrane protein, interacts with calmodulin (Ca-influx)	inhibitors needed	inhibitors needed
	Vb	NS2B	NS3 cofactor/part of the replication complex	inhibitors needed	inhibitors needed
	VI	NS3	protease/helicase	ganoderma lucidum triterpenoid, ganodermanontriol (20)	ivermectin (21)
	VIIa	NS4A	ER membrane protein/also part of replication complex	inhibitors needed	inhibitors needed
	VIIb	NS4B	ER membrane protein/also part of replication complex	inhibitors needed	inhibitors needed
	VIII	NS5	RdRp/methyltrans ferase/helicase	mycophenolic acid (28)	ribavirin, ZX-2401
host proteins	IX	calmodulin	Ca-influx. interacts with NS2A	inhibitors needed	inhibitors needed
	X	signal peptidase/Signalase	cleaves signal peptides, in Dengue four cleavages (prM, E, NS1, and NS4B)	cavinafungin (44)	inhibitors needed
	XI	Aalpha-glucosidase	aids in ER release of glycoproteins E and NS 1	nojirimycin (45), deoxynojirimycin (46)	CM-10-18 (deoxynojirimycin analogue)
	XII	80S ribosome	translation of viral polypeptide	inhibitors needed	geneticin (neomycin analogue) (47)

^{^a}

Roman numbering corresponds to numbering in Figure 2. Numbers in parentheses correspond to structures in Figures 5–11.

Dengue is the most prevalent mosquito-borne viral disease in the world.(41) The dengue virus consists of four serotypes, which introduces considerable complication in the disease and its clinical course. Infection with one serotype does not confer immunity to another serotype. Rather, infection with a different serotype can create an antibody-dependent enhancement of the disease. This makes it very difficult to develop a universal vaccine for all the Dengue serotypes(41) and makes imperative the development of small-molecule therapeutics.

West Nile virus infections first appeared in the United States in 1999. The most common route of human infection is by a mosquito bite with the natural reservoir mainly being in birds. Since 1999 an estimated 7 million humans have been infected in the United States; this makes the West Nile virus the most common mosquito-borne virus infection and also the virus that is responsible for the most cases of viral encephalitis in the country.(42) According to the CDC there are no currently approved treatments for West Nile virus, other than standard supportive care.(43)

The Zika virus was first isolated from a monkey in Uganda in 1947, and transmission to humans was first detected in 1952. So far, only 12 cases in Puerto Rico and one case in Virginia have been recorded in the United States (CDC.gov). It is, like many other Flaviviridae, transmitted by mosquitoes and is widespread in Africa and Asia Pacific countries. In 2015, reports of the virus spreading to Brazil started circulating, and several thousand babies were born with microcephaly.(44) The virus has since spread through South America and the Caribbean.

The Japanese Encephalitis Virus (JEV) was first discovered in the 1870s in Japan. It is widespread throughout Asia with about 69 000 cases per year.(45) Several different genotypes and the unpredictable spread of the JEV makes developing specific pharmaceutical treatments very attractive. Several vaccines exist against different genotypes, and one manufactured by IXIARO must be given as two doses with 28 days between followed by a yearly booster.(46) This elaborate vaccination schedule can be prohibitive for travelers, and thus there is an unmet medical need for specific agents to treat JEV infections.

Several flaviviruses are transmitted via ticks, an example being tick-borne encephalitis (TBE). TBE is endemic to Eurasia and is becoming more widespread. A recent review provides details on the viral life cycle and viral and host proteins involved in transmission.(47)

Viruses of the family Flaviviridae have a positive RNA strand that can, upon entry into the cell, immediately hijack the ribosome for translation. The size of the RNA genome varies from about 10.6 to 10.9 kb. The RNA encodes for 10 proteins, three of which are structural and seven are nonstructural (Figure 4). The orfs for the structural proteins contain the nucleocapsid protein (C), the envelope protein (M), and the major spike (envelope) glycoprotein (E) of the capsid. The seven remaining orfs encode for nonstructural proteins (NSP).

NS1, in at least the Zika virus, appears to ubiquitinate Arg63 of the metalloproteinase 9 (MMP9) to increase its stability. MMP9 degrades structural proteins and tight junctions between cells such that the virus can invade tissues more easily.(48) Involvement of MMP9 in West Nile infection has also been reported, but there is no experimental data to support NS1 ubiquitination. Instead, some evidence exists that the interferon pathway is downregulated by this protein.(49) The Dengue virus NS1 was examined by Glasner(50) and was reported to break down extracellular glycocalyx and cause cell-intrinsic vascular leakage. Regardless of the mechanism of action of NS1, it appears to be an important virulence factor that may be targeted for potential drug development. The NS2 orf encodes for two proteins; NS2A is a transmembrane protein and in Dengue has been shown to bind directly to calmodulin, the protein involved in calcium influx.(51) There have been no efforts to date to develop inhibitors of NS2A; however, a known calmodulin inhibitor has been shown to inhibit the dengue virus.(51,52) The NS2B protein is a hydrophobic protein that serves as a cofactor to the NS3 protease.(53)NS2B has not been validated as an independent drug target, but only when in combination with NS3.(54) The Dengue virus NS4 orf encodes for a membrane protein in the endoplasmic reticulum membrane. It consists of NS4A (127 aa) and NS4B (248 aa). These two are connected by a 23-residue linker from the C terminal of NS4A.(47) After integration into the membrane, the 23 aa linker is cleaved by a host signal peptidase (signalase). NS4 has 11 helices, and the C terminal containing helices 9 and 9′ flip from the ER membrane to the cell membrane, where it interacts with the RNA-dependent RNA polymerase (RdRp) NS5, also a key drug target in Flaviviridae.(55,56)

Filoviridae

Filoviruses, such as Ebola virus (EBOV) and Marburg virus (MARV), are known as zoonotic pathogens that cause rare yet severe diseases affecting humans and other primates. Ebola virus disease (EVD) was first discovered in 1976 as a result of consecutive outbreaks in two areas of central Africa, in South Sudan and Zaire.(57) EVD is often a deadly disease, and typical symptoms include fever, headache, vomiting, and diarrhea. Some people in severe cases can suffer internal and external bleeding. It was later discovered that these outbreaks were caused by genetically distinct EBOVs, Sudan ebolavirus and Zaire ebolavirus. Many outbreaks of EVD have occurred since 1976, primarily in Africa.(58) Today, there are five characterized species of the genus Ebolavirus: Sudan ebolavirus (SUDV), Zaire ebolavirus (EBOV), Reston ebolavirus (RESTV), Taï Forest ebolavirus (TAFV), and Bundibugyo ebolavirus (BDBV). RESTV is the only known filovirus that does not cause severe disease in humans; however, it can be fatal in monkeys and pigs.(59,60)

Marburg virus disease (MVD) was first observed in 1967 in Marburg, Germany, and is caused by the filovirus Marburg Marburgvirus (MARV). The symptoms of MVD are similar to those of EVD.(61) MVD appears in sporadic outbreaks in African countries as well.(62) The family of Filoviridae is a member of the order Mononegavirales and generally has a filamentous morphology (about 1000 nm in length with a diameter of 80 nm). It has been reported that fruit bats serve as a wildlife reservoir in nature for EBOV and MARV.(63,64) Bats carrying the virus transmit it to other animals such as monkeys(65) and chimpanzees,(66) as well as to humans. Human-to-human transmission can occur through contact with a patient’s blood and bodily fluids.(67) In December 2019, the first vaccine, rVSV-ZEBOV, was approved for the prevention of EVD by the Food and Drug Administration (FDA) in the United States,(68) and other vaccines are now in development.(69)

Figure 3 shows the generalized life cycle of filoviruses.(62) The filovirus infects its host by the GP protein binding to several host molecules on the cell membrane, including the T-cell immunoglobulin mucin receptor 1 (TIM1), also known as hepatitis A virus cellular receptor 1 (HAVCR1), C-type lectins such as dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN), and β-integrins.(70−72) The virus is then incorporated into the cell through macropinocytosis.(73) Next, two host cell cysteine proteases, cathepsin B and cathepsin L, cleave the surface GP protein, and the processed GP binds to the Niemann–Pick C1 (NPC1) cholesterol transporter.(74,75) This interaction leads to the fusion of the virus with the endosomal membrane and release of the viral RNA into the cytoplasm for transcription and replication in the inclusion body. Viral mRNAs produced by an RdRp are translated into proteins associated with VP30, VP35, and L by host ribosomes (primary transcription). The synthesized viral proteins are used in secondary transcription and vRNA replication. Following transcription, the GP protein, a type I transmembrane glycoprotein, is produced as a precursor protein known as GP₀; this is then cleaved post-translationally by a furin-like protease to yield the ectodomains GP₁ and GP₂. These proteins form dimers, which in turn form trimers to produce the mature and functional heterotrimeric GP.(76,77) The mature GP protein is transported to the cell membrane in secretory vesicles. vRNA is replicated through a complementary positive sense RNA (cRNA) along with VP35 and L.(78) After translation, viral proteins are assembled to form the nucleocapsid, then transported to the plasma membrane. Finally, budding to form new virus particles is mediated by VP40 and GP at the membrane (Figure 3, Table 4).(79)

Table 4. Validated and Potential Drug Targets in Filoviridae and NP Inhibitorsa

	number	target protein	function	natural product inhibitors	NP-inspired inhibitors
viral proteins	I	VP35	polymerase cofactor responsible for transcription and replication with L protein	myricetin (26), epigallocatechin gallate (31)	inhibitors needed
	II	VP40	matrix protein involved in budding	inhibitors needed	inhibitors needed
	III	GP	host cell recognition	ellagic acid (6), gallic acid (7), cyanovirin-N (11)	triterpenoid derivatives (8, 9), a borneol derivative (10)
	IV	VP30	transcriptional activator	inhibitors needed	inhibitors needed
	V	VP24	structural protein, important role in nucleocapsid formation	inhibitors needed	inhibitors needed
	VI	L protein	RNA-dependent RNA polymerase	inhibitors needed	favipiravir (22), remdesivir (1), BCX4430 (30)
host proteins	VII	cathepsin B/cathepsin L	endosomal protease, cleaves spike protein facilitating membrane fusion and entry	gallinamide A (35), tokaramide A (39), miraziridine A (40)	dichlorobenzyl aloperine dihydrochloride (41), E-64d (42), CA074 (43)

^{^a}

Roman numbering corresponds to numbering in Figure 3. Numbers in parentheses corresponds to structures in Figures 5–11.

Genome Structures

Schematic diagrams for the genomes of coronaviruses (Coronaviridae), Dengue virus (Flaviviridae), and Ebola virus (Filoviridae) are provided in Figure 4. The genes labeled by Roman numerals are encoding for potential druggable protein targets and accord with the same Roman numerals in Figures 2–4 and Tables 1–3. The coronavirus genome is one of the larger known viral genomes at over 30 kb, with the viral replicase gene cassette comprising roughly two-thirds of these nucleotides (orf1a/orf1ab); the remaining one-third contains structural and accessory proteins.(33,80,81) The replicase is translated as two large polyproteins 1a and 1ab, which are autoproteolytically cleaved(22) into the 16 proteins that form the replicase/transcriptase complex (Figures 1 and 4A). The family of Flaviviridae viruses, characterized by a positive-sense RNA single-strand, upon cellular recognition, immediately hijacks the host’s ribosome to translate its viral RNA. Flaviviridae RNA genomes vary in size from about 10.6 to 10.9 kb. The RNA encodes for 10 proteins: three structural and seven nonstructural (Figure 4B). The orfs for the structural proteins contain the nucleocapsid protein (C), the envelope protein (M), and the major spike (envelope) glycoprotein (E) of the capsid. The seven remaining orfs encode for nonstructural proteins (NS). The Filoviridae genome is a single-strand negative-sense RNA approximately 19 kb in length.(82,83) Seven viral proteins are encoded in this genome: the nucleoprotein (NP), a polymerase cofactor protein (VP35), a matrix protein (VP40), a glycoprotein (GP), a transcriptional activator (VP30), a nucleocapsid-associated protein (VP24), and an RdRp (L) (Figure 4C).(62,78) EBOV produces some secreted GPs, soluble GP (sGP) and small soluble GP (ssGP), via a transcriptional editing event derived from the same GP gene, whereas MARV does not. It has been reported that sGP may act as a decoy antigen to disturb the host immune response as a result of developing antibodies against GPs.(76)

In this review, we discuss both validated as well as prospective protein targets under investigation for the potential treatment of Coronaviridae, Flaviviridae, and Filoviridae viral infections. We focus this analysis on natural products and NP-like or inspired inhibitors of viral infection or replication and modulators of immune evasion. We opted to organize our treatment of potential therapeutic targets for the three classes of RNA viruses by biochemical target rather than by virus. The arrangement by virus family was rejected, as very similar targets would contribute to repetitive discussions of the same agents. Additionally, we conceived that insights would be gained by comparison and contrast of the same or similar targets in different virus families and their therapeutic modulators. Finally, therapeutics effective against a given target in one family may have as yet unrealized application to a comparable target in another viral family. For this combination of reasons, we have chosen to arrange and present the natural product inhibitors of these RNA-containing viruses by respective biochemical target. Reviews covering synthetic or other natural product inhibitors have appeared elsewhere and are largely excluded from this review, as are compounds reported with only in silico data that have not been further validated.(37,84−86) In addition to the more well-studied targets, we also discuss prospective targets based on recent reports characterizing some of these lesser-known viral proteins and their functions.

Protein Targets and Drug Development

Across viral diversity there are several biochemical themes and mechanisms that are conserved. For example, different families of viruses exploit different host surface proteins to gain entry into target cells, and the general mechanisms employed show great similarity to one another. Similarly, the viral replication cycle has points of commonality across different viral families, including (1) exploiting host proteins to gain entry into cells, (2) commandeering a host’s protein manufacturing machinery, (3) manipulating a host’s innate immune system to evade detection, and (4) siphoning the host’s resources to replicate, mature, and export new virions so as to propagate infection. The proteins responsible for carrying out these biochemical steps, both those of viral and host origin, are presented in some detail and then used to organize this perspective review by target across viral families so as to emphasize similarities and differences. In so doing, we present new connections and present a fresh approach for potential antiviral drug discovery.

As we search for new answers to the threat of global pandemics, where better to begin looking than to nature? In this discussion, we will review natural products and natural product-inspired compounds that have activities reported against viruses of the Coronaviridae, Flaviviridae, and Filoviridae outlined above. We have chosen to focus on these families of RNA viruses because of their potential to cause pandemics in human populations. Here we reveal gaps and shortcomings in past drug development efforts and hope to inspire a renewed vigor in antiviral natural product discovery. Generally, the individual protein targets that we discuss are homologous between viral families; however that is not to say that every compound discussed herein will be universally applicable. Additional investigation and careful structural analysis of each protein target should be pursued in any drug development campaign.

A. Viral Proteins

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Viruses have many nuanced mechanisms for promoting infection and propagation. They exploit host receptors and proteases to enter undetected into cells, then suppress the innate immune response, and ultimately manipulate the host to manufacture new virions for export, all with only a handful of viral proteins at their disposal. There are four main classes of proteins that cover the majority of druggable space of these viral genomes: structural proteins such as the spike protein, nonstructural proteins such as viral proteases, proteins involved in replication, and accessory proteins that perform a variety of functions nonessential for replication but important for propagation. This latter class of protein may prove to be useful targets as well.

Structural Proteins

Structural proteins make up a smaller portion of the viral genome; however it is well known that the spike glycoproteins facilitate host recognition and endocytosis. Therefore, spike proteins have been an active target for drug discovery and have focused on disrupting binding to host receptors to prevent entry into cells. Indeed, a number of vaccine and convalescent plasma efforts have focused on developing antibodies against spike proteins.(57,87) However, in this section we will review small-molecule NPs and their inspired agents that inhibit the function of these receptor-binding proteins and thus block viral uptake into cells (Figure 5).

The Coronaviridae have five structural proteins in their genomes including an S protein responsible for cellular recognition, a small envelope (E) protein that is essential for proper virion assembly in most coronaviruses and is implicated in inducing apoptosis, a membrane (M) protein that comprises the majority of the virus envelope, an RNA-binding nucleocapsid (N) protein that complexes with genome RNA to form the viral capsid and is also known to be an interferon antagonist, and in some betacoronaviruses, a hemagglutinin-esterase (HE) protein that forms a second, smaller spike on the envelope. This second spike protein may serve to enhance virus attachment via binding to sialic acid-containing molecules. These proteins provide a vessel for the viral RNA and perform critical functions during assembly, though they are seldom the target of drug discovery efforts because of the late-stage nature of their existence in viral replication. After the emergence of SARS in 2002, there has been an ongoing effort to develop inhibitors for these viruses with an emphasis on preventing viral entry via inhibition of S binding. Inhibitors of this spike–receptor binding interaction have largely been based on peptide fragments of the S protein(88,89) or variations thereof.(90) Although these showed efficacy in vitro, the translation of these peptides into the clinic may be arduous, and as of yet, none have been approved for treatment for coronavirus infections.

Two natural products, griffithsin (2) and emodin (3), have been validated as disruptors of viral receptor binding to date, inhibiting SARS-CoV S at 48 nM and 200 μM respectively.(91,92) Compound 2, a small protein isolated from the red algae Griffithsia, has demonstrated broad-spectrum ability to bind to viral glycoproteins and prevent binding to cellular receptors including HIV and EBOV with minimal toxicity.(93) The activity of 2 appears to be due to several binding sites for monosaccharides such as mannose and glucose, and it is currently under development for use in the clinic. Compound 3 is a small plant-derived anthraquinone that was found to specifically inhibit S protein interaction of SARS-CoV1/2 with host-derived ACE2 in a dose-dependent manner.

Because there are many Flaviviridae that pose a risk of endemic disease, we opted to use the Dengue virus as a proxy for all Flaviviridae (Figure 2, Table 3), as discussing all members of this family would become highly repetitive. In general, the Flaviviridae have three structural proteins, the capsid (C), M, and E proteins (Figure 2, Table 3). The C protein forms the capsid that becomes unraveled inside the endosome during endocytosis. Few efforts have been directed toward inhibiting C. One example is the dissociation of C from lipid droplets by the compound nordihydroguaiaretic acid (4) isolated from the creosote brush. Fat metabolism and lipid droplets play a role in Dengue viral replication.(94) The M protein is initially translated as a pro-protein (prM), and the precursor portion is cleaved in the trans Golgi network by a host furin protease. However, the precursor portion is often not cleaved, and many immature viral particles are secreted. It remains to be determined if furin is a good drug target; however, Imran et al. developed a peptide that inhibits furin cleavage of prM, and Braun and Sauter in their 2019 review argue that a furin inhibitor could be useful for both combating infectious diseases as well as cancer.(95) The major envelope protein (E) is essential for the virus to enter the cell via clathrin-mediated endocytosis. There are several host receptor candidates, but one suggestion appears to be the glycosaminoglycan (GAG) receptor. The E protein binds to GAGs, some of which contain heparin sulfates, and the heparin sulfate mimic PG545 (5) disrupts that binding by acting as a decoy receptor.(96)

The structural proteins in Filoviridae include the nucleoprotein (NP), which encapsulates the viral genome, glycoprotein (GP), nucleocapsid-associated protein (VP24), and matrix protein (VP40). The GP is an essential spike protein that, like many other viruses, interacts with a receptor expressed on the host cell to facilitate entry. A screening program evaluated 373 extracts from 128 traditional Chinese medicines for activity as EBOV inhibitors. The extract of Rhodiola rosea (Crassulaceae) was identified as a specific inhibitor at 12.5 μg/mL using a pseudotyped EBOV screening test.(97) Furthermore, ellagic acid (6) and gallic acid (7) of R. rosea were the most effective compounds in this assay system. Compound 6 had an IC₅₀ value of 1.4 and 6.4 μM against EBOV and MARV pseudovirions, respectively, while 7 showed an approximately 4-fold lesser activity against each pseudovirion. It should be noted that 6 and 7 are often classified as pan-assay interference compounds (PAINS) in that they give false-positive results in a wide range of biological screening assays. The mechanism by which these compounds (6 and 7) block viral entry is not clear; however, it was suggested that they act at a similar postbinding step in the endosome as the cathepsin B inhibitor CA074 or as the entry inhibitor benztropine that binds to the EBOV-GP and interferes with GP-mediated fusion in the endosome.(98)

Two triterpenoid derivatives (8 and 9), derived from the naturally occurring oleanane-type triterpene echinocystic acid, were found to inhibit EBOV–host fusion.(99) The IC₅₀ values for 8 and 9 against the EBOV pseudotyped viruses were 59.2 and 467.3 nM, respectively, as evaluated in A549 and 293T cells. Heptad repeat-2 (HR2), a prevalent heptad repeat sequence comprising an α-helical coil in the GP, was identified as a site accessible to these triterpenoid analogues and results in antagonizing EBOV–cell fusion. This results from interacting with the hydrophobic helix and blocking of the HR1-HR2 interaction critical to common trimer-of-hairpins formation. In addition, compounds 8 and 9 were able to inhibit the infection of MARV using a Marburg pseudoparticle entry assay with IC₅₀ values of 2.29 and 5.52 μM, respectively.

Kononova et al. reported that an N-heterocyclic borneol derivative exhibited antiviral activity via inhibition of MARV-GP-dependent virus entry.(100) Borneol is a bicyclic monoterpenoid found in essential oils of numerous medicinal plants. The N-heterocyclic bornyl ester 10, containing a methylpiperidine moiety, showed an IC₅₀ value of 4 μM using a MARV GP-mediated VSIV pseudotype system.

The natural product cyanovirin-N (11) is an 11 kDa protein that was isolated from cultures of the cyanobacterium Nostoc ellipsosporum.(101) It has been reported that 11 inhibits HIV infection by binding to the surface envelope glycoprotein (gp120) through an interaction between 11 and high-mannose oligosaccharides on gp120. In 2003, Barrientos et al. reported that 11 also binds with high specificity to the EBOV GP and shows antiviral activity in vitro with an EC₅₀ value of 100 nM.(102) Similar to its inhibitory mechanism of HIV infection, oligosaccharide-mediated 11–GP interaction plays an important role in the inhibition of EBOV infection.

Proteases

Although there are only one to three proteases in each of the virus families we discuss here, they are absolutely essential for replication. Importantly, after initial translation of the viral RNA into large polyproteins, these proteases, from within the polyprotein, fold into active form and cleave the polyprotein into its individual components.(16) These cleaved proteins in turn form the replicase complex that allows the virus to reproduce. Inhibition of these proteases has proven to be an effective way to mitigate replication and spread of the viruses. Because they are so few and so essential, a large amount of effort has gone into drug discovery efforts to screen and generate new protease inhibitors (Figure 6). In this section we cover recent reports of viral protease inhibitor discovery and outline suggestions for future success in this area. Interestingly, the filoviruses do not possess their own proteases and rely completely on the host proteases for replication.

Coronaviruses, with the exception of SARS-CoV-1/2, possess three proteases including two papain-like proteases and a chymotrypsin-like protease (3CLpro or Mpro); the latter protease does not have a known human homologue. SARS-CoV-1/2 lack one of the papain-like proteases, although this does not appear to have any impact on its ability to replicate and is likely redundant in other coronaviruses. These proteases are responsible for viral protein maturation after translation and have been at the center of drug discovery efforts against coronaviruses. That they are each essential for viral replication makes them especially attractive for targeting with small molecules. A large body of work exists in the literature of synthetic compounds targeting these proteases and has been reviewed previously.(36,37,103) Because of their inherent peptidase activity, much effort has been put toward designing peptidomimetic inhibitors of these proteases. The main protease sequence is quite conserved across the Coronaviridae family and beyond, and inhibitors designed for 3CLpro have found use against other viruses as well. Extensive structure–activity relationships have been established for this enzyme, and several crystal structures have been reported with bound inhibitors (PDB: 1UK4, 4YOG, 6Y2F, and others). One of the most important features of these inhibitors is the absolute requirement for a Gln or Gln-like residue at P1 followed by a generally hydrophobic side chain at P2; the latter pocket has been shown to be quite flexible. Interestingly, this specificity is not seen in any human enzyme, thus making the 3CLpro a prime target for peptidomimetic inhibition without competing off-target effects. A number of compounds with micromolar to nanomolar in vitro activity are depicted in Figure 6, most notably the approved drug rupintrivir (12), which was developed earlier to target the rhinovirus 3C protease. Some natural products, mainly flavonoids, have been reported to have mild inhibitory activity against 3CLpro as well including herbacetin (13), pectolinarin (14), and rhoifolin (15) with IC₅₀ values of 33, 38, and 27 μm, respectively.(104) Interestingly, there have been very few efforts to screen natural products against this promising target.(105) However, there have been several screening studies that have identified natural product inhibitors of Coronaviridae propagation without identifying a target; some of these may target the 3CLpro protease, and we will cover these in a later section.

The papain-like protease cleaves the viral polyprotein at fewer sites than the main protease, though inhibition is still effective at preventing replication. As a whole, this protease is less sought after as a drug target due to closer homology to human enzymes that may lead to off-target effects. As a result, there has been little development of peptidomimetic molecules designed against this protease. In contrast, there have been a number of reports of natural products inhibiting its activity including tomentin B at 6.1 μm(106) (16), hirsutenone at 4.1 μm(107) (17), tanshinones from 14.4 to 226.7 μm(108) (18), psoralidin at 4.2 μm(109) (19), and others depicted in Figure 6.(110) Many of these phytochemicals were identified from extract screening, and like the 3CLpro, there has not been a large-scale effort to explore a wider diversity of natural product scaffolds against it. With most compounds reported eliciting low micromolar activity and inherently nonspecific nature of planar, aromatic phytochemicals, there remains much to be desired. Nevertheless, these studies may provide a good starting point for a medicinal chemistry campaign.

The Flaviviridae genome is smaller than the Coronaviridae and only contains one orf that encodes for a protease, the NS3 orf (Figure 4B). NS3 belongs to the S7 serine protease family and requires NS2b as a cofactor for full activity.(111) The NS2B-NS3 protease was virtually screened, and triterpenoids from Ganoderma lucidum were suggested to be active. When tested in an in vitro Dengue virus inhibition assay, ganodermanontriol (20) (Figure 6) was found to inhibit the virus by 25% at 25 μM.(112) The NS2B-NS3 complex is crucial for cleavage of the polypeptide as well as providing helicase activity during replication. Ivermectin (a mixture of two analogs, only one shown, compound 21) (Figure 6), isolated from Streptomyces avermitilis, is a well-known antiparasitic drug. By molecular modeling it was determined that it could also bind effectively to the helicase portion of NS3 where the single-stranded RNA is bound. Ivermectin (21) has been found to reduce SARS-CoV-2 viral loads by 5000-fold in Vero cells treated at a high dose (2.5 μg/mL, >50 times the dose used in humans to treat onchocerchiasis).(166) Various reports of the prophylactic or early stage treatment with ivermectin are appearing in Rxiv form from India and South America, with indications that the target is helicase as found in Dengue virus; however, there are cautionary notes about its premature widespread use.(167,168) Nevertheless, an approved clinical treatment protocol has appeared in Peru (the I-MASK+ protocol; see https://covid19criticalcare.com/). Compound 20 also inhibits Dengue helicase. NS2B-NS3 is an important target, and continued investigation and identification of inhibitors for the NS2B-NS3 complex is warranted.

Replicase/Transcriptase Complex Proteins

The viral replicase complex consists of several key proteins including the RdRp and helicase that are solely responsible for generating new genomic as well as subgenomic viral RNAs; these in turn are responsible for the production of structural proteins that assemble into new virions. Several critical features exist in this assortment of proteins, especially the RdRp, that can be targeted with small molecules to disrupt replication, and considerable effort has been expended to discover inhibitors of RdRp activity. Approved drugs such as favipiravir (22), ribavirin (23), and remdesivir (1) were all developed to target this polymerase, and its highly conserved nature across viral families has made it a promising target for drug development. In this section we discuss the various NP-inspired RdRp inhibitors that have been discovered to date (Figure 7).

In the Coronaviridae, the majority of the known effective inhibitors of RdRp are derived from its natural nucleotide substrates. These NP-inspired RdRp inhibitors include favipiravir (22), remdesivir (1), ribavirin (23), galdesivir (24), and β-d-N4-hydroxycytidine (25).(36,113) While these nucleotide analogues were developed as inhibitors of RdRp activity in other viruses, they also have activity to these more newly emergent coronaviruses. Coronaviridae helicase NSP13 is also instrumental for viral replication, and two flavonoid natural products, myricetin (26) and scutellarein (27), have shown inhibitory activity with IC₅₀ values of 2.71 and 0.86 μM, respectively (Figure 8).(114)

Figure 8. Inhibitors of viral helicase. All of these are natural products.

In the Flaviviridae, the NS2B-NS3 complex confers helicase activity as well as protease activity; the NS5 protein has been designated as the RdRp. NS5 is indirectly inhibited by mycophenolic acid (MPA) (28) (Figure 7), a natural product originally isolated from Penicillium glaucum in 1896. MPA as well as 23 inhibit inosine monophosphate dehydrogenase and, in so doing, limit the amount of guanosine available to the RNA polymerase for RNA synthesis.(115) Several synthetic compounds have been designed as direct inhibitors of NS5.(116) The NS4 orf produces two full-length membrane proteins, NS4A and NS4B. They are linked by a 23-residue C-terminal region of NS4A, and the full-length NS4 is cleaved by the NS2B-NS3 protease into NS4A and 2K-NS4B. The 2k fragment is a signal peptide that traffics NS4B to the endoplasmic reticulum (ER). NS4A also inserts into the ER membrane and is quite hydrophobic due to its eight transmembrane regions. NS4A stabilizes the membrane-associated replication machinery.(51) Reddey et al. have identified several possible inhibitors to both NS4A and NS4B.(51)

Methyltransferase (MTase) is an important enzyme for replication of Coronaviridae and Flaviviridae and is crucial for their RNA cap formation. The natural product sinefungin (29) was first isolated as an antibiotic from a strain of Streptomyces griseolus in 1973.(117) This compound has a potent interaction with the MTases of SARS-CoV-2,(118) ZIKV,(119) and DENV (Figure 7).(120)

Natural products have inspired the discovery of additional L protein (e.g., RNA-dependent RNA polymerase; see Table 4, Figure 4) inhibitors. Compound 22 (Figure 7) mimics the structure of nucleic acids and has a broad-spectrum activity against a wide variety of both negative-strand and positive-strand RNA viruses. It is first converted to its phosphoribosyl derivative and subsequently to the triphosphate before it inhibits the RNA polymerase, principally through direct competition with GTP.(121) Oestereich et al. reported that 22 suppressed replication of EBOV in cell cultures with IC₅₀ and IC₉₀ values of 67 μM and 110 μM, respectively.(122) Remdesivir (1), a prodrug, is also converted to its triphosphate metabolite and interferes with viral RdRp activity. In cell-based assays, it has a potency against a broad range of filoviruses including MARV and several variants of EBOV.(123) Compound 1 also inhibited EBOV replication in multiple relevant human cell types with EC₅₀ values of 0.06–0.14 μM. Another synthetic adenosine analogue, BCX4430 (30), inhibits RNA polymerase function by inducing RNA chain termination, which occurs two bases after the incorporation of 30 monophosphate, perhaps as a result of inhibitory stereochemical distortions of the nascent RNA chain.(124) Moderate antiviral activity of 30 has been reported against members of the Filoviridae; EC₅₀ values were 11.8 μM for EBOV, 3.4 μM for SUDV, and 4.4–6.7 μM for MARV, respectively. Weak activity against positive-sense RNA viruses has also been reported: DENV-2 (EC₅₀ 32.8 μM), SARS-CoV (EC₅₀ 57.7 μM), and MERS-CoV (EC₅₀ 68.4 μM).

Daino et al. have tested the extract from Limonium morisianum (Plumbaginaceae) in a fluorescence-based rVP35-dsRNA interaction assay.(125) The extract was shown to inhibit VP35-dsRNA binding at a concentration of 19 μg/mL, and two flavonoid compounds, myricetin (26) and (−)-epigallocatechin-3-O-gallate (31), were identified as the active inhibitors (IC₅₀ values were 2.7 and 43.5 μM respectively). In addition, molecular docking studies revealed that 26 binds to the highly conserved region of the VP35 RNA binding pocket. However, compounds 26 and 31 may also be considered PAINS due to their widespread biological activity.

Accessory Proteins

Accessory proteins are typically not considered essential for replication but play other roles in the viral life cycle such as immune evasion, targeting degradation of host RNAs, and inducing apoptosis. Some viruses have few accessory proteins, whereas others have many, such as the coronaviruses. Several have been characterized and their biochemical function is known; for others they remain to be investigated. In this section we cover a collection of known accessory proteins and their functions and discuss opportunities for drug discovery.

Two notable accessory proteins from the Coronaviridae include NSP1(126) and orf8b,(127) and a comprehensive review of the full list of accessory proteins and their role in pathogenesis was reported in 2012.(128) Both of these proteins were found to take part in immune evasion by two distinct mechanisms. NSP1 was reported to promote host mRNA degradation and thus suppress host gene expression, including proteins involved in the host innate immune system. Alternatively, orf8b has been observed to trigger intracellular stress pathways via formation of insoluble aggregates that induce ER stress, lysosomal damage, and subsequent activation of transcription factor EB involved in lysosomal biogenesis, leading to cell death. However, there have been no reports of inhibitors targeting these proteins to date, and clarification of the mechanisms by which these viruses evade immune detection is still needed.

The FlaviviridaeNS1 protein appears to be an anti-host factor; however, it has many attributed functions and mechanisms. As indicated above, the Zika virus NS1 has been shown to stabilize metalloproteinase 9 (MMP9). A higher concentration of MMP9 aids viral entry into cells by breaking down tight intercellular junctions and cellular structural proteins.(48) However, in the West Nile virus it appears that NS1 downregulates interferon, and in Dengue it breaks down the glycocalyx. Another function appears to be as a GAG-binding protein. Regardless of mechanism, NS1 inhibitors could be promising candidates for development. An effort to inhibit NS1 binding was achieved with a synthetic heparan sulfate mimetic, 5. This mimic blocked NS1 binding completely and decreased viremia in mice.(96)NS1 is also indirectly inhibited by the bicyclic alkaloid castanospermine (32) as well as its prodrug ester celgosivir (33) (Figure 9). These compounds interfere with the glycosylation of NS1 and create misfolding of the protein.(129,130)

Figure 9. Inhibitors of selected accessory proteins. Celgosivir is a derivative of the natural product castanospermine.

B. Host Proteins

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Viruses often utilize host proteins, such as cathepsin L (CatL) or TMPRSS2/4 in the case of SARS-CoV-1/2, for cellular recognition, entry, and translation. Thus, these host proteins can also be targeted to hinder viral infections. In this section we cover the host proteins of interest in antiviral drug discovery, their functions, and efforts to find suitable inhibitors among natural products and their derivatives. It should be noted that the compounds discussed in this section are preclinical agents, and toxicity and other side effects will need to be assessed when targeting host proteins.

Proteases

After receptor binding, host proteases either at the cell surface or in endosomes are responsible for critical cleavage events that induce fusion of the viral capsid with the cell or endosome membrane and the subsequent release of its genetic material into the cell cytoplasm. Across the three families of viruses in this review, it appears that only a few host proteases are implicated, none of which are completely essential for viability. There have been a number of drug discovery campaigns targeting these proteases in the context of other diseases and, more recently, a recognition that they may be viable antiviral drug targets as well. In this section, we will cover a number of inhibitors of host proteases that prevent viral entry by blocking processing of the spike glycoproteins and membrane fusion (Figure 10).

TMPRSS2 and TMPRSS4 are transmembrane serine proteases located on the surface of human cells. They have been shown to cleave the coronavirus extracellular spike protein S after the virus has bound to surface ACE2 receptors, and this allows viral fusion to the cell membrane. These proteases are essential for viral entry in several different tissues.(24,28) Despite the essentiality of this process, there are very few known inhibitors, and only one is a natural product. Aprotinin (34) is a small protein that is marketed as a bovine pancreatic trypsin inhibitor; it has also shown inhibitory activity against TMPRSS2.(131) In addition to these surface proteases, cathepsin L and B (CatL/B) promote membrane fusion of the virus via an endocytic pathway. Unlike TMPRSS2/4, there are a number of reviews describing the activity and role in human physiology and disease of CatL and Cat-B.(132,133) Furthermore, a number of natural products have been reported with inhibitory activity against these important enzymes, such as gallinamide A (35), nicolaiodesin C (36), grassypeptolide (37), and leupeptin (38), against CatL. The wide variety of natural products effective and selective against these proteases raises hopes that useful antiviral therapeutics may emerge from continued investigation.

CatL was also reported to be involved in the entry of JEV into cells.(134) It was shown that a CatL inhibitor could decrease shedding of the Flaviviridae anti-host factor protein NS1 with a subsequent decrease in endothelial permeability. It would be worthwhile to continue to explore cathepsin L inhibitors for use in treatment of Dengue, JEV, and other Flaviviridae viruses.(135)

The mostly linear lipopeptide gallinamide A (35), isolated from a Schizothrix sp. cyanobacterium, selectively inhibited CatL with an IC₅₀ value of 5.0 nM.(136) It was also shown that 35 was remarkably selective for CatL, as it was only modestly active to CatB with an IC₅₀ value of 11.7 μM. From the marine sponge Theonella aff. mirabilis, tokaramide A (39) and miraziridine A (40) were isolated. These selectively inhibited CatB with IC₅₀ values of 29 ng/mL and 1.4 μg/mL, respectively.(137−139) Zhang et al. reported a new aloperine derivative (41) that exhibited activity against EBOV and MARV with EC₅₀ values of 4.8 and 7.1 μM, respectively. Aloperine was reported as a component of the seeds and leaves of Sophora alopecuroides (Fabaceae). Aloperine was shown to selectively inhibit CatB but had no activity toward CatL.(140) This remarkable selectivity of 41 for CatB over CatL was subsequently explained through a molecular docking analysis.

Chandran et al. measured the antiviral effects of the peptide derivatives E-64d (42) and CA074 (43) using EBOV. Vero cells were pretreated with 42 (300 μM) or 43 (80 μM) and exposed to EBOV. Yields of infectious EBOV progeny and expression of cell-associated GP₁ were markedly reduced, suggesting that EBOV multiplication in Vero cells is sensitive to these inhibitors of endosomal cysteine proteases in general and of CatB in particular.(75) Compound E-64d (42), also known as EST, is a synthetic analogue of E-64 that was first isolated from the extract of a solid media culture of Aspergillus japonicus.(141,142) Additionally, 43, a new epoxysuccinyl peptide with a structure similar to 42, was designed as a specific inhibitor of CatB.(143)

Furin is a protease located in the trans golgi apparatus. It belongs to the subtilisin-like pro-protein convertase family, and it aids in cleaving precursor proteins into mature proteins. During viral infections, furin cleaves a precursor spike protein into mature spike S proteins.(95) As discussed above for the Flaviviridae, furin is also responsible for cleavage of the prM protein to the M protein; however, some prM-coated viral particles escape from the cell before furin cleavage. These immature virus particles are known to generate antibodies, and these antibodies are proposed to enhance the disease if an individual is infected with a different serotype of the Dengue virus.(144) Therefore, furin is not likely a good drug target, as it may increase the severity of subsequent infection with Dengue.

Others

There are a handful of other targets that show promise in additional areas of the viral life cycle and may be used in combination with direct inhibitors of viral proteases or RdRp. Here we discuss these targets and their potential for inhibition by natural products to hinder virus reproduction and distribution (Figure 11).

Calmodulin (calcium-modulated protein) in normal cells senses calcium levels and regulates calcium flux into the cells. During Dengue infection the viral protein NS2A interacts with calmodulin. A synthetic calmodulin inhibitor was shown to inhibit virus production,(52) suggesting that natural products that are calmodulin inhibitors could also be useful. In fact, plants and fungi have been a rich source of structurally diverse calmodulin inhibitors, and these should be further evaluated for their anti-Dengue effects.

The normal function of signalase/signal peptidase is to cleave signal peptides when they are trafficked to the endoplasmic reticulum.(145) In Dengue, the host cell signalase is used to cleave the viral polyprotein between the prM, E, NS1, and NS4B proteins. In a phenotypic screen the fungal natural product cavinafungin (44) was shown to inhibit replication of all four serotypes of dengue virus, as well as Zika virus, with an IC₅₀ in the low nanomolar range. Compound 44 was initially isolated in 2015 from the fungus Colispora cavincola, and subsequently, the antiviral target was identified as signalase by using a CRISPR/Cas9-based chemogenomic profiling where the subunits of the signal peptidase were identified.(146)

Alpha-glucosidase, located in the ER, adds N-linked sugars to proteins. Inhibitors that block this addition have been shown to decrease the production of several ER-budding viruses, such as Dengue and Japanese encephalitis virus.(147) In particular, these inhibitors affect the glycosylation of the NS1 and the E proteins. Oral administration of glucose mimics such as nojirimycin (45) and its derivative 1-deoxynojirimycin (46) to mice was effective at inhibiting viral replication.(147) Compound 46 (duvoglustat or moranolin) was first reported in mulberry leaves.(148) Medicinal chemistry efforts starting with derivative CM-10-18 of deoxynojirimycin resulted in potent inhibitors of alpha-glucosidase. Moreover, they were shown to inhibit bovine viral diarrhea virus (a proxy for Dengue virus) at high nanomolar or low micromolar ranges while not showing any overt cytotoxicity.(149) Furthermore, miglitol (a derivative of 1-deoxynojirimycin) and acarbose, approved type-II diabetes drugs that target alpha-glucosidase, have also shown antiviral properties to Filoviruses and Flaviviruses.(150,151)

The 80S ribosome is a very general target that, when inhibited, blocks all translation including production of viral polyproteins. Geneticin (47), an analogue of neomycin, was tested for its ability to inhibit Dengue virus and found to inhibit the cytopathic effect resulting from Dengue virus infection with an EC₅₀ of 3.0 μg/mL in BHK cells. Curiously, the closely related analogues kanamycin, gentamycin, and guanidylated geneticin showed no protective effect in this cytopathic assay.(152)

Silvestrol (48), isolated from the fruits and twigs of Aglaia silvestris (Meliaceae),(153) is a potent inhibitor of the ATP-dependent DEAD-box RNA helicase eIF4A. This helicase activity appears to be essential for 5′-cap-dependent translation of mRNAs with highly structured 5′-UTRs to enable binding of the translation preinitiation complex in eukaryotes.(154) Biedenkopf et al. reported inhibition of viral propagation by treatment with 10 nM silvestrol.

It has been suggested that EBOV GP-mediated entry and fusion requires acidification within the endosome. This acidification is produced by vacuolar ATPases that create a proton gradient. Yonezawa et al. pretreated target cells with the vacuolar ATPase inhibitor bafilomycin A1 (49), a macrolide antibiotic isolated from mycelia of Streptomyces griseus.(155) They evaluated the effects of incubation of 49 in a virion pseudotyped with EBOV GP.(156) As a result, treatment with compound 49 at 5–500 nM nearly completely blocked detection of viral entry and fusion mediated by EBOV GP.

Yonezawa et al. also reported that compounds that impair microfilament function inhibit EBOV GP-mediated entry and fusion. They demonstrated that cytochalasins B (50) and D (51), obtained from the molds Helminthosporium dematiodeum and Metarrhizium anisopliae,(157) latrunculin A (52) from the marine sponge Latrunculia magnifica,(158) and jasplakinolide (53) from the marine sponge Jaspis johnstoni(159) were all active inhibitors of EBOV cell entry. They suggested that microtubules and actin filaments play key roles in these antiviral events. Similarly, Beck et al. reported that the chondramides (54–58), antifungal and cytostatic depsipeptides, inhibited EBOV GP-mediated cell entry with IC₅₀ values of 24–42 nM. The chondramides are known to exert modulatory effects on the actin cytoskeleton.(160) Chondramides A (54), B (55), C (56), and A4 (57) and propionyl chondramide C1 (58) were isolated from two myxobacterial strains, Chondromyces crocatus and Chondromyces sp. MSr9030.(161,162)

C. Unknown Targets

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During the course of drug discovery there have been a number of reports that do not specify a target or investigate a mechanism by which a compound acts. Although the compounds reported in this section were shown to have antiviral activity, the nature of their effect is unknown and requires more investigation (Figure 12). A small screening effort revealed several disparate micromolar inhibitors of SARS-CoV infection including the existing natural product drugs reserpine (59) (an indole alkaloid from Indian snakeroot Rauvolfia serpentina), aescin (60) (saponins from the horse chestnut Aesculus hippocastanum), and valinomycin (61) (a cyclic depsipeptide from Streptomyces spp.).(105) In a recent study, the FDA-approved cyclic alkaloid cepharanthine (62) and a veterinary product related to ivermectin (21), selamectin (63), were found to completely inhibit the cytopathic effects of betacoronaviruses in cell culture at 10 μM; however, no target nor mechanism was proposed.(163) The alkaloid lycorine (64) was also found to inhibit viral replication with an EC₅₀ of 15.7 nM.(164) Eugenol (65), a ubiquitous phenolic compound in plants, was found to have activity against EBOV with an EC₅₀ value of 1.3 μM.(165) Further exploration of the targets and mechanisms of these reported natural product inhibitors would be invaluable for future antiviral drug development.

Figure 12. Inhibitors with demonstrated antiviral activity without a known target or mechanism of action. All of these compounds are natural products.

Summary and Outlook

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Natural products have been underexplored for their potentially useful antiviral activity, especially to RNA viruses causing endemic and pandemic infections. Nevertheless, several useful compounds based on natural products have emerged from these efforts, most notably in the purine-based inhibitors of the viral replicase complex component, the RNA-dependent RNA polymerase (RdRp), and protease inhibitors, including those that target proteases that are virally encoded and those that are host derived. Another broad class of natural product with anti-RNA virus activity include those with polyphenolic structures; however, these are generally considered to be PAINS and nonselective to these viral targets. From a broad perspective, this review covers anti-RNA virus natural products that illustrate a large number of different molecular architectures, suggesting a variety of enzymatic protein targets and a range of inhibitory mechanisms. This foreshadows an even richer potential for the contribution that natural products can make to our antiviral pharmacopeia as more thorough and broader screening occurs in the future.

It is clear that human populations will continue to see more endemics and pandemics in the future, be they caused by viruses, bacteria or other infectious agents. Thus, it is simply common sense that we should put into place the infrastructure necessary to more rapidly develop treatments when future pandemics occur. One such recommendation is to create and maintain international compound libraries with substances that possess antiviral, antibacterial, or antiparasitic activity. These could be rapidly deployed into relevant biological screening systems as new pandemics arise. This resource could be internationally housed, and a logical entity might be the World Health Organization. But to accomplish this, new types of international treaties and agreements need to be drawn up in advance to cover the evolving concepts of intellectual property and inherent national ownership of genetic resources. Similarly, new international legislation needs to be written in advance of the next pandemic so as to cover the rights and responsibilities of international scientific teams so that they may form quickly and with a transparent sharing of data and results. Because the private sector is likely the segment of society that will bring new therapeutics to people, laws and policies that protect economic interests while simultaneously promoting openness and collaboration need to be put in place. Ultimately, the discovery and development of new pharmaceuticals from nature provides a justification for biodiversity preservation that is very understandable by the lay public and, thus, is ultimately good for human society, the planet, and the valuation of our rich biodiversity.

The authors declare no competing financial interest.

Author Information

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Corresponding Authors
- Lena Gerwick - Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, United States; http://orcid.org/0000-0001-6108-9000; Email: [email protected]
- William H. Gerwick - Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, United States; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093, United States; http://orcid.org/0000-0003-1403-4458; Email: [email protected]
Authors
- Mitchell P. Christy - Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, United States
- Yoshinori Uekusa - Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, United States; Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
Notes
The authors declare no competing financial interest.

Acknowledgments

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We thank J. Matthews for creating Figures 1–3 and R. Rex, NIH R01 NS109075, and the UCSD Chancellor’s Office for generous financial assistance used in the construction of the manuscript. We further dedicate this review to R. Rex, a believer in the multidimensional value of scientific research.

References

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Science (New York, N.Y.) (1984), 224 (4648), 506-8 ISSN:0036-8075.
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Dolutegravir/Rilpivirine: A Review in HIV-1 Infection
Blair, Hannah A.
Drugs (2018), 78 (16), 1741-1750CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)
Dolutegravir/rilpivirine (Juluca) is the first two-drug single-tablet regimen (STR) to be approved for the treatment of HIV-1 infection in adults. The fixed-dose STR combines the integrase strand transfer inhibitor dolutegravir with the non-nucleoside reverse transcriptase inhibitor rilpivirine. In two phase III non-inferiority trials (SWORD-1 and SWORD-2) in treatment-experienced patients already virol. suppressed on their current antiretroviral (ART) regimen, switching to once-daily dolutegravir plus rilpivirine maintained virol. suppression over 48 wk. Switching to a two-drug regimen of dolutegravir plus rilpivirine was also assocd. with high rates of virol. suppression in real-world observational studies. Switching to once-daily dolutegravir plus rilpivirine was generally well tolerated and assocd. with more favorable renal and bone parameters than remaining on the current ART regimen. Longer-term, dolutegravir plus rilpivirine demonstrated durable maintenance of virol. suppression and remained generally well tolerated for up to 100 wk. Thus, dolutegravir/rilpivirine provides a convenient alternative treatment option for some adults with HIV-1 infection and no history of virol. failure who are already virol. suppressed on (and wish to switch from) their current ART regimen.
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Zuckerman, J. N.; Powell, L.; Lequin, R. M.; Zuckerman, A. J. Determination of Hepatitis A Antibody Response to Vaccination by an Enzyme Immunoassay. J. Virol. Methods 1996, 56 (1), 27– 31, DOI: 10.1016/0166-0934(95)01898-0
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14
Determination of hepatitis A antibody response to vaccination by an enzyme immunoassay
Zuckerman, Jane N.; Powell, Lee; Lequin, Rudolf M.; Zuckerman, Arie J.
Journal of Virological Methods (1996), 56 (1), 27-31CODEN: JVMEDH; ISSN:0166-0934. (Elsevier)
The quant. responses to vaccination with hepatitis A vaccine was detd. in 113 volunteers using a com. available ELISA for total antibodies to hepatitis A. Administration of vaccine or control prepn. was carried out according to two regimens; at 0, 1 and 12 mo (regimen I) and at 0, 0.5 and 12 mo (regimen II). Seroconversion rates (concns. of HAV antibodies >50 IU/l) were between 94 and 97% at month 1 for regimen I and regimen II, resp. The geometric mean titers (GMTs) fell gradually by month 12, and increased rapidly 10-100 fold 1 mo after the booster dose at month 12. The GMTs of the groups receiving the control prepn. remained below 50 IU/l. No significant differences were found between the antibody responses after regimen I or regimen II. It is concluded that the antibody test (Hepanostika HAV Antibody) can be used safely and adequately for quantitation of responses to hepatitis A immunization.
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15
Deutsch, L.; Houri, I.; Ben-Ari, Z.; Shlomai, A.; Veitsman, E.; Cohen-Ezra, O.; Issachar, A.; Mor, O.; Gozlan, Y.; Bruck, R.; Menachem, Y.; Zelber-Sagi, S.; Katchman, H.; Shibolet, O. Ombitasvir/Paritaprevir/Ritonavir & Dasabuvir ± Ribavirin Following Protease Inhibitors Failure - a Prospective Multi-Centre Trial. BMC Infect. Dis. 2020, 20 (1), 264, DOI: 10.1186/s12879-020-4921-3
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Ombitasvir/paritaprevir/ritonavir & dasabuvir ± ribavirin following protease inhibitors failure - a prospective multi-centre trial
Deutsch, Liat; Houri, Inbal; Ben-Ari, Ziv; Shlomai, Amir; Veitsman, Ella; Cohen-Ezra, Oranit; Issachar, Assaf; Mor, Orna; Gozlan, Yael; Bruck, Rafael; Menachem, Yoram; Zelber-Sagi, Shira; Katchman, Helena; Shibolet, Oren
BMC Infectious Diseases (2020), 20 (1), 264CODEN: BIDMBJ; ISSN:1471-2334. (BioMed Central Ltd.)
Abstr.: Background: Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma. Treatment with first generation protease inhibitors (PI) + peg-interferon (pegIFN) and ribavirin (RBV) achieved sustained virol. response (SVR) rates of 65-75% but was assocd. with multiple side effects. The aim of this study was to evaluate safety and efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir (3D) ± RBV in HCV genotype 1 patients that failed previous treatment with first generation PIs. Methods: An investigator-initiated, open-label, multi-center clin. trial. HCV Genotype 1 patients who were previously null/partial responders or relapsers to telaprevir, boceprevir or simepravir+pegIFN/RBV and met eligibility criteria were included. 3D ± RBV were administrated for 12 or 24 wk according to label. The primary outcome was antiviral response (SVR12); Secondary outcomes were patient reported outcomes, adverse events and resistance assocd. variants. Results: Thirty-nine patients initiated treatment according to study protocol (59% men, age 54.0 ± 8.7 years, BMI 28.7 ± 4.5 kg/m2). Thirty-seven (94.9%) completed the study. Thirty-five patients had genotype 1b (9 cirrhotics) and 4 had genotype 1a (2 cirrhotics). Intention-to-treat SVR12 was 92.3% and per-protocol SVR12 was 97.3%. The rate of advanced fibrosis (FibroScan score F3-4) declined from 46.2 to 25.7% (P = 0.045). Abnormal ALT levels declined from 84.6 to 8.6% (P < 0.001). Seven patients (17.9%) experienced serious adverse events (3 Psychiatric admissions, 1 pneumonia, 1 ankle fracture, 2 palpitations), and 12 patients (30.8%) experienced self-reported adverse events, mostly weakness. Conclusion: 3D ± RBV is safe and effective in achieving SVR among patients with HCV genotype 1 who failed previous first-generation PI treatment. Trial registration: NCT02646111 (submitted to ClinicalTrials.gov, Dec. 28, 2015).
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Pol, S.; Lagaye, S. The Remarkable History of the Hepatitis C Virus. Genes Immun. 2019, 20 (5), 436– 446, DOI: 10.1038/s41435-019-0066-z
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The remarkable history of the hepatitis C virus
Pol Stanislas; Pol Stanislas; Pol Stanislas; Pol Stanislas; Lagaye Sylvie; Pol Stanislas; Lagaye Sylvie
Genes and immunity (2019), 20 (5), 436-446 ISSN:.
The infection with the hepatitis C virus (HCV) is an example of the translational research success. The reciprocal interactions between clinicians and scientists have allowed in 30 years the initiation of empirical treatments by interferon, the discovery of the virus, the development of serological and virological tools for diagnosis but also for prognosis (the non-invasive biochemical or morphological fibrosis tests, the predictors of the specific immune response including genetic IL28B polymorphisms). Finally, well-tolerated and effective treatments with oral antivirals inhibiting HCV non-structural viral proteins involved in viral replication have been marketed this last decade, allowing the cure of all infected subjects. HCV chronic infection, which is a public health issue, is a hepatic disease, which may lead to a cirrhosis and an hepatocellular carcinoma (HCC) but also a systemic disease with extra-hepatic manifestations either associated with a cryoglobulinemic vasculitis or chronic inflammation. The HCV infection is the only chronic viral infection, which may be cured: the so-called sustained virologic response, defined by undetectable HCV RNA 12 weeks after the end of the treatment, significantly reduces the risk of morbidity and mortality associated with hepatic and extra-hepatic manifestations, which are mainly reversible. The history of HCV ends with the pangenotypic efficacy of the multiple combinations, easy to use for 8-12 weeks with one to three pills per day and little problems of tolerance. This explains the short 30 years from the virus discovery to the viral hepatitis elimination policy proposed by the World Health Organization (WHO) in 2016.
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Perlman, S. Another Decade, Another Coronavirus. N. Engl. J. Med. 2020, 382 (8), 760– 762, DOI: 10.1056/NEJMe2001126
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17
Another Decade, Another Coronavirus
Perlman Stanley
The New England journal of medicine (2020), 382 (8), 760-762 ISSN:.
There is no expanded citation for this reference.
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Dong, E.; Du, H.; Gardner, L. An Interactive Web-Based Dashboard to Track COVID-19 in Real Time. Lancet Infect. Dis. 2020, 20 (5), 533– 534, DOI: 10.1016/S1473-3099(20)30120-1
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18
An interactive web-based dashboard to track COVID-19 in real time
Dong, Ensheng; Du, Hongru; Gardner, Lauren
Lancet Infectious Diseases (2020), 20 (5), 533-534CODEN: LIDABP; ISSN:1473-3099. (Elsevier Ltd.)
The authors describe the development of an online interactive dashboard, hosted by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University, Baltimore, MD, USA, to visualize and track reported cases of coronavirus disease 2019 (COVID-19) in real time. The dashboard, first shared publicly on Jan 22, illustrates the location and no. of confirmed COVID-19 cases, deaths, and recoveries for all affected countries. It was developed to provide researchers, public health authorities, and the general public with a user-friendly tool to track the outbreak as it unfolds. All data collected and displayed are made freely available, initially through Google Sheets and now through a GitHub repository, along with the feature layers of the dashboard, which are now included in the Esri Living Atlas.
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Gorbalenya, A. E.; Baker, S. C.; Baric, R. S.; de Groot, R. J.; Drosten, C.; Gulyaeva, A. A.; Haagmans, B. L.; Lauber, C.; Leontovich, A. M.; Neuman, B. W.; Penzar, D.; Perlman, S.; Poon, L. L. M.; Samborskiy, D. V.; Sidorov, I. A.; Sola, I.; Ziebuhr, J. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The Species Severe Acute Respiratory Syndrome-Related Coronavirus : Classifying 2019-NCoV and Naming It SARS-CoV-2. Nat. Microbiol. 2020, 5 (4), 536– 544, DOI: 10.1038/s41564-020-0695-z
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20
Weiss, S. R.; Leibowitz, J. L. Chapter 4 - Coronavirus Pathogenesis. In Advances in Virus Research; Maramorosch, K., Shatkin, A. J., Murphy, F. A., Eds.; Academic Press, 2011; Vol. 81, pp 85– 164.
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There is no corresponding record for this reference.
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Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R.; Niu, P.; Zhan, F.; Ma, X.; Wang, D.; Xu, W.; Wu, G.; Gao, G. F.; Tan, W. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N. Engl. J. Med. 2020, 382 (8), 727– 733, DOI: 10.1056/NEJMoa2001017
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21
A novel coronavirus from patients with pneumonia in China, 2019
Zhu, Na; Zhang, Dingyu; Wang, Wenling; Li, Xingwang; Yang, Bo; Song, Jingdong; Zhao, Xiang; Huang, Baoying; Shi, Weifeng; Lu, Roujian; Niu, Peihua; Zhan, Faxian; Ma, Xuejun; Wang, Dayan; Xu, Wenbo; Wu, Guizhen; Gao, George F.; Tan, Wenjie
New England Journal of Medicine (2020), 382 (8), 727-733CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)
In Dec. 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. Complete genome sequences of the three novel coronaviruses were submitted to GISAID (BetaCoV/Wuhan/ IVDC-HB-01/2019, accession ID: EPI_ISL_402119; BetaCoV/Wuhan/IVDC-HB-04/2020, accession ID: EPI_ISL_402120; BetaCoV/Wuhan/IVDC-HB-05/2019, accession ID: EPI_ISL_402121).
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Muramatsu, T.; Takemoto, C.; Kim, Y.-T.; Wang, H.; Nishii, W.; Terada, T.; Shirouzu, M.; Yokoyama, S. SARS-CoV 3CL Protease Cleaves Its C-Terminal Autoprocessing Site by Novel Subsite Cooperativity. Proc. Natl. Acad. Sci. U. S. A. 2016, 113 (46), 12997– 13002, DOI: 10.1073/pnas.1601327113
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22
SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity
Muramatsu, Tomonari; Takemoto, Chie; Kim, Yong-Tae; Wang, Hongfei; Nishii, Wataru; Terada, Takaho; Shirouzu, Mikako; Yokoyama, Shigeyuki
Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (46), 12997-13002CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
The 3C-like protease (3CLpro) of severe acute respiratory syndrome coronavirus (SARS-CoV) cleaves 11 sites in the polyproteins, including its own N- and C-terminal autoprocessing sites, by recognizing P4-P1 and P1'. In this study, we detd. the crystal structure of 3CLpro with the C-terminal prosequence and the catalytic-site C145A mutation, in which the enzyme binds the C-terminal prosequence of another mol. Surprisingly, Phe at the P3' position [Phe(P3')] is snugly accommodated in the S3' pocket. Mutations of Phe(P3') impaired the C-terminal autoprocessing, but did not affect N-terminal autoprocessing. This difference was ascribed to the P2 residue, Phe(P2) and Leu(P2), in the C- and N-terminal sites, as follows. The S3' subsite is formed by Phe(P2)-induced conformational changes of 3CLpro and the direct involvement of Phe(P2) itself. In contrast, the N-terminal prosequence with Leu(P2) does not cause such conformational changes for the S3' subsite formation. In fact, the mutation of Phe(P2) to Leu in the C-terminal autoprocessing site abolishes the dependence on Phe(P3'). These mechanisms explain why Phe is required at the P3' position when the P2 position is occupied by Phe rather than Leu, which reveals a type of subsite cooperativity. Moreover, the peptide consisting of P4-P1 with Leu(P2) inhibits protease activity, whereas that with Phe(P2) exhibits a much smaller inhibitory effect, because Phe(P3') is missing. Thus, this subsite cooperativity likely exists to avoid the autoinhibition of the enzyme by its mature C-terminal sequence, and to retain the efficient C-terminal autoprocessing by the use of Phe(P2).
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Zhang, T.; Wu, Q.; Zhang, Z. Probable Pangolin Origin of SARS-CoV-2 Associated with the COVID-19 Outbreak. Curr. Biol. 2020, 30 (7), 1346– 1351, DOI: 10.1016/j.cub.2020.03.022
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23
Probable Pangolin Origin of SARS-CoV-2 Associated with the COVID-19 Outbreak
Zhang, Tao; Wu, Qunfu; Zhang, Zhigang
Current Biology (2020), 30 (7), 1346-1351.e2CODEN: CUBLE2; ISSN:0960-9822. (Cell Press)
An outbreak of coronavirus disease 2019 (COVID-19) caused by the 2019 novel coronavirus (SARS-CoV-2) began in the city of Wuhan in China and has widely spread worldwide. Currently, it is vital to explore potential intermediate hosts of SARS-CoV-2 to control COVID-19 spread. Therefore, we reinvestigated published data from pangolin lung samples from which SARS-CoV-like CoVs were detected by Liu et al. (2019). We found genomic and evolutionary evidence of the occurrence of a SARS-CoV-2-like CoV (named Pangolin-CoV) in dead Malayan pangolins (Manis javanica). Pangolin-CoV is 91.02% and 90.55% identical to SARS-CoV-2 and BatCoV RaTG13, resp., at the whole-genome level. Aside from bat CoV RaTG13, Pangolin-CoV is the most closely related CoV to SARS-CoV-2. The S1 protein of Pangolin-CoV is much more closely related to SARS-CoV-2 than to RaTG13. Five key amino acid residues involved in the interaction with human ACE2 are completely consistent between Pangolin-CoV and SARS-CoV-2, but four amino acid mutations are present in RaTG13. Both Pangolin-CoV and RaTG13 lost the putative furin recognition sequence motif at S1/S2 cleavage site that can be obsd. in the SARS-CoV-2. Conclusively, this study suggests that pangolin species are a natural reservoir of SARS-CoV-2-like CoVs.
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Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T. S.; Herrler, G.; Wu, N.-H.; Nitsche, A.; Müller, M. A.; Drosten, C.; Pöhlmann, S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020, 181 (2), 271– 280, DOI: 10.1016/j.cell.2020.02.052
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SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor
Hoffmann, Markus; Kleine-Weber, Hannah; Schroeder, Simon; Krueger, Nadine; Herrler, Tanja; Erichsen, Sandra; Schiergens, Tobias S.; Herrler, Georg; Wu, Nai-Huei; Nitsche, Andreas; Mueller, Marcel A.; Drosten, Christian; Poehlmann, Stefan
Cell (Cambridge, MA, United States) (2020), 181 (2), 271-280.e8CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clin. use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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Yan, R.; Zhang, Y.; Li, Y.; Xia, L.; Guo, Y.; Zhou, Q. Structural Basis for the Recognition of SARS-CoV-2 by Full-Length Human ACE2. Science 2020, 367 (6485), 1444– 1448, DOI: 10.1126/science.abb2762
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25
Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2
Yan, Renhong; Zhang, Yuanyuan; Li, Yaning; Xia, Lu; Guo, Yingying; Zhou, Qiang
Science (Washington, DC, United States) (2020), 367 (6485), 1444-1448CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious coronavirus disease 2019 (COVID-19) epidemic. Here, we present cryo-electron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter B0AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resoln. of 2.9 angstroms, with a local resoln. of 3.5 angstroms at the ACE2-RBD interface. The ACE2-B0AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues. These findings provide important insights into the mol. basis for coronavirus recognition and infection.
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Lu, G.; Hu, Y.; Wang, Q.; Qi, J.; Gao, F.; Li, Y.; Zhang, Y.; Zhang, W.; Yuan, Y.; Bao, J.; Zhang, B.; Shi, Y.; Yan, J.; Gao, G. F. Molecular Basis of Binding between Novel Human Coronavirus MERS-CoV and Its Receptor CD26. Nature 2013, 500 (7461), 227– 231, DOI: 10.1038/nature12328
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Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26
Lu, Guangwen; Hu, Yawei; Wang, Qihui; Qi, Jianxun; Gao, Feng; Li, Yan; Zhang, Yanfang; Zhang, Wei; Yuan, Yuan; Bao, Jinku; Zhang, Buchang; Shi, Yi; Yan, Jinghua; Gao, George F.
Nature (London, United Kingdom) (2013), 500 (7461), 227-231CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
The newly emergent Middle East respiratory syndrome coronavirus (MERS-CoV) can cause severe pulmonary disease in humans, representing the second example of a highly pathogenic coronavirus, the first being SARS-CoV. CD26 (also known as dipeptidyl peptidase 4, DPP4) was recently identified as the cellular receptor for MERS-CoV. The engagement of the MERS-CoV spike protein with CD26 mediates viral attachment to host cells and virus-cell fusion, thereby initiating infection. Here we delineate the mol. basis of this specific interaction by presenting the first crystal structures of both the free receptor binding domain (RBD) of the MERS-CoV spike protein and its complex with CD26. Furthermore, binding between the RBD and CD26 is measured using real-time surface plasmon resonance with a dissocn. const. of 16.7nM. The viral RBD is composed of a core subdomain homologous to that of the SARS-CoV spike protein, and a unique strand-dominated external receptor binding motif that recognizes blades IV and V of the CD26 β-propeller. The at. details at the interface between the two binding entities reveal a surprising protein-protein contact mediated mainly by hydrophilic residues. Sequence alignment indicates, among betacoronaviruses, a possible structural conservation for the region homologous to the MERS-CoV RBD core, but a high variation in the external receptor binding motif region for virus-specific pathogenesis such as receptor recognition.
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Wrapp, D.; Wang, N.; Corbett, K. S.; Goldsmith, J. A.; Hsieh, C.-L.; Abiona, O.; Graham, B. S.; McLellan, J. S. Cryo-EM Structure of the 2019-NCoV Spike in the Prefusion Conformation. Science 2020, 367 (6483), 1260– 1263, DOI: 10.1126/science.abb2507
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27
Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation
Wrapp, Daniel; Wang, Nianshuang; Corbett, Kizzmekia S.; Goldsmith, Jory A.; Hsieh, Ching-Lin; Abiona, Olubukola; Graham, Barney S.; McLellan, Jason S.
Science (Washington, DC, United States) (2020), 367 (6483), 1260-1263CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
The outbreak of a novel coronavirus (2019-nCoV) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure development, we detd. a 3.5-angstrom-resoln. cryo-electron microscopy structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also provide biophys. and structural evidence that the 2019-nCoV S protein binds angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute respiratory syndrome (SARS)-CoV S. Addnl., we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two RBDs. The structure of 2019-nCoV S should enable the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis.
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Zang, R.; Castro, M. F. G.; McCune, B. T.; Zeng, Q.; Rothlauf, P. W.; Sonnek, N. M.; Liu, Z.; Brulois, K. F.; Wang, X.; Greenberg, H. B.; Diamond, M. S.; Ciorba, M. A.; Whelan, S. P. J.; Ding, S. TMPRSS2 and TMPRSS4 Promote SARS-CoV-2 Infection of Human Small Intestinal Enterocytes. Sci. Immunol. 2020, 5 (47), eabc3582 DOI: 10.1126/sciimmunol.abc3582 .
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Simmons, G.; Gosalia, D. N.; Rennekamp, A. J.; Reeves, J. D.; Diamond, S. L.; Bates, P. Inhibitors of Cathepsin L Prevent Severe Acute Respiratory Syndrome Coronavirus Entry. Proc. Natl. Acad. Sci. U. S. A. 2005, 102 (33), 11876– 11881, DOI: 10.1073/pnas.0505577102
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29
Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry
Simmons, Graham; Gosalia, Dhaval N.; Rennekamp, Andrew J.; Reeves, Jacqueline D.; Diamond, Scott L.; Bates, Paul
Proceedings of the National Academy of Sciences of the United States of America (2005), 102 (33), 11876-11881CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
Severe acute respiratory syndrome (SARS) is caused by an emergent coronavirus (SARS-CoV), for which there is currently no effective treatment. SARS-CoV mediates receptor binding and entry by its spike (S) glycoprotein, and infection is sensitive to lysosomotropic agents that perturb endosomal pH. We demonstrate here that the lysosomotropic-agent-mediated block to SARS-CoV infection is overcome by protease treatment of target-cell-assocd. virus. In addn., SARS-CoV infection was blocked by specific inhibitors of the pH-sensitive endosomal protease cathepsin L. A cell-free membrane-fusion system demonstrates that engagement of receptor followed by proteolysis is required for SARS-CoV membrane fusion and indicates that cathepsin L is sufficient to activate membrane fusion by SARS-CoV S. These results suggest that SARS-CoV infection results from a unique, three-step process: receptor binding and induced conformational changes in S glycoprotein followed by cathepsin L proteolysis within endosomes. The requirement for cathepsin L proteolysis identifies a previously uncharacterized class of inhibitor for SARS-CoV infection.
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Gierer, S.; Bertram, S.; Kaup, F.; Wrensch, F.; Heurich, A.; Krämer-Kühl, A.; Welsch, K.; Winkler, M.; Meyer, B.; Drosten, C.; Dittmer, U.; von Hahn, T.; Simmons, G.; Hofmann, H.; Pöhlmann, S. The Spike Protein of the Emerging Betacoronavirus EMC Uses a Novel Coronavirus Receptor for Entry, Can Be Activated by TMPRSS2, and Is Targeted by Neutralizing Antibodies. J. Virol. 2013, 87 (10), 5502– 5511, DOI: 10.1128/JVI.00128-13
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The spike protein of the emerging betacoronavirus EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing antibodies
Gierer, Stefanie; Bertram, Stephanie; Kaup, Franziska; Wrensch, Florian; Heurich, Adeline; Kraemer-Kuehl, Annika; Welsch, Kathrin; Winkler, Michael; Meyer, Benjamin; Drosten, Christian; Dittmer, Ulf; von Hahn, Thomas; Simmons, Graham; Hofmann, Heike; Poehlmann, Stefan
Journal of Virology (2013), 87 (10), 5502-5511CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
The novel human coronavirus EMC (hCoV-EMC), which recently emerged in Saudi Arabia, is highly pathogenic and could pose a significant threat to public health. The elucidation of hCoV-EMC interactions with host cells is crit. to our understanding of the pathogenesis of this virus and to the identification of targets for antiviral intervention. Here we investigated the viral and cellular determinants governing hCoV-EMC entry into host cells. We found that the spike protein of hCoV-EMC (EMC-S) is incorporated into lentiviral particles and mediates transduction of human cell lines derived from different organs, including the lungs, kidneys, and colon, as well as primary human macrophages. Expression of the known coronavirus receptors ACE2, CD13, and CEACAM1 did not facilitate EMC-S-driven transduction, suggesting that hCoV-EMC uses a novel receptor for entry. Directed protease expression and inhibition analyses revealed that TMPRSS2 and endosomal cathepsins activate EMC-S for virus-cell fusion and constitute potential targets for antiviral intervention. Finally, EMC-S-driven transduction was abrogated by serum from an hCoV-EMC-infected patient, indicating that EMC-S-specific neutralizing antibodies can be generated in patients. Collectively, our results indicate that hCoV-EMC uses a novel receptor for protease-activated entry into human cells and might be capable of extrapulmonary spread. In addn., they define TMPRSS2 and cathepsins B and L as potential targets for intervention and suggest that neutralizing antibodies contribute to the control of hCoV-EMC infection.
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Yuan, M.; Wu, N. C.; Zhu, X.; Lee, C.-C. D.; So, R. T. Y.; Lv, H.; Mok, C. K. P.; Wilson, I. A. A Highly Conserved Cryptic Epitope in the Receptor-Binding Domains of SARS-CoV-2 and SARS-CoV. Science 2020, 368, 630 DOI: 10.1126/science.abb7269 .
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A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV
Yuan, Meng; Wu, Nicholas C.; Zhu, Xueyong; Lee, Chang-Chun D.; So, Ray T. Y.; Lv, Huibin; Mok, Chris K. P.; Wilson, Ian A.
Science (Washington, DC, United States) (2020), 368 (6491), 630-633CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has now become a pandemic, but there is currently very little understanding of the antigenicity of the virus. We therefore detd. the crystal structure of CR3022, a neutralizing antibody previously isolated from a convalescent SARS patient, in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein at 3.1-angstrom resoln. CR3022 targets a highly conserved epitope, distal from the receptor binding site, that enables cross-reactive binding between SARS-CoV-2 and SARS-CoV. Structural modeling further demonstrates that the binding epitope can only be accessed by CR3022 when at least two RBDs on the trimeric S protein are in the "up" conformation and slightly rotated. These results provide mol. insights into antibody recognition of SARS-CoV-2.
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Kawase, M.; Shirato, K.; van der Hoek, L.; Taguchi, F.; Matsuyama, S. Simultaneous Treatment of Human Bronchial Epithelial Cells with Serine and Cysteine Protease Inhibitors Prevents Severe Acute Respiratory Syndrome Coronavirus Entry. J. Virol. 2012, 86 (12), 6537– 6545, DOI: 10.1128/JVI.00094-12
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Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry
Kawase, Miyuki; Shirato, Kazuya; van der Hoek, Lia; Taguchi, Fumihiro; Matsuyama, Shutoku
Journal of Virology (2012), 86 (12), 6537-6545CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
The type II transmembrane protease TMPRSS2 activates the spike (S) protein of severe acute respiratory syndrome coronavirus (SARS-CoV) on the cell surface following receptor binding during viral entry into cells. In the absence of TMPRSS2, SARS-CoV achieves cell entry via an endosomal pathway in which cathepsin L may play an important role, i.e., the activation of spike protein fusogenicity. This study shows that a com. serine protease inhibitor (camostat) partially blocked infection by SARS-CoV and human coronavirus NL63 (HCoV-NL63) in HeLa cells expressing the receptor angiotensin-converting enzyme 2 (ACE2) and TMPRSS2. Simultaneous treatment of the cells with camostat and EST [(23,25)trans-epoxysuccinyl-L-leucylamindo-3-methylbutane Et ester], a cathepsin inhibitor, efficiently prevented both cell entry and the multistep growth of SARS-CoV in human Calu-3 airway epithelial cells. This efficient inhibition could be attributed to the dual blockade of entry from the cell surface and through the endosomal pathway. These observations suggest camostat as a candidate antiviral drug to prevent or depress TMPRSS2-dependent infection by SARS-CoV.
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Fehr, A. R.; Perlman, S. Coronaviruses: An Overview of Their Replication and Pathogenesis. In Coronaviruses: Methods and Protocols; Maier, H. J., Bickerton, E., Britton, P., Eds.; Methods in Molecular Biology; Springer: New York, NY, 2015; pp 1– 23.
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There is no corresponding record for this reference.
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Yin, W.; Mao, C.; Luan, X.; Shen, D.-D.; Shen, Q.; Su, H.; Wang, X.; Zhou, F.; Zhao, W.; Gao, M.; Chang, S.; Xie, Y.-C.; Tian, G.; Jiang, H.-W.; Tao, S.-C.; Shen, J.; Jiang, Y.; Jiang, H.; Xu, Y.; Zhang, S.; Zhang, Y.; Xu, H. E. Structural Basis for Inhibition of the RNA-Dependent RNA Polymerase from SARS-CoV-2 by Remdesivir. Science 2020, 368, 1499 DOI: 10.1126/science.abc1560 .
[Crossref], [PubMed], [CAS], Google Scholar
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Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir
Yin, Wanchao; Mao, Chunyou; Luan, Xiaodong; Shen, Dan-Dan; Shen, Qingya; Su, Haixia; Wang, Xiaoxi; Zhou, Fulai; Zhao, Wenfeng; Gao, Minqi; Chang, Shenghai; Xie, Yuan-Chao; Tian, Guanghui; Jiang, He-Wei; Tao, Sheng-Ce; Shen, Jingshan; Jiang, Yi; Jiang, Hualiang; Xu, Yechun; Zhang, Shuyang; Zhang, Yan; Xu, H. Eric
Science (Washington, DC, United States) (2020), 368 (6498), 1499-1504CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global crisis. Replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp) enzyme, a target of the antiviral drug remdesivir. Here, we report the cryo-electron microscopy structure of the SARS-CoV-2 RdRp, both in the apo form at 2.8-angstrom resoln. and in complex with a 50-base template-primer RNA and remdesivir at 2.5-angstrom resoln. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp, where remdesivir is covalently incorporated into the primer strand at the first replicated base pair, and terminates chain elongation. Our structures provide insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.
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Gordon, C. J.; Tchesnokov, E. P.; Woolner, E.; Perry, J. K.; Feng, J. Y.; Porter, D. P.; Gotte, M. Remdesivir Is a Direct-Acting Antiviral That Inhibits RNA-Dependent RNA Polymerase from Severe Acute Respiratory Syndrome Coronavirus 2 with High Potency. J. Biol. Chem. 2020, 295, 6785, DOI: 10.1074/jbc.RA120.013679
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Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency
Gordon, Calvin J.; Tchesnokov, Egor P.; Woolner, Emma; Perry, Jason K.; Feng, Joy Y.; Porter, Danielle P.; Gotte, Matthias
Journal of Biological Chemistry (2020), 295 (20), 6785-6797CODEN: JBCHA3; ISSN:1083-351X. (American Society for Biochemistry and Molecular Biology)
Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed to control this current pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of SARS-CoV-2 depends on the viral RNA-dependent RNA polymerase (RdRp), which is the likely target of the investigational nucleotide analog remdesivir (RDV). RDV shows broad-spectrum antiviral activity against RNA viruses, and previous studies with RdRps from Ebola virus and Middle East respiratory syndrome coronavirus (MERS-CoV) have revealed that delayed chain termination is RDV's plausible mechanism of action. Here, we expressed and purified active SARS-CoV-2 RdRp composed of the nonstructural proteins nsp8 and nsp12. Enzyme kinetics indicated that this RdRp efficiently incorporates the active triphosphate form of RDV (RDV-TP) into RNA. Incorporation of RDV-TP at position i caused termination of RNA synthesis at position i + 3. We obtained almost identical results with SARS-CoV, MERS-CoV, and SARS-CoV-2 RdRps. A unique property of RDV-TP is its high selectivity over incorporation of its natural nucleotide counterpart ATP. In this regard, the triphosphate forms of 2'-C-methylated compds., including sofosbuvir, approved for the management of hepatitis C virus infection, and the broad-acting antivirals favipiravir and ribavirin, exhibited significant deficits. Furthermore, we provide evidence for the target specificity of RDV, as RDV-TP was less efficiently incorporated by the distantly related Lassa virus RdRp, and termination of RNA synthesis was not obsd. These results collectively provide a unifying, refined mechanism of RDV-mediated RNA synthesis inhibition in coronaviruses and define this nucleotide analog as a direct-acting antiviral.
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Sanders, J. M.; Monogue, M. L.; Jodlowski, T. Z.; Cutrell, J. B. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA 2020, DOI: 10.1001/jama.2020.6019 .
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Pillaiyar, T.; Manickam, M.; Namasivayam, V.; Hayashi, Y.; Jung, S.-H. An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy. J. Med. Chem. 2016, 59 (14), 6595– 6628, DOI: 10.1021/acs.jmedchem.5b01461
[ACS Full Text ], [CAS], Google Scholar
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An Overview of Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy
Pillaiyar, Thanigaimalai; Manickam, Manoj; Namasivayam, Vigneshwaran; Hayashi, Yoshio; Jung, Sang-Hun
Journal of Medicinal Chemistry (2016), 59 (14), 6595-6628CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Severe acute respiratory syndrome (SARS) is caused by a newly emerged coronavirus that infected more than 8000 individuals and resulted in more than 800 (10-15%) fatalities in 2003. The causative agent of SARS has been identified as a novel human coronavirus (SARS-CoV), and its viral protease, SARS-CoV 3CLpro, has been shown to be essential for replication and has hence been recognized as a potent drug target for SARS infection. Currently, there is no effective treatment for this epidemic despite the intensive research that has been undertaken since 2003 (over 3500 publications). This perspective focuses on the status of various efficacious anti-SARS-CoV 3CLpro chemotherapies discovered during the last 12 years (2003-2015) from all sources, including lab. synthetic methods, natural products, and virtual screening. We describe here mainly peptidomimetic and small mol. inhibitors of SARS-CoV 3CLpro. Attempts have been made to provide a complete description of the structural features and binding modes of these inhibitors under many conditions.
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Lee, H.; Lei, H.; Santarsiero, B. D.; Gatuz, J. L.; Cao, S.; Rice, A. J.; Patel, K.; Szypulinski, M. Z.; Ojeda, I.; Ghosh, A. K.; Johnson, M. E. Inhibitor Recognition Specificity of MERS-CoV Papain-like Protease May Differ from That of SARS-CoV. ACS Chem. Biol. 2015, 10 (6), 1456– 1465, DOI: 10.1021/cb500917m
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Inhibitor Recognition Specificity of MERS-CoV Papain-like Protease May Differ from That of SARS-CoV
Lee, Hyun; Lei, Hao; Santarsiero, Bernard D.; Gatuz, Joseph L.; Cao, Shuyi; Rice, Amy J.; Patel, Kavankumar; Szypulinski, Michael Z.; Ojeda, Isabel; Ghosh, Arun K.; Johnson, Michael E.
ACS Chemical Biology (2015), 10 (6), 1456-1465CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
The Middle East Respiratory Syndrome coronavirus (MERS-CoV) papain-like protease (PLpro) blocking loop 2 (BL2) structure differs significantly from that of SARS-CoV PLpro, where it has been proven to play a crucial role in SARS-CoV PLpro inhibitor binding. Four SARS-CoV PLpro lead inhibitors were tested against MERS-CoV PLpro, none of which were effective against MERS-CoV PLpro. Structure and sequence alignments revealed that two residues, Y269 and Q270, responsible for inhibitor binding to SARS-CoV PLpro, were replaced by T274 and A275 in MERS-CoV PLpro, making crit. binding interactions difficult to form for similar types of inhibitors. High-throughput screening (HTS) of 25 000 compds. against both PLpro enzymes identified a small fragment-like noncovalent dual inhibitor. Mode of inhibition studies by enzyme kinetics and competition surface plasmon resonance (SPR) analyses suggested that this compd. acts as a competitive inhibitor with an IC50 of 6 μM against MERS-CoV PLpro, indicating that it binds to the active site, whereas it acts as an allosteric inhibitor against SARS-CoV PLpro with an IC50 of 11 μM. These results raised the possibility that inhibitor recognition specificity of MERS-CoV PLpro may differ from that of SARS-CoV PLpro. In addn., inhibitory activity of this compd. was selective for SARS-CoV and MERS-CoV PLpro enzymes over two human homologs, the ubiquitin C-terminal hydrolases 1 and 3 (hUCH-L1 and hUCH-L3).
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Salles, T. S.; da Encarnação Sá-Guimarães, T.; de Alvarenga, E. S. L.; Guimarães-Ribeiro, V.; de Meneses, M. D. F.; de Castro-Salles, P. F.; dos Santos, C. R.; do Amaral Melo, A. C.; Soares, M. R.; Ferreira, D. F.; Moreira, M. F. History, Epidemiology and Diagnostics of Dengue in the American and Brazilian Contexts: A Review. Parasites Vectors 2018, 11 (1), 264, DOI: 10.1186/s13071-018-2830-8
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History, epidemiology and diagnostics of dengue in the American and Brazilian contexts: a review
Salles Tiago Souza; da Encarnacao Sa-Guimaraes Thayane; de Alvarenga Evelyn Seam Lima; Guimaraes-Ribeiro Victor; do Amaral Melo Ana Claudia; Soares Marcia Regina; Moreira Monica Ferreira; Salles Tiago Souza; de Meneses Marcelo Damiao Ferreira; Ferreira Davis Fernandes; de Castro-Salles Patricia Faria; Dos Santos Carlucio Rocha; do Amaral Melo Ana Claudia; Moreira Monica Ferreira; Ferreira Davis Fernandes
Parasites & vectors (2018), 11 (1), 264 ISSN:.
Dengue virus (DENV), an arbovirus transmitted by mosquitoes, has become a major threat to American human life, reaching approximately 23 million cases from 1980 to 2017. Brazil is among the countries most affected by this terrible viral disease, with 13.6 million cases. DENV has four different serotypes, DENV1-4, which show a broad clinical spectrum. Dengue creates a staggering epidemiological and economic burden for endemic countries. Without a specific therapy and with a commercial vaccine that presents some problems relative to its full effectiveness, initiatives to improve vector control strategies, early disease diagnostics and the development of vaccines and antiviral drugs are priorities. In this study, we present the probable origins of dengue in America and the trajectories of its spread. Overall, dengue diagnostics are costly, making the monitoring of dengue epidemiology more difficult and affecting physicians' therapeutic decisions regarding dengue patients, especially in developing countries. This review also highlights some recent and important findings regarding dengue in Brazil and the Americas. We also summarize the existing DENV polymerase chain reaction (PCR) diagnostic tests to provide an improved reference since these tests are useful and accurate at discriminating DENV from other flaviviruses that co-circulate in the Americas. Additionally, these DENV PCR assays ensure virus serotyping, enabling epidemiologic monitoring.
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Michelitsch, A.; Tews, B. A.; Klaus, C.; Bestehorn-Willmann, M.; Dobler, G.; Beer, M.; Wernike, K. In Vivo Characterization of Tick-Borne Encephalitis Virus in Bank Voles (Myodes Glareolus). Viruses 2019, 11 (11), 1069, DOI: 10.3390/v11111069
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In vivo characterization of Tick-borne encephalitis virus in bank voles (Myodes glareolus)
Michelitsch, Anna; Tews, Birke Andrea; Klaus, Christine; Bestehorn-Willmann, Malena; Dobler, Gerhard; Beer, Martin; Wernike, Kerstin
Viruses (2019), 11 (11), 1069CODEN: VIRUBR; ISSN:1999-4915. (MDPI AG)
Tick-borne encephalitis is the most important tick-transmitted zoonotic virus infection in Eurasia, causing severe neurol. symptoms in humans. The causative agent, the tick-borne encephalitis virus (TBEV), circulates between ticks and a variety of mammalian hosts. To study the interaction between TBEV and one of its suspected reservoir hosts, bank voles of the Western evolutionary lineage were inoculated s.c. with either one of eight TBEV strains or the related attenuated Langat virus, and were euthanized after 28 days. In addn., a subset of four strains was characterized in bank voles of the Carpathian linage. Six bank voles were inoculated per strain, and were housed together in groups of three with one uninfected in-contact animal each. Generally, most bank voles did not show any clin. signs1 over the course of infection. However, one infected bank vole died and three had to be euthanized prematurely, all of which had been inoculated with the identical TBEV strain (Battaune 17-H9, isolated in 2017 in Germany from a bank vole). All inoculated animals seroconverted, while none of the in-contact animals did. Viral RNA was detected via real-time RT-PCR in the whole blood samples of 31 out of 74 inoculated and surviving bank voles. The corresponding serum sample remained PCR-neg. in nearly all cases (29/31). In addn., brain and/or spine samples tested pos. in 11 cases, mostly correlating with a pos. whole blood sample. Our findings suggest a good adaptation of TBEV to bank voles, combining in most cases a low virulence phenotype with detectable virus replication and hinting at a reservoir host function of bank voles for TBEV.
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Aguas, R.; Dorigatti, I.; Coudeville, L.; Luxemburger, C.; Ferguson, N. M. Cross-Serotype Interactions and Disease Outcome Prediction of Dengue Infections in Vietnam. Sci. Rep. 2019, 9 (1), 9395, DOI: 10.1038/s41598-019-45816-6
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Cross-serotype interactions and disease outcome prediction of dengue infections in Vietnam
Aguas R; Dorigatti I; Ferguson N M; Aguas R; Aguas R; Coudeville L; Luxemburger C
Scientific reports (2019), 9 (1), 9395 ISSN:.
Dengue pathogenesis is extremely complex. Dengue infections are thought to induce life-long immunity from homologous challenges as well as a multi-factorial heterologous risk enhancement. Here, we use the data collected from a prospective cohort study of dengue infections in schoolchildren in Vietnam to disentangle how serotype interactions modulate clinical disease risk in the year following serum collection. We use multinomial logistic regression to correlate the yearly neutralizing antibody measurements obtained with each infecting serotype in all dengue clinical cases collected over the course of 6 years (2004-2009). This allowed us to extrapolate a fully discretised matrix of serotype interactions, revealing clear signals of increased risk of clinical illness in individuals primed with a previous dengue infection. The sequences of infections which produced a higher risk of dengue fever upon secondary infection are: DEN1 followed by DEN2; DEN1 followed by DEN4; DEN2 followed by DEN3; and DEN4 followed by DEN3. We also used this longitudinal data to train a machine learning algorithm on antibody titre differences between consecutive years to unveil asymptomatic dengue infections and estimate asymptomatic infection to clinical case ratios over time, allowing for a better characterisation of the population's past exposure to different serotypes.
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Hadfield, J.; Brito, A. F.; Swetnam, D. M.; Vogels, C. B. F.; Tokarz, R. E.; Andersen, K. G.; Smith, R. C.; Bedford, T.; Grubaugh, N. D. Twenty Years of West Nile Virus Spread and Evolution in the Americas Visualized by Nextstrain. PLoS Pathog. 2019, 15 (10), e1008042, DOI: 10.1371/journal.ppat.1008042
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Twenty years of west nile virus spread and evolution in the americas visualized by nextstrain
Hadfield, James; Brito, Anderson F.; Swetnam, Daniele M.; Vogels, Chantal B. F.; Tokarz, Ryan E.; Andersen, Kristian G.; Smith, Ryan C.; Bedford, Trevor; Grubaugh, Nathan D.
PLoS Pathogens (2019), 15 (10), e1008042CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
It has been 20 years since West Nile virus first emerged in the Americas, and since then, little progress has been made to control outbreaks caused by this virus. After its first detection in New York in 1999, West Nile virus quickly spread across the continent, causing an epidemic of human disease and massive bird die-offs. Now the virus has become endemic to the United States, where an estd. 7 million human infections have occurred, making it the leading mosquito-borne virus infection and the most common cause of viral encephalitis in the country. To bring new attention to one of the most important mosquito-borne viruses in the Americas, we provide an interactive review using Nextstrain: a visualization tool for real-time tracking of pathogen evolution. Nextstrain utilizes a growing database of more than 2,000 West Nile virus genomes and harnesses the power of phylogenetics for students, educators, public health workers, and researchers to visualize key aspects of virus spread and evolution. Using Nextstrain, we use virus genomics to investigate the emergence of West Nile virus in the U S, followed by its rapid spread, evolution in a new environment, establishment of endemic transmission, and subsequent international spread. For each figure, we include a link to Nextstrain to allow the readers to directly interact with and explore the underlying data in new ways. We also provide a brief online narrative that parallels this review to further explain the data and highlight key epidemiol. and evolutionary features. Mirroring the dynamic nature of outbreaks, the Nextstrain links provided within this paper are constantly updated as new West Nile virus genomes are shared publicly, helping to stay current with the research. Overall, our review showcases how genomics can track West Nile virus spread and evolution, as well as potentially uncover novel targeted control measures to help alleviate its public health burden.
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https://www.cdc.gov/westnile/healthcareproviders/healthCareProviders-TreatmentPrevention.html.
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Rodrigues, L. C. Microcephaly and Zika Virus Infection. Lancet 2016, 387 (10033), 2070– 2072, DOI: 10.1016/S0140-6736(16)00742-X
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Microcephaly and Zika virus infection
Rodrigues Laura C
Lancet (London, England) (2016), 387 (10033), 2070-2072 ISSN:.
There is no expanded citation for this reference.
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Turtle, L.; Solomon, T. Japanese Encephalitis — the Prospects for New Treatments. Nat. Rev. Neurol. 2018, 14 (5), 298– 313, DOI: 10.1038/nrneurol.2018.30
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Japanese encephalitis - the prospects for new treatments
Turtle Lance; Solomon Tom; Turtle Lance; Solomon Tom
Nature reviews. Neurology (2018), 14 (5), 298-313 ISSN:.
Japanese encephalitis is a mosquito-borne disease that occurs in Asia and is caused by Japanese encephalitis virus (JEV), a member of the genus Flavivirus. Although many flaviviruses can cause encephalitis, JEV causes particularly severe neurological manifestations. The virus causes loss of more disability-adjusted life years than any other arthropod-borne virus owing to the frequent neurological sequelae of the condition. Despite substantial advances in our understanding of Japanese encephalitis from in vitro studies and animal models, studies of pathogenesis and treatment in humans are lagging behind. Few mechanistic studies have been conducted in humans, and only four clinical trials of therapies for Japanese encephalitis have taken place in the past 10 years despite an estimated incidence of 69,000 cases per year. Previous trials for Japanese encephalitis might have been too small to detect important benefits of potential treatments. Many potential treatment targets exist for Japanese encephalitis, and pathogenesis and virological studies have uncovered mechanisms by which these drugs could work. In this Review, we summarize the epidemiology, clinical features, prevention and treatment of Japanese encephalitis and focus on potential new therapeutic strategies, based on repurposing existing compounds that are already suitable for human use and could be trialled without delay. We use our newly improved understanding of Japanese encephalitis pathogenesis to posit potential treatments and outline some of the many challenges that remain in tackling the disease in humans.
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https://www.cdc.gov/japaneseencephalitis/vaccine/index.html.
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Velay, A.; Paz, M.; Cesbron, M.; Gantner, P.; Solis, M.; Soulier, E.; Argemi, X.; Martinot, M.; Hansmann, Y.; Fafi-Kremer, S. Tick-Borne Encephalitis Virus: Molecular Determinants of Neuropathogenesis of an Emerging Pathogen. Crit. Rev. Microbiol. 2019, 45 (4), 472– 493, DOI: 10.1080/1040841X.2019.1629872
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Tick-borne encephalitis virus: molecular determinants of neuropathogenesis of an emerging pathogen
Velay Aurelie; Paz Magali; Cesbron Marlene; Gantner Pierre; Solis Morgane; Fafi-Kremer Samira; Velay Aurelie; Gantner Pierre; Solis Morgane; Soulier Eric; Fafi-Kremer Samira; Argemi Xavier; Hansmann Yves; Martinot Martin
Critical reviews in microbiology (2019), 45 (4), 472-493 ISSN:.
Tick-borne encephalitis virus (TBEV) is a zoonotic agent causing severe encephalitis. The transmission cycle involves the virus, the Ixodes tick vector, and a vertebrate reservoir, such as small mammals (rodents, or shrews). Humans are accidentally involved in this transmission cycle. Tick-borne encephalitis (TBE) has been a growing public health problem in Europe and Asia over the past 30 years. The mechanisms involved in the development of TBE are very complex and likely multifactorial, involving both host and viral factors. The purpose of this review is to provide an overview of the current literature on TBE neuropathogenesis in the human host and to demonstrate the emergence of common themes in the molecular pathogenesis of TBE in humans. We discuss and review data on experimental study models and on both viral (molecular genetics of TBEV) and host (immune response, and genetic background) factors involved in TBE neuropathogenesis in the context of human infection.
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Hui, L.; Nie, Y.; Li, S.; Guo, M.; Yang, W.; Huang, R.; Chen, J.; Liu, Y.; Lu, X.; Chen, Z.; Yang, Q.; Wu, Y. Matrix Metalloproteinase 9 Facilitates Zika Virus Invasion of the Testis by Modulating the Integrity of the Blood-Testis Barrier. PLoS Pathog. 2020, 16 (4), e1008509, DOI: 10.1371/journal.ppat.1008509
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Matrix metalloproteinase 9 facilitates Zika virus invasion of the testis by modulating the integrity of the blood-testis barrier
Hui, Lixia; Nie, Yiwen; Li, Shihua; Guo, Moujian; Yang, Wei; Huang, Rui; Chen, Junsen; Liu, Yingxia; Lu, Xuancheng; Chen, Zhen; Yang, Qingyu; Wu, Ying
PLoS Pathogens (2020), 16 (4), e1008509/1-e1008509/22CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
Zika virus (ZIKV) is a unique flavivirus with high tropism to the testes. ZIKV can persist in human semen for months and can cause testicular damage in male mice. However, the mechanisms through which ZIKV enters the testes remain unclear. In this study, we revealed that matrix metalloproteinase 9 (MMP9) was upregulated by ZIKV infection in cell culture and in A129 mice. Furthermore, using an in vitro Sertoli cell barrier model and MMP9-/- mice, we found that ZIKV infection directly affected the permeability of the bloodtestis barrier (BTB), and knockout or inhibition of MMP9 reduced the effects of ZIKV on the Sertoli cell BTB, highlighting its role in ZIKV-induced disruption of the BTB. Interestingly, the protein levels of MMP9 were elevated by ZIKV nonstructural protein 1 (NS1) in primary mouse Sertoli cells (mSCs) and other cell lines. Moreover, the interaction between NS1 and MMP9 induced the K63-linked polyubiquitination of MMP9, which enhanced the stability of MMP9. The upregulated MMP9 level led to the degrdn. of essential proteins involved in the maintenance of the BTB, such as tight junction proteins (TJPs) and type IV collagens. Collectively, we concluded that ZIKV infection promoted the expression of MMP9 which was further stabilized by NS1 induced K63-linked polyubiquitination to affect the TJPs/ type IV collagen network, thereby disrupting the BTB and facilitating ZIKV entry into the testes.
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Wang, P.; Dai, J.; Bai, F.; Kong, K.-F.; Wong, S. J.; Montgomery, R. R.; Madri, J. A.; Fikrig, E. Matrix Metalloproteinase 9 Facilitates West Nile Virus Entry into the Brain. J. Virol. 2008, 82 (18), 8978– 8985, DOI: 10.1128/JVI.00314-08
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Matrix metalloproteinase 9 facilitates West Nile virus entry into the brain
Wang, Penghua; Dai, Jianfeng; Bai, Fengwei; Kong, Kok-Fai; Wong, Susan J.; Montgomery, Ruth R.; Madri, Joseph A.; Fikrig, Erol
Journal of Virology (2008), 82 (18), 8978-8985CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
West Nile virus (WNV) is the most-common cause of mosquito-borne encephalitis in the United States. Invasion of the brain by WNV is influenced by viral and host factors, and the mol. mechanism underlying disruption of the blood-brain barrier is likely multifactorial. Here we show that matrix metalloproteinase 9 (MMP9) is involved in WNV entry into the brain by enhancing blood-brain barrier permeability. Murine MMP9 expression was induced in the circulation shortly after WNV infection, and the protein levels remained high even when viremia subsided. In the murine brain, MMP9 expression and its enzymic activity were upregulated and MMP9 was shown to partly localize to the blood vessels. Interestingly, we also found that cerebrospinal fluid from patients suffering from WNV contained increased MMP9 levels. The peripheral viremia and expression of host cytokines were not altered in MMP9-/- mice; however, these animals were protected from lethal WNV challenge. The resistance of MMP9-/- mice to WNV infection correlated with an intact blood-brain barrier since IgG, Evans blue leakage into brain, and type IV collagen degrdn. were markedly reduced in the MMP9-/- mice compared with their levels in controls. Consistent with this, the brain viral loads, selected inflammatory cytokines, and leukocyte infiltrates were significantly reduced in the MMP9-/- mice compared to their levels in wild-type mice. These data suggest that MMP9 plays a role in mediating WNV entry into the central nervous system and that strategies to interrupt this process may influence the course of West Nile encephalitis.
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Glasner, D. R.; Ratnasiri, K.; Puerta-Guardo, H.; Espinosa, D. A.; Beatty, P. R.; Harris, E. Dengue Virus NS1 Cytokine-Independent Vascular Leak Is Dependent on Endothelial Glycocalyx Components. PLoS Pathog. 2017, 13 (11), e1006673, DOI: 10.1371/journal.ppat.1006673
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Dengue virus NS1 cytokine-independent vascular leak is dependent on endothelial glycocalyx components
Glasner, Dustin R.; Ratnasiri, Kalani; Puerta-Guardo, Henry; Espinosa, Diego A.; Robert Beatty, P.; Harris, Eva
PLoS Pathogens (2017), 13 (11), e1006673/1-e1006673/22CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
Dengue virus (DENV) is the most prevalent, medically important mosquito-borne virus. Disease ranges from uncomplicated dengue to life-threatening disease, characterized by endothelial dysfunction and vascular leakage. Previously, we demonstrated that DENV nonstructural protein 1 (NS1) induces endothelial hyperpermeability in a systemic mouse model and human pulmonary endothelial cells, where NS1 disrupts the endothelial glycocalyx-like layer. NS1 also triggers release of inflammatory cytokines from PBMCs via TLR4. Here, we examd. the relative contributions of inflammatory mediators and endothelial cell-intrinsic pathways. In vivo, we demonstrated that DENV NS1 but not the closely-related West Nile virus NS1 triggers localized vascular leak in the dorsal dermis of wild-type C57BL/6 mice. In vitro, we showed that human dermal endothelial cells exposed to DENV NS1 do not produce inflammatory cytokines (TNF-a, IL-6, IL-8) and that blocking these cytokines does not affect DENV NS1-induced endothelial hyperpermeability. Further, we demonstrated that DENV NS1 induces vascular leak in TLR4- or TNF-a receptor-deficient mice at similar levels to wild-type animals. Finally, we blocked DENV NS1-induced vascular leak in vivo using inhibitors targeting mols. involved in glycocalyx disruption. Taken together, these data indicate that DENV NS1-induced endothelial cell-intrinsic vascular leak is independent of inflammatory cytokines but dependent on endothelial glycocalyx components.
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Gopala Reddy, S. B.; Chin, W.-X.; Shivananju, N. S. Dengue Virus NS2 and NS4: Minor Proteins, Mammoth Roles. Biochem. Pharmacol. 2018, 154, 54– 63, DOI: 10.1016/j.bcp.2018.04.008
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Dengue virus NS2 and NS4: Minor proteins, mammoth roles
Gopala Reddy, Sindhoora Bhargavi; Chin, Wei-Xin; Shivananju, Nanjunda Swamy
Biochemical Pharmacology (Amsterdam, Netherlands) (2018), 154 (), 54-63CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)
A review. Despite the ever-increasing global incidence of dengue fever, there are no specific chemotherapy regimens for its treatment. Structural studies on dengue virus (DENV) proteins have revealed potential drug targets. Major DENV proteins such as the envelope protein and non-structural (NS) proteins 3 and 5 have been extensively investigated in antiviral studies, but with limited success in vitro. However, the minor NS proteins NS2 and NS4 have remained relatively underreported. Emerging evidence indicating their indispensable roles in virus propagation and host immunomodulation should encourage us to target these proteins for drug discovery. This review covers current knowledge on DENV NS2 and NS4 proteins from structural and functional perspectives and assesses their potential as targets for antiviral design. Antiviral targets in NS2A include surface-exposed transmembrane regions involved in pathogenesis, while those in NS2B include protease-binding sites in a conserved hydrophilic domain. Ideal drug targets in NS4A include helix α4 and the PEPEKQR sequence, which are essential for NS4A-2K cleavage and NS4A-NS4B assocn., resp. In NS4B, the cytoplasmic loop connecting helixes α5 and α7 is an attractive target for antiviral design owing to its role in dimerization and NS4B-NS3 interaction. Findings implicating NS2A, NS2B, and NS4A in membrane-modulation and viroporin-like activities indicate an opportunity to target these proteins by disrupting their assocn. with membrane lipids. Despite the lack of 3D structural data, recent topol. findings and progress in structure-prediction methods should be sufficient impetus for targeting NS2 and NS4 for drug design.
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Bautista-Carbajal, P.; Soto-Acosta, R.; Angel-Ambrocio, A. H.; Cervantes-Salazar, M.; Loranca-Vega, C. I.; Herrera-Martínez, M.; del Angel, R. M. The Calmodulin Antagonist W-7 (N-(6-Aminohexyl)-5-Chloro-1-Naphthalenesulfonamide Hydrochloride) Inhibits DENV Infection in Huh-7 Cells. Virology 2017, 501, 188– 198, DOI: 10.1016/j.virol.2016.12.004
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The calmodulin antagonist W-7 (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride) inhibits DENV infection in Huh-7 cells
Bautista-Carbajal, Patricia; Soto-Acosta, Ruben; Angel-Ambrocio, Antonio H.; Cervantes-Salazar, Margot; Loranca-Vega, Circe I.; Herrera-Martinez, Mayra; del Angel, Rosa M.
Virology (2017), 501 (), 188-198CODEN: VIRLAX; ISSN:0042-6822. (Elsevier B.V.)
Dengue virus (DENV) replicative cycle occurs in the endoplasmic reticulum where calcium ions play an important role in cell signaling. Calmodulin (CaM) is the primary sensor of intracellular Ca2+ levels in eukaryotic cells. In this paper, the effect of the calmodulin antagonist W-7 in DENV infection in Huh-7 cells was evaluated. W7 inhibited viral yield, NS1 secretion and viral RNA and protein synthesis. Moreover, luciferase activity, encoded by a DENV replicon, was also reduced. A decrease in the replicative complexes formation was clearly obsd. in W7 treated cells. Docking simulations suggest 2 possible mechanisms of action for W7: the direct inhibition of NS2B-NS3 activity and/or inhibition of the interaction between NS2A with Ca2+-CaM complex. This last possibility was supported by the in vitro interaction obsd. between recombinant NS2A and CaM. These results indicate that Ca2+-CaM plays an important role in DENV replication.
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Falgout, B.; Pethel, M.; Zhang, Y. M.; Lai, C. J. Both Nonstructural Proteins NS2B and NS3 Are Required for the Proteolytic Processing of Dengue Virus Nonstructural Proteins. J. Virol. 1991, 65 (5), 2467– 2475, DOI: 10.1128/JVI.65.5.2467-2475.1991
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Both nonstructural proteins NS2B and NS3 are required for the proteolytic processing of dengue virus nonstructural proteins
Falgout, Barry; Pethel, Michele; Zhang, Yi Ming; Lai, Ching Juh
Journal of Virology (1991), 65 (5), 2467-75CODEN: JOVIAM; ISSN:0022-538X.
The cleavages at the junctions of the flavivirus nonstructural (NS) proteins NS2A/NS2B, NS2B/NS3, NS3/NS4A, and NS4B/NS5 share an amino acid sequence motif and are presumably catalyzed by a virus-encoded protease. Recombinant vaccinia viruses expressing various portions of the NS region of the dengue virus type 4 polyprotein were constructed. By analyzing immune ppts. of 35S-labeled lysates of recombinant virus-infected cells, the NS2A/NS2B, NS2B/NS3, and NS3/NS4A cleavages could be monitored. A polyprotein composed of NS2A, NS2B, and the N-terminal 184 amino acids of NS3 was cleaved at the NS2A/NS2B and NS2B/NS3 junctions, whereas a similar polyprotein contg. only the first 77 amino acids of NS3 was not cleaved. This finding is consistent with the proposal that the N-terminal 180 amino acids of NS3 constitute a protease domain. Polyproteins contg. NS2A and NS3 with large in-frame deletions of NS2B were not cleaved at the NS2A/NS2B or NS2B/NS3 junctions. Coinfection with a recombinant expressing NS2B complemented these NS2B deletions for NS2B/NS3 cleavage and probably also for NS2A/NS2B cleavage. Thus, NS2B is also required for the NS2A/NS2B and NS2B/NS3 cleavages and can act in trans. Other expts. showed that NS2B was needed, apparently in cis, for NS3/NS4A cleavage and for a series of internal cleavages in NS3. Indirect evidence that NS3 can also act in trans was obtained. Models are discussed for a two-component protease activity requiring both NS2B and NS3.
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Timiri, A. K.; Sinha, B. N.; Jayaprakash, V. Progress and Prospects on DENV Protease Inhibitors. Eur. J. Med. Chem. 2016, 117, 125– 143, DOI: 10.1016/j.ejmech.2016.04.008
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Progress and prospects on DENV protease inhibitors
Timiri, Ajay Kumar; Sinha, Barij Nayan; Jayaprakash, Venkatesan
European Journal of Medicinal Chemistry (2016), 117 (), 125-143CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
New treatments are desperately required to combat increasing rate of dengue fever cases reported in tropical and sub-tropical parts of the world. Among the ten proteins (structural and non-structural) encoded by dengue viral genome, NS2B-NS3 protease is an ideal target for drug discovery. It is responsible for the processing of poly protein that is required for genome replication of the virus. Moreover, inhibitors designed against proteases were found successful in Human Immuno-deficiency Virus (HIV) and Hepatitis C Virus (HCV). Complete mol. mechanism and a survey of inhibitors reported against dengue protease will be helpful in designing effective and potent inhibitors. This review provides an insight on mol. mechanism of dengue virus protease and covers up-to-date information on different inhibitors reported against dengue proteases with medicinal chem. perspective.
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Miller, S.; Sparacio, S.; Bartenschlager, R. Subcellular Localization and Membrane Topology of the Dengue Virus Type 2 Non-Structural Protein 4B. J. Biol. Chem. 2006, 281 (13), 8854– 8863, DOI: 10.1074/jbc.M512697200
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Subcellular Localization and Membrane Topology of the Dengue Virus Type 2 Non-structural Protein 4Bd2
Miller, Sven; Sparacio, Sandra; Bartenschlager, Ralf
Journal of Biological Chemistry (2006), 281 (13), 8854-8863CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
Dengue virus (DV) is a member of the family Flavoviridae: these pos. strand RNA viruses encode a polyprotein that is processed in case of DV into 10 proteins. Although for most of these proteins distinct functions have been defined, this is less clear for the highly hydrophobic non-structural protein (NS) 4B. Despite its possible role as an antagonist of the interferon-induced antiviral response, this protein may play an addnl. more direct role for viral replication. In this study we detd. the subcellular localization, membrane assocn., and membrane topol. of DV NS4B. We found that NS4B resides primarily in cytoplasmic foci originating from the endoplasmic reticulum. NS4B colocalizes with NS3 and double-stranded RNA, an intermediate of viral replication, arguing that NS4B is part of the membrane-bound viral replication complex. Biochem. anal. revealed that NS4B is an integral membrane protein, and that its preceding 2K signal sequence is not required for this integration. We identified three membrane-spanning segments in the C-terminal part of NS4B that are sufficient to target a cytosolic marker protein to intracellular membranes. Furthermore, we established a membrane topol. model of NS4B in which the N-terminal part of the protein is localized in the endoplasmic reticulum lumen, whereas the C-terminal part is composed of three trans-membrane domains with the C-terminal tail localized in the cytoplasm. This topol. model provides a good starting point for a detailed investigation of the function of NS4B in the DV life cycle.
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Li, Y.; Wong, Y. L.; Lee, M. Y.; Li, Q.; Wang, Q.-Y.; Lescar, J.; Shi, P.-Y.; Kang, C. Secondary Structure and Membrane Topology of the Full-Length Dengue Virus NS4B in Micelles. Angew. Chem., Int. Ed. 2016, 55 (39), 12068– 12072, DOI: 10.1002/anie.201606609
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Secondary Structure and Membrane Topology of the Full-Length Dengue Virus NS4B in Micelles
Li, Yan; Wong, Ying Lei; Lee, Michelle Yueqi; Li, Qingxin; Wang, Qing-Yin; Lescar, Julien; Shi, Pei-Yong; Kang, Cong-Bao
Angewandte Chemie, International Edition (2016), 55 (39), 12068-12072CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Dengue virus nonstructural protein 4B (NS4B) is a membrane protein consisting of 248 residues with a crucial role in virus replication and interference with the host innate immunity. The Dengue virus serotype 3 NS4B was reconstituted into lyso-myristoyl phosphatidylglycerol (LMPG) micelles. Backbone resonance assignment of NS4B was obtained using conventional soln. NMR expts. Further studies suggested that NS4B contained 11 helixes and 6 of them form 5 potential transmembrane regions. This study provides at. level information for an important drug target to control flavivirus infections.
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Feldmann, H.; Klenk, H.-D. Marburg and Ebola Viruses. In Advances in Virus Research; Maramorosch, K., Murphy, F. A., Shatkin, A. J., Eds.; Academic Press, 1996; Vol. 47, pp 1– 52.
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Di Paola, N.; Sanchez-Lockhart, M.; Zeng, X.; Kuhn, J. H.; Palacios, G. Viral Genomics in Ebola Virus Research. Nat. Rev. Microbiol. 2020, 18, 1– 14, DOI: 10.1038/s41579-020-0354-7
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Miranda, M. E. G.; Miranda, N. L. J. Reston Ebolavirus in Humans and Animals in the Philippines: A Review. J. Infect. Dis. 2011, 204, S757– S760, DOI: 10.1093/infdis/jir296
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Barrette, R. W.; Metwally, S. A.; Rowland, J. M.; Xu, L.; Zaki, S. R.; Nichol, S. T.; Rollin, P. E.; Towner, J. S.; Shieh, W.-J.; Batten, B.; Sealy, T. K.; Carrillo, C.; Moran, K. E.; Bracht, A. J.; Mayr, G. A.; Sirios-Cruz, M.; Catbagan, D. P.; Lautner, E. A.; Ksiazek, T. G.; White, W. R.; McIntosh, M. T. Discovery of Swine as a Host for the Reston Ebolavirus. Science 2009, 325 (5937), 204– 206, DOI: 10.1126/science.1172705
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Discovery of Swine as a Host for the Reston ebolavirus
Barrette, Roger W.; Metwally, Samia A.; Rowland, Jessica M.; Xu, Lizhe; Zaki, Sherif R.; Nichol, Stuart T.; Rollin, Pierre E.; Towner, Jonathan S.; Shieh, Wun-Ju; Batten, Brigid; Sealy, Tara K.; Carrillo, Consuelo; Moran, Karen E.; Bracht, Alexa J.; Mayr, Gregory A.; Sirios-Cruz, Magdalena; Catbagan, Davinio P.; Lautner, Elizabeth A.; Ksiazek, Thomas G.; White, William R.; McIntosh, Michael T.
Science (Washington, DC, United States) (2009), 325 (5937), 204-206CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
Since the discovery of the Marburg and Ebola species of filovirus, seemingly random, sporadic fatal outbreaks of disease in humans and nonhuman primates have given impetus to identification of host tropisms and potential reservoirs. Domestic swine in the Philippines, experiencing unusually severe outbreaks of porcine reproductive and respiratory disease syndrome, have now been discovered to host Reston ebolavirus (REBOV). Although REBOV is the only member of Filoviridae that has not been assocd. with disease in humans, its emergence in the human food chain is of concern. REBOV isolates were found to be more divergent from each other than from the original virus isolated in 1989, indicating polyphyletic origins and that REBOV has been circulating since, and possibly before, the initial discovery of REBOV in monkeys.
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Brauburger, K.; Hume, A. J.; Mühlberger, E.; Olejnik, J. Forty-Five Years of Marburg Virus Research. Viruses 2012, 4 (10), 1878– 1927, DOI: 10.3390/v4101878
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Forty-five years of Marburg virus research
Brauburger Kristina; Hume Adam J; Muhlberger Elke; Olejnik Judith
Viruses (2012), 4 (10), 1878-927 ISSN:.
In 1967, the first reported filovirus hemorrhagic fever outbreak took place in Germany and the former Yugoslavia. The causative agent that was identified during this outbreak, Marburg virus, is one of the most deadly human pathogens. This article provides a comprehensive overview of our current knowledge about Marburg virus disease ranging from ecology to pathogenesis and molecular biology.
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Messaoudi, I.; Amarasinghe, G. K.; Basler, C. F. Filovirus Pathogenesis and Immune Evasion: Insights from Ebola Virus and Marburg Virus. Nat. Rev. Microbiol. 2015, 13 (11), 663– 676, DOI: 10.1038/nrmicro3524
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Filovirus pathogenesis and immune evasion: insights from Ebola virus and Marburg virus
Messaoudi, Ilhem; Amarasinghe, Gaya K.; Basler, Christopher F.
Nature Reviews Microbiology (2015), 13 (11), 663-676CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)
A review. Ebola viruses and Marburg viruses, members of the filovirus family, are zoonotic pathogens that cause severe disease in people, as highlighted by the latest Ebola virus epidemic in West Africa. Filovirus disease is characterized by uncontrolled virus replication and the activation of host responses that contribute to pathogenesis. Underlying these phenomena is the potent suppression of host innate antiviral responses, particularly the type I interferon response, by viral proteins, which allows high levels of viral replication. In this Review, we describe the mechanisms used by filoviruses to block host innate immunity and discuss the links between immune evasion and filovirus pathogenesis.
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Leroy, E. M.; Kumulungui, B.; Pourrut, X.; Rouquet, P.; Hassanin, A.; Yaba, P.; Délicat, A.; Paweska, J. T.; Gonzalez, J.-P.; Swanepoel, R. Fruit Bats as Reservoirs of Ebola Virus. Nature 2005, 438 (7068), 575– 576, DOI: 10.1038/438575a
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Fruit bats as reservoirs of Ebola virus
Leroy, Eric M.; Kumulungui, Brice; Pourrut, Xavier; Rouquet, Pierre; Hassanin, Alexandre; Yaba, Philippe; Delicat, Andre; Paweska, Janusz T.; Gonzalez, Jean-Paul; Swanepoel, Robert
Nature (London, United Kingdom) (2005), 438 (7068), 575-576CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
There is no expanded citation for this reference.
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Towner, J. S.; Amman, B. R.; Sealy, T. K.; Carroll, S. A. R.; Comer, J. A.; Kemp, A.; Swanepoel, R.; Paddock, C. D.; Balinandi, S.; Khristova, M. L.; Formenty, P. B. H.; Albarino, C. G.; Miller, D. M.; Reed, Z. D.; Kayiwa, J. T.; Mills, J. N.; Cannon, D. L.; Greer, P. W.; Byaruhanga, E.; Farnon, E. C.; Atimnedi, P.; Okware, S.; Katongole-Mbidde, E.; Downing, R.; Tappero, J. W.; Zaki, S. R.; Ksiazek, T. G.; Nichol, S. T.; Rollin, P. E. Isolation of Genetically Diverse Marburg Viruses from Egyptian Fruit Bats. PLoS Pathog. 2009, 5 (7), e1000536, DOI: 10.1371/journal.ppat.1000536
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65
Jahrling, P. B.; Geisbert, T. W.; Johnson, E. D.; Peters, C. J.; Dalgard, D. W.; Hall, W. C. Preliminary Report: Isolation of Ebola Virus from Monkeys Imported to USA. Lancet 1990, 335 (8688), 502– 505, DOI: 10.1016/0140-6736(90)90737-P
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Preliminary report: isolation of Ebola virus from monkeys imported to USA
Jahrling P B; Geisbert T W; Dalgard D W; Johnson E D; Ksiazek T G; Hall W C; Peters C J
Lancet (London, England) (1990), 335 (8688), 502-5 ISSN:0140-6736.
An epizootic caused by an Ebola-related filovirus and by simian haemorrhagic fever virus began among cynomolgus monkeys in a US quarantine facility after introduction of monkeys from the Philippines. This incident, the first in which a filovirus has been isolated from non-human primates without deliberate infection, raises the possibility that cynomolgus monkeys could be a reservoir of Ebola virus infection.
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Le Guenno, B.; Formenty, P.; Wyers, M.; Gounon, P.; Walker, F.; Boesch, C. Isolation and Partial Characterisation of a New Strain of Ebola Virus. Lancet 1995, 345 (8960), 1271– 1274, DOI: 10.1016/S0140-6736(95)90925-7
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66
Isolation and partial characterisation of a new strain of Ebola virus
Le Guenno B; Formenty P; Formentry P; Wyers M; Gounon P; Walker F; Boesch C
Lancet (London, England) (1995), 345 (8960), 1271-4 ISSN:0140-6736.
We have isolated a new strain of Ebola virus from a non-fatal human case infected during the autopsy of a wild chimpanzee in the Cote-d'Ivoire. The wild troop to which this animal belonged has been decimated by outbreaks of haemorrhagic syndromes. This is the first time that a human infection has been connected to naturally-infected monkeys in Africa. Data from the long-term survey of this troop of chimpanzees could answer questions about the natural reservoir of the Ebola virus.
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Dowell, S. F.; Mukunu, R.; Ksiazek, T. G.; Khan, A. S.; Rollin, P. E.; Peters, C. J. Transmission of Ebola Hemorrhagic Fever: A Study of Risk Factors in Family Members, Kikwit, Democratic Republic of the Congo, 1995. J. Infect. Dis. 1999, 179, S87– S91, DOI: 10.1086/514284
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U.S. Food and Drug Administration. FDA news release, December 19, 2019. First FDA-approved vaccine for the prevention of Ebola virus disease, marking a critical milestone in public health preparedness and response. https://www.fda.gov/news-events/press-announcements/first-fda-approved-vaccine-prevention-ebola-virus-disease-marking-critical-milestone-public-health (accessed May 21, 2020).
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There is no corresponding record for this reference.
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Suschak, J. J.; Schmaljohn, C. S. Vaccines against Ebola Virus and Marburg Virus: Recent Advances and Promising Candidates. Hum. Vaccines Immunother. 2019, 15 (10), 2359– 2377, DOI: 10.1080/21645515.2019.1651140
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There is no corresponding record for this reference.
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Kondratowicz, A. S.; Lennemann, N. J.; Sinn, P. L.; Davey, R. A.; Hunt, C. L.; Moller-Tank, S.; Meyerholz, D. K.; Rennert, P.; Mullins, R. F.; Brindley, M.; Sandersfeld, L. M.; Quinn, K.; Weller, M.; McCray, P. B.; Chiorini, J.; Maury, W. T-Cell Immunoglobulin and Mucin Domain 1 (TIM-1) Is a Receptor for Zaire Ebolavirus and Lake Victoria Marburgvirus. Proc. Natl. Acad. Sci. U. S. A. 2011, 108 (20), 8426– 8431, DOI: 10.1073/pnas.1019030108
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70
T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor for Zaire Ebolavirus and Lake Victoria Marburgvirus
Kondratowicz, Andrew S.; Lennemann, Nicholas J.; Sinn, Patrick L.; Davey, Robert A.; Hunt, Catherine L.; Moller-Tank, Sven; Meyerholz, David K.; Rennert, Paul; Mullins, Robert F.; Brindley, Melinda; Sandersfeld, Lindsay M.; Quinn, Kathrina; Weller, Melodie; McCray, Paul B., Jr.; Chiorini, John; Maury, Wendy
Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (20), 8426-8431, S8426/1-S8426/7CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
The glycoproteins (GP) of enveloped viruses facilitate entry into the host cell by interacting with specific cellular receptors. Despite extensive study, a cellular receptor for the deadly filoviruses Ebolavirus and Marburgvirus has yet to be identified and characterized. Here, we show that T-cell Ig and mucin domain 1 (TIM-1) binds to the receptor binding domain of the Zaire Ebola virus (EBOV) glycoprotein, and ectopic TIM-1 expression in poorly permissive cells enhances EBOV infection by 10- to 30-fold. Conversely, redn. of cell-surface expression of TIM-1 by RNAi decreased infection of highly permissive Vero cells. TIM-1 expression within the human body is broader than previously appreciated, with expression on mucosal epithelia from the trachea, cornea, and conjunctiva - tissues believed to be important during in vivo transmission of filoviruses. Recognition that TIM-1 serves as a receptor for filoviruses on these mucosal epithelial surfaces provides a mechanistic understanding of routes of entry into the human body via inhalation of aerosol particles or hand-to-eye contact. ARD5, a monoclonal antibody against the IgV domain of TIM-1, blocked EBOV binding and infection, suggesting that antibodies or small mols. directed against this cellular receptor may provide effective filovirus antivirals.
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Takada, A.; Watanabe, S.; Ito, H.; Okazaki, K.; Kida, H.; Kawaoka, Y. Downregulation of B1 Integrins by Ebola Virus Glycoprotein: Implication for Virus Entry. Virology 2000, 278 (1), 20– 26, DOI: 10.1006/viro.2000.0601
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71
Downregulation of β1 Integrins by Ebola Virus Glycoprotein: Implication for Virus Entry
Takada, Ayato; Watanabe, Shinji; Ito, Hiroshi; Okazaki, Katsunori; Kida, Hiroshi; Kawaoka, Yoshihiro
Virology (2000), 278 (1), 20-26CODEN: VIRLAX; ISSN:0042-6822. (Academic Press)
Filoviruses, including Ebola virus, are cytotoxic. To investigate the role of the Ebola virus glycoprotein (GP) in this cytopathic effect, we transiently expressed the GP in human kidney 293T cells. Expression of wild-type GP, but not the secretory form of the mol. lacking a membrane anchor, induced rounding and detachment of the cells, as did a chimeric GP contg. its ectodomain and influenza virus hemagglutinin transmembrane-cytoplasmic domain. These results indicate that the GP ectodomain and its anchorage to the membrane are required for GP-induced morphol. changes in host cells. Since cell rounding and detachment could be assocd. with reduced levels of cell adhesion mols., we also studied the expression of integrins, which are major mols. for adhesion to extracellular matrixes, and found that the β1 integrin group is downregulated by the GP. This result was further extended by expts. in which anti-β1 monoclonal antibodies or purified integrins inhibited the infectivity of vesicular stomatitis virus pseudotyped with the GP. We suggest that integrins, esp. the β1 group, might interact with the GP and perhaps be involved in Ebola virus entry into cells. (c) 2000 Academic Press.
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Takada, A.; Fujioka, K.; Tsuiji, M.; Morikawa, A.; Higashi, N.; Ebihara, H.; Kobasa, D.; Feldmann, H.; Irimura, T.; Kawaoka, Y. Human Macrophage C-Type Lectin Specific for Galactose and N-Acetylgalactosamine Promotes Filovirus Entry. J. Virol. 2004, 78 (6), 2943– 2947, DOI: 10.1128/JVI.78.6.2943-2947.2004
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72
Human macrophage C-type lectin specific for galactose and N-acetylgalactosamine promotes filovirus entry
Takada, Ayato; Fujioka, Kouki; Tsuiji, Makoto; Morikawa, Akiko; Higashi, Nobuaki; Ebihara, Hideki; Kobasa, Darwyn; Feldmann, Heinz; Irimura, Tatsuro; Kawaoka, Yoshihiro
Journal of Virology (2004), 78 (6), 2943-2947CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
Filoviruses cause lethal hemorrhagic disease in humans and nonhuman primates. An initial target of filovirus infection is the mononuclear phagocytic cell. Calcium-dependent (C-type) lectins such as dendritic cell- or liver/lymph node-specific ICAM-3 grabbing nonintegrin (DC-SIGN or L-SIGN, resp.), as well as the hepatic asialoglycoprotein receptor, bind to Ebola or Marburg virus glycoprotein (GP) and enhance the infectivity of these viruses in vitro. Here, we demonstrate that a recently identified human macrophage galactose- and N-acetylgalactosamine-specific C-type lectin (hMGL), whose ligand specificity differs from DC-SIGN and L-SIGN, also enhances the infectivity of filoviruses. This enhancement was substantially weaker for the Reston and Marburg viruses than for the highly pathogenic Zaire virus. We also show that the heavily glycosylated, mucin-like domain on the filovirus GP is required for efficient interaction with this lectin. Furthermore, hMGL, like DC-SIGN and L-SIGN, is present on cells known to be major targets of filoviruses (i.e., macrophages and dendritic cells), suggesting a role for these C-type lectins in viral replication in vivo. We propose that filoviruses use different C-type lectins to gain cellular entry, depending on the cell type, and promote efficient viral replication.
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Nanbo, A.; Imai, M.; Watanabe, S.; Noda, T.; Takahashi, K.; Neumann, G.; Halfmann, P.; Kawaoka, Y. Ebolavirus Is Internalized into Host Cells via Macropinocytosis in a Viral Glycoprotein-Dependent Manner. PLoS Pathog. 2010, 6 (9), e1001121, DOI: 10.1371/journal.ppat.1001121
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74
Carette, J. E.; Raaben, M.; Wong, A. C.; Herbert, A. S.; Obernosterer, G.; Mulherkar, N.; Kuehne, A. I.; Kranzusch, P. J.; Griffin, A. M.; Ruthel, G.; Cin, P. D.; Dye, J. M.; Whelan, S. P.; Chandran, K.; Brummelkamp, T. R. Ebola Virus Entry Requires the Cholesterol Transporter Niemann–Pick C1. Nature 2011, 477 (7364), 340– 343, DOI: 10.1038/nature10348
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74
Ebola virus entry requires the cholesterol transporter Niemann-Pick C1
Carette, Jan E.; Raaben, Matthijs; Wong, Anthony C.; Herbert, Andrew S.; Obernosterer, Gregor; Mulherkar, Nirupama; Kuehne, Ana I.; Kranzusch, Philip J.; Griffin, April M.; Ruthel, Gordon; Dal Cin, Paola; Dye, John M.; Whelan, Sean P.; Chandran, Kartik; Brummelkamp, Thijn R.
Nature (London, United Kingdom) (2011), 477 (7364), 340-343CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
Infections by the Ebola and Marburg filoviruses cause a rapidly fatal hemorrhagic fever in humans for which no approved antivirals are available. Filovirus entry is mediated by the viral spike glycoprotein (GP), which attaches viral particles to the cell surface, delivers them to endosomes and catalyzes fusion between viral and endosomal membranes. Addnl. host factors in the endosomal compartment are probably required for viral membrane fusion; however,despite considerable efforts, these crit. host factors have defied mol. identification. Here we describe a genome-wide haploid genetic screen in human cells to identify host factors required for Ebola virus entry. Our screen uncovered 67 mutations disrupting all six members of the homotypic fusion and vacuole protein-sorting (HOPS) multisubunit tethering complex, which is involved in the fusion of endosomes to lysosomes, and 39 independent mutations that disrupt the endo/lysosomal cholesterol transporter protein Niemann-Pick C1 (NPC1). Cells defective for the HOPS complex or NPC1 function, including primary fibroblasts derived from human Niemann-Pick type C1 disease patients, are resistant to infection by Ebola virus and Marburg virus, but remain fully susceptible to a suite of unrelated viruses. We show that membrane fusion mediated by filovirus glycoproteins and viral escape from the vesicular compartment require the NPC1 protein, independent of its known function in cholesterol transport. Our findings uncover unique features of the entry pathway used by filoviruses and indicate potential antiviral strategies to combat these deadly agents.
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Chandran, K.; Sullivan, N. J.; Felbor, U.; Whelan, S. P.; Cunningham, J. M. Endosomal Proteolysis of the Ebola Virus Glycoprotein Is Necessary for Infection. Science 2005, 308 (5728), 1643– 1645, DOI: 10.1126/science.1110656
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75
Endosomal Proteolysis of the Ebola Virus Glycoprotein Is Necessary for Infection
Chandran, Kartik; Sullivan, Nancy J.; Felbor, Ute; Whelan, Sean P.; Cunningham, James M.
Science (Washington, DC, United States) (2005), 308 (5728), 1643-1645CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
Ebola virus (EboV) causes rapidly fatal hemorrhagic fever in humans and there is currently no effective treatment. We found that the infection of African green monkey kidney (Vero) cells by vesicular stomatitis viruses bearing the EboV glycoprotein (GP) requires the activity of endosomal cysteine proteases. Using selective protease inhibitors and protease-deficient cell lines, we identified an essential role for cathepsin B (CatB) and an accessory role for cathepsin L (CatL) in EboV GP-dependent entry. Biochem. studies demonstrate that CatB and CatL mediate entry by carrying out proteolysis of the EboV GP subunit GP1 and support a multi-step mechanism that explains the relative contributions of these enzymes to infection. CatB and CatB/CatL inhibitors diminish the multiplication of infectious EboV-Zaire in cultured cells and may merit investigation as anti-EboV drugs.
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Zhu, W.; Banadyga, L.; Emeterio, K.; Wong, G.; Qiu, X. The Roles of Ebola Virus Soluble Glycoprotein in Replication, Pathogenesis, and Countermeasure Development. Viruses 2019, 11 (11), 999, DOI: 10.3390/v11110999
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76
The Roles of Ebola virus soluble glycoprotein in replication, pathogenesis, and countermeasure development
Zhu, Wenjun; Banadyga, Logan; Emeterio, Karla; Wong, Gary; Qiu, Xiangguo
Viruses (2019), 11 (11), 999CODEN: VIRUBR; ISSN:1999-4915. (MDPI AG)
A review. Ebola virus (EBOV) is a highly lethal pathogen that has caused several outbreaks of severe hemorrhagic fever in humans since its emergence in 1976. The EBOV glycoprotein (GP1,2) is the sole viral envelope protein and a major component of immunogenicity; it is encoded by the GP gene along with two truncated versions: sol. GP (sGP) and small sol. GP (ssGP). sGP is, in fact, the primary product of the GP gene, and it is secreted in abundance during EBOV infection. Since sGP shares large portions of its sequence with GP1,2, it has been hypothesized that sGP may subvert the host immune response by inducing antibodies against sGP rather than GP1,2. Several reports have shown that sGP plays multiple roles that contribute to the complex pathogenesis of EBOV. In this review, we focus on sGP and discuss its possible roles with regards to the pathogenesis of EBOV and the development of specific antiviral drugs.
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Volchkov, V. E.; Feldmann, H.; Volchkova, V. A.; Klenk, H.-D. Processing of the Ebola Virus Glycoprotein by the Proprotein Convertase Furin. Proc. Natl. Acad. Sci. U. S. A. 1998, 95 (10), 5762– 5767, DOI: 10.1073/pnas.95.10.5762
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77
Processing of the Ebola virus glycoprotein by the proprotein convertase furin
Volchkov, Viktor E.; Feldmann, Heinz; Volchkova, Valentina A.; Klenk, Hans-Dieter
Proceedings of the National Academy of Sciences of the United States of America (1998), 95 (10), 5762-5767CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
The authors investigated the processing and maturation of the envelope glycoprotein (GP) of Ebola virus. When GP expressed from vaccinia virus vectors was analyzed by pulse-chase expts., the mature form and two different precursors were identified. First, the endoplasmic reticulum form preGPer, full-length GP with oligomannosidic N-glycans, was detected. PreGPer (110 kDa) was replaced by the Golgi-specific form preGP (160 kDa), full-length GP contg. mature carbohydrates. PreGP was finally converted by proteolysis into mature GP1,2, which consisted of two disulfide-linked cleavage products, the amino-terminal 140-kDa fragment GP1, and the carboxyl-terminal 26-kDa fragment GP2. GP1,2 was also identified in Ebola virions. Studies employing site-directed mutagenesis revealed that GP was cleaved at a multibasic amino acid motif located at positions 497 to 501 of the ORF. Cleavage was blocked by a peptidyl chloromethylketone contg. such a motif. GP is cleaved by the proprotein convertase furin. This was indicated by the observation that cleavage did not occur when GP was expressed in furin-defective LoVo cells but that it was restored in these cells by vector-expressed furin. The Reston subtype, which differs from all other Ebola viruses by its low human pathogenicity, has a reduced cleavability due to a mutation at the cleavage site. As a result of these observations, it should now be considered that proteolytic processing of GP may be an important determinant for the pathogenicity of Ebola virus.
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Mühlberger, E. Filovirus Replication and Transcription. Future Virol. 2007, 2 (2), 205– 215, DOI: 10.2217/17460794.2.2.205
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78
Filovirus replication and transcription
Muehlberger, Elke
Future Virology (2007), 2 (2), 205-215CODEN: FVUIAM; ISSN:1746-0794. (Future Medicine Ltd.)
A review. The highly pathogenic filoviruses, Marburg and Ebola virus, belong to the nonsegmented neg.-sense RNA viruses of the order Mononegavirales. The mode of replication and transcription is similar for these viruses. On one hand, the neg.-sense RNA genome serves as a template for replication, to generate progeny genomes, and, on the other hand, for transcription, to produce mRNAs. Despite the similarities in the replication/transcription strategy, filoviruses have evolved structural and functional properties that are unique among the nonsegmented neg.-sense RNA viruses. Moreover, there are also striking differences in the replication and transcription mechanisms of Marburg and Ebola virus. This includes nucleocapsid formation, the structure of the genomic replication promoter, the protein requirement for transcription and the use of mRNA editing. In this article, the current knowledge of the replication and transcription strategy of Marburg and Ebola virus is reviewed, with focus on the obsd. differences.
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Noda, T.; Sagara, H.; Suzuki, E.; Takada, A.; Kida, H.; Kawaoka, Y. Ebola Virus VP40 Drives the Formation of Virus-Like Filamentous Particles Along with GP. J. Virol. 2002, 76 (10), 4855– 4865, DOI: 10.1128/JVI.76.10.4855-4865.2002
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79
Ebola virus VP40 drives the formation of virus-like filamentous particles along with GP
Noda, Takeshi; Sagara, Hiroshi; Suzuki, Emiko; Takada, Ayato; Kida, Hiroshi; Kawaoka, Yoshihiro
Journal of Virology (2002), 76 (10), 4855-4865CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
Using biochem. assays, it has been demonstrated that expression of Ebola virus VP40 alone in mammalian cells induced prodn. of particles with a d. similar to that of virions. To det. the morphol. properties of these particles, cells expressing VP40 and the particles released from the cells were examd. by electron microscopy. VP40 induced budding from the plasma membrane of filamentous particles, which differed in length but had uniform diams. of approx. 65 nm. When the Ebola virus glycoprotein (GP) responsible for receptor binding and membrane fusion was expressed in cells, we found pleomorphic particles budding from the plasma membrane. By contrast, when GP was coexpressed with VP40, GP was found on the filamentous particles induced by VP40. These results demonstrated the central role of VP40 in formation of the filamentous structure of Ebola virions and may suggest an interaction between VP40 and GP in morphogenesis.
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Coleman, C. M.; Frieman, M. B. Coronaviruses: Important Emerging Human Pathogens. J. Virol. 2014, 88 (10), 5209– 5212, DOI: 10.1128/JVI.03488-13
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80
Coronaviruses: important emerging human pathogens
Coleman, Christopher M.; Frieman, Matthew B.
Journal of Virology (2014), 88 (10), 5209-5212, 5 pp.CODEN: JOVIAM; ISSN:1098-5514. (American Society for Microbiology)
A review. The identification of Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 reaffirmed the importance of understanding how coronaviruses emerge, infect, and cause disease. By comparing what is known about severe acute respiratory syndrome coronavirus (SARS-CoV) to what has recently been found for MERS-CoV, researchers are discovering similarities and differences that may be important for pathogenesis. Here we discuss what is known about each virus and what gaps remain in our understanding, esp. concerning MERS-CoV.
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Wu, A.; Peng, Y.; Huang, B.; Ding, X.; Wang, X.; Niu, P.; Meng, J.; Zhu, Z.; Zhang, Z.; Wang, J.; Sheng, J.; Quan, L.; Xia, Z.; Tan, W.; Cheng, G.; Jiang, T. Genome Composition and Divergence of the Novel Coronavirus (2019-NCoV) Originating in China. Cell Host Microbe 2020, 27 (3), 325– 328, DOI: 10.1016/j.chom.2020.02.001
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81
Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China
Wu, Aiping; Peng, Yousong; Huang, Baoying; Ding, Xiao; Wang, Xianyue; Niu, Peihua; Meng, Jing; Zhu, Zhaozhong; Zhang, Zheng; Wang, Jiangyuan; Sheng, Jie; Quan, Lijun; Xia, Zanxian; Tan, Wenjie; Cheng, Genhong; Jiang, Taijiao
Cell Host & Microbe (2020), 27 (3), 325-328CODEN: CHMECB; ISSN:1931-3128. (Elsevier Inc.)
An in-depth annotation of the newly discovered coronavirus (2019-nCoV) genome has revealed differences between 2019-nCoV and severe acute respiratory syndrome (SARS) or SARS-like coronaviruses. A systematic comparison identified 380 amino acid substitutions between these coronaviruses, which may have caused functional and pathogenic divergence of 2019-nCoV.
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Sanchez, A.; Rollin, P. E. Complete Genome Sequence of an Ebola Virus (Sudan Species) Responsible for a 2000 Outbreak of Human Disease in Uganda. Virus Res. 2005, 113 (1), 16– 25, DOI: 10.1016/j.virusres.2005.03.028
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82
Complete genome sequence of an Ebola virus (Sudan species) responsible for a 2000 outbreak of human disease in Uganda
Sanchez, Anthony; Rollin, Pierre E.
Virus Research (2005), 113 (1), 16-25CODEN: VIREDF; ISSN:0168-1702. (Elsevier B.V.)
The entire genomic RNA of the Gulu (Uganda 2000) strain of Ebola virus was sequenced and compared to the genomes of other filoviruses. These data represents the first comprehensive genetic anal. for a representative isolate of the Sudan species of Ebola virus. The genome organization of the Sudan species is nearly identical to that of the Zaire species, but the presence of a gene overlap (between GP and VP30 genes) and a longer trailer sequence distinguish it from that of the Reston species. As has been obsd. with other filoviruses, stemloop structures were predicted to form at the 5' end of Ebola Sudan mRNA mols., and the genomic RNA termini showed a high degree of sequence complimentarity. Comparisons of the amino acid sequences of encoded gene products shows that there is a comparable level of identity or similarity between Ebola virus species, with Sudan and Zaire actually showing a slightly closer relationship to the Reston species than to one another. These comparisons also indicated that the VP24 is the most conserved Ebola virus protein (followed closely by the VP40 and L proteins), while the GP is the least conserved gene product. The most divergent regions were seen in the C-terminus of GP1 (mucin-like region) and within the C-terminal third of the nucleoprotein sequence.
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Feldmann, H.; Mühlberger, E.; Randolf, A.; Will, C.; Kiley, M. P.; Sanchez, A.; Klenk, H.-D. Marburg Virus, a Filovirus: Méssenger RNAs, Gene Order, and Regulatory Elements of the Replication Cycle. Virus Res. 1992, 24 (1), 1– 19, DOI: 10.1016/0168-1702(92)90027-7
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83
Marburg virus, a filovirus: messenger RNAs, gene order, and regulatory elements of the replication cycle
Feldmann, Heinz; Muehlberger, Elke; Randolf, Anke; Will, Christiane; Kiley, Michael P.; Sanchez, Anthony; Klenk, Hans Dieter
Virus Research (1992), 24 (1), 1-19CODEN: VIREDF; ISSN:0168-1702.
The genome of Marburg virus (MBG), a filovirus, is 19.1 kb in length and thus the largest one found with neg.-strand RNA viruses. The gene order - 3' untranslated region-NP-VP35-VP40-GP-VP30-VP24-L-5' untranslated region-resembles that of other non-segmented neg.-strand (NNS) RNA viruses. Six species of polyadenylated subgenomic RNAs, isolated from MBG-infected cells, are complementary to the neg.-strand RNA genome. They can be translated in vitro into the known structural proteins NP, GP (non-glycosylated form), VP40, VP35, VP30 and VP24. At the gene boundaries conserved transcriptional start (3'-NNCUNCNUNUAAUU-5') and stop signals (3'-UAAUUCUUUUU-5') are located contg. the highly conserved pentamer 3'-UAAUU-5'. Comparison with other NNS RNA viruses shows conservation primarily in the termination signals, whereas the start signals are more variable. The intergenic regions vary in length and nucleotide compn. All genes have relatively long 3' and 5' end non-coding regions. The putative 3' and 5' leader RNA sequences of the MBG genome resemble those of other NNS RNA viruses in length, conservation at the 3' and 5' ends, and in being complementary at their extremities. The data support the concept of a common taxonomic order Mononegavirales comprising the Filoviridae, Paramyxoviridae, and Rhabdoviridae families.
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Hoenen, T.; Groseth, A.; Feldmann, H. Therapeutic Strategies to Target the Ebola Virus Life Cycle. Nat. Rev. Microbiol. 2019, 17 (10), 593– 606, DOI: 10.1038/s41579-019-0233-2
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84
Therapeutic strategies to target the Ebola virus life cycle
Hoenen, Thomas; Groseth, Allison; Feldmann, Heinz
Nature Reviews Microbiology (2019), 17 (10), 593-606CODEN: NRMACK; ISSN:1740-1526. (Nature Research)
A review. Following the Ebola virus disease epidemic in west Africa, there has been increased awareness of the need for improved therapies for emerging diseases, including viral haemorrhagic fevers such as those caused by Ebola virus and other filoviruses. Our continually improving understanding of the virus life cycle coupled with the increased availability of 'omics' analyses and high-throughput screening technologies has enhanced our ability to identify potential viral and host factors and aspects involved in the infection process that might be intervention targets. In this Review we address compds. that have shown promise to various degrees in interfering with the filovirus life cycle, including monoclonal antibodies such as ZMapp, mAb114 and REGN-EB3 and inhibitors of viral RNA synthesis such as remdesivir and TKM-Ebola. Furthermore, we discuss the general potential of targeting aspects of the virus life cycle such as the entry process, viral RNA synthesis and gene expression, as well as morphogenesis and budding.
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García, L. L.; Padilla, L.; Castaño, J. C. Inhibitors Compounds of the Flavivirus Replication Process. Virol. J. 2017, 14 (1), 95, DOI: 10.1186/s12985-017-0761-1
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85
Inhibitors compounds of the flavivirus replication process
Garcia, Leidy L.; Padilla, Leonardo; Castano, Jhon C.
Virology Journal (2017), 14 (), 95/1-95/12CODEN: VJIOA4; ISSN:1743-422X. (BioMed Central Ltd.)
Flaviviruses are small viruses with single-stranded RNA, which include the yellow fever virus, dengue virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, and Zika virus; and are causal agents of the most important emerging diseases that have no available treatment to date. In recent years, the strategy has focused on the development of replication inhibitors of these viruses designed to act mainly by affecting the activity of enzyme proteins, such as NS3 and NS5, which perform important functions in the viral replication process. This article describes the importance of flaviviruses and the development of mols. used as inhibitors of viral replication in this genus.
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86
Islam, M. T.; Sarkar, C.; El-Kersh, D. M.; Jamaddar, S.; Uddin, S. J.; Shilpi, J. A.; Mubarak, M. S. Natural products and their derivatives against coronavirus: A review of the non-clinical and pre-clinical data. Phytother. Res. 2020, 34, 2471– 2492, DOI: 10.1002/ptr.6700
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86
Natural products and their derivatives against coronavirus: A review of the non-clinical and pre-clinical data
Islam, Muhammad T.; Sarkar, Chandan; El-Kersh, Dina M.; Jamaddar, Sarmin; Uddin, Shaikh J.; Shilpi, Jamil A.; Mubarak, Mohammad S.
Phytotherapy Research (2020), 34 (10), 2471-2492CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)
A review. Several corona viral infections have created serious threats in the last couple of decades claiming the death of thousands of human beings. Recently, corona viral epidemic raised the issue of developing effective antiviral agents at the earliest to prevent further losses. Natural products have always played a crucial role in drug development process against various diseases, which resulted in screening of such agents to combat emergent mutants of corona virus. This review focuses on those natural compds. that showed promising results against corona viruses. Although inhibition of viral replication is often considered as a general mechanism for antiviral activity of most of the natural products, studies have shown that some natural products can interact with key viral proteins that are assocd. with virulence. In this context, some of the natural products have antiviral activity in the nanomolar concn. (e.g., lycorine, homoharringtonine, silvestrol, ouabain, tylophorine, and 7-methoxycryptopleurine) and could be leads for further drug development on their own or as a template for drug design. In addn., a good no. of natural products with anti-corona virus activity are the major constituents of some common dietary supplements, which can be exploited to improve the immunity of the general population in certain epidemics.
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87
Ehrhardt, S. A.; Zehner, M.; Krähling, V.; Cohen-Dvashi, H.; Kreer, C.; Elad, N.; Gruell, H.; Ercanoglu, M. S.; Schommers, P.; Gieselmann, L.; Eggeling, R.; Dahlke, C.; Wolf, T.; Pfeifer, N.; Addo, M. M.; Diskin, R.; Becker, S.; Klein, F. Polyclonal and Convergent Antibody Response to Ebola Virus Vaccine RVSV-ZEBOV. Nat. Med. 2019, 25 (10), 1589– 1600, DOI: 10.1038/s41591-019-0602-4
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87
Polyclonal and convergent antibody response to Ebola virus vaccine rVSV-ZEBOV
Ehrhardt, Stefanie A.; Zehner, Matthias; Kraehling, Verena; Cohen-Dvashi, Hadas; Kreer, Christoph; Elad, Nadav; Gruell, Henning; Ercanoglu, Meryem S.; Schommers, Philipp; Gieselmann, Lutz; Eggeling, Ralf; Dahlke, Christine; Wolf, Timo; Pfeifer, Nico; Addo, Marylyn M.; Diskin, Ron; Becker, Stephan; Klein, Florian
Nature Medicine (New York, NY, United States) (2019), 25 (10), 1589-1600CODEN: NAMEFI; ISSN:1078-8956. (Nature Research)
Recombinant vesicular stomatitis virus-Zaire Ebola virus (rVSV-ZEBOV) is the most advanced Ebola virus vaccine candidate and is currently being used to combat the outbreak of Ebola virus disease (EVD) in the Democratic Republic of the Congo (DRC). Here we examine the humoral immune response in a subset of human volunteers enrolled in a phase 1 rVSV-ZEBOV vaccination trial by performing comprehensive single B cell and electron microscopy structure analyses. Four studied vaccinees show polyclonal, yet reproducible and convergent B cell responses with shared sequence characteristics. EBOV-targeting antibodies cross-react with other Ebolavirus species, and detailed epitope mapping revealed overlapping target epitopes with antibodies isolated from EVD survivors. Moreover, in all vaccinees, we detected highly potent EBOV-neutralizing antibodies with activities comparable or superior to the monoclonal antibodies currently used in clin. trials. These include antibodies combining the IGHV3-15/IGLV1-40 Ig gene segments that were identified in all investigated individuals. Our findings will help to evaluate and d.c. and future vaccination strategies and offer opportunities for novel EVD therapies.
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Bosch, B. J.; Martina, B. E. E.; van der Zee, R.; Lepault, J.; Haijema, B. J.; Versluis, C.; Heck, A. J. R.; de Groot, R.; Osterhaus, A. D. M. E.; Rottier, P. J. M. Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection Inhibition Using Spike Protein Heptad Repeat-Derived Peptides. Proc. Natl. Acad. Sci. U. S. A. 2004, 101 (22), 8455– 8460, DOI: 10.1073/pnas.0400576101
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88
Severe acute respiratory syndrome coronavirus (SARS-CoV) infection inhibition using spike protein heptad repeat-derived peptides
Bosch, Berend Jan; Martina, Byron E. E.; Van Der Zee, Ruurd; Lepault, Jean; Haijema, Bert Jan; Versluis, Cees; Heck, Albert J. R.; De Groot, Raoul; Osterhaus, Albert D. M. E.; Rottier, Peter J. M.
Proceedings of the National Academy of Sciences of the United States of America (2004), 101 (22), 8455-8460CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
The coronavirus SARS-CoV is the primary cause of the life-threatening severe acute respiratory syndrome (SARS). With the aim of developing therapeutic agents, we have tested peptides derived from the membrane-proximal (HR2) and membrane-distal (HR1) heptad repeat region of the spike protein as inhibitors of SARS-CoV infection of Vero cells. It appeared that HR2 peptides, but not HR1 peptides, were inhibitory. Their efficacy was, however, significantly lower than that of corresponding HR2 peptides of the murine coronavirus mouse hepatitis virus (MHV) in inhibiting MHV infection. Biochem. and electron microscopical analyses showed that, when mixed, SARS-CoV HR1 and HR2 peptides assemble into a six-helix bundle consisting of HR1 as a central triple-stranded coiled coil in assocn. with three HR2 α-helixes oriented in an antiparallel manner. The stability of this complex, as measured by its resistance to heat dissocn., appeared to be much lower than that of the corresponding MHV complex, which may explain the different inhibitory potencies of the HR2 peptides. Analogous to other class I viral fusion proteins, the six-helix complex supposedly represents a postfusion conformation that is formed after insertion of the fusion peptide, proposed here for coronaviruses to be located immediately upstream of HR1, into the target membrane. The resulting close apposition of fusion peptide and spike transmembrane domain facilitates membrane fusion. The inhibitory potency of the SARS-CoV HR2-peptides provides an attractive basis for the development of a therapeutic drug for SARS.
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Sainz, B.; Mossel, E. C.; Gallaher, W. R.; Wimley, W. C.; Peters, C. J.; Wilson, R. B.; Garry, R. F. Inhibition of Severe Acute Respiratory Syndrome-Associated Coronavirus (SARS-CoV) Infectivity by Peptides Analogous to the Viral Spike Protein. Virus Res. 2006, 120 (1), 146– 155, DOI: 10.1016/j.virusres.2006.03.001
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89
Inhibition of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infectivity by peptides analogous to the viral spike protein
Sainz, Bruno; Mossel, Eric C.; Gallaher, William R.; Wimley, William C.; Peters, C. J.; Wilson, Russell B.; Garry, Robert F.
Virus Research (2006), 120 (1-2), 146-155CODEN: VIREDF; ISSN:0168-1702. (Elsevier B.V.)
Severe acute respiratory syndrome-assocd. coronavirus (SARS-Co-V) is the cause of an atypical pneumonia that affected Asia, North America and Europe in 2002-2003. The viral spike (S) glycoprotein is responsible for mediating receptor binding and membrane fusion. Recent studies have proposed that the carboxyl terminal portion (S2 subunit) of the S protein is a class I viral fusion protein. The Wimley and White interfacial hydrophobicity scale was used to identify regions within the Co-V S2 subunit that may preferentially assoc. with lipid membranes with the premise that peptides analogous to these regions may function as inhibitors of viral infectivity. Five regions of high interfacial hydrophobicity spanning the length of the S2 subunit of SARS-Co-V and murine hepatitis virus (MHV) were identified. Peptides analogous to regions of the N-terminus or the pretransmembrane domain of the S2 subunit inhibited SARS-Co-V plaque formation by 40-70% at concns. of 15-30 μM. Interestingly, peptides analogous to the SARS-Co-V or MHV loop region inhibited viral plaque formation by >80% at similar concns. The obsd. effects were dose-dependent (IC50 values of 2-4 μM) and not a result of peptide-mediated cell cytotoxicity. The antiviral activity of the Co-V peptides tested provides an attractive basis for the development of new fusion peptide inhibitors corresponding to regions outside the fusion protein heptad repeat regions.
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Xia, S.; Liu, M.; Wang, C.; Xu, W.; Lan, Q.; Feng, S.; Qi, F.; Bao, L.; Du, L.; Liu, S.; Qin, C.; Sun, F.; Shi, Z.; Zhu, Y.; Jiang, S.; Lu, L. Inhibition of SARS-CoV-2 (Previously 2019-NCoV) Infection by a Highly Potent Pan-Coronavirus Fusion Inhibitor Targeting Its Spike Protein That Harbors a High Capacity to Mediate Membrane Fusion. Cell Res. 2020, 30 (4), 343– 355, DOI: 10.1038/s41422-020-0305-x
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90
Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
Xia, Shuai; Liu, Meiqin; Wang, Chao; Xu, Wei; Lan, Qiaoshuai; Feng, Siliang; Qi, Feifei; Bao, Linlin; Du, Lanying; Liu, Shuwen; Qin, Chuan; Sun, Fei; Shi, Zhengli; Zhu, Yun; Jiang, Shibo; Lu, Lu
Cell Research (2020), 30 (4), 343-355CODEN: CREEB6; ISSN:1001-0602. (Nature Research)
The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the mol. mechanism that underlies viral infection must first be defined. Therefore, we herein established a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that SARS-CoV-2 showed a superior plasma membrane fusion capacity compared to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in the SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be assocd. with enhanced interactions with the HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted the HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. Here we generated a series of lipopeptides derived from EK1 and found that EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than the original EK1 peptide, resp. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, and potently inhibited the replication of 5 live human coronaviruses examd., including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by the currently circulating SARS-CoV-2 and other emerging SARSr-CoVs.
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Ho, T.-Y.; Wu, S.-L.; Chen, J.-C.; Li, C.-C.; Hsiang, C.-Y. Emodin Blocks the SARS Coronavirus Spike Protein and Angiotensin-Converting Enzyme 2 Interaction. Antiviral Res. 2007, 74 (2), 92– 101, DOI: 10.1016/j.antiviral.2006.04.014
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91
Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction
Ho, Tin-Yun; Wu, Shih-Lu; Chen, Jaw-Chyun; Li, Chia-Cheng; Hsiang, Chien-Yun
Antiviral Research (2007), 74 (2), 92-101CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
Severe acute respiratory syndrome (SARS) is an emerging infectious disease caused by a novel coronavirus (SARS-CoV). SARS-CoV spike (S) protein, a type I membrane-bound protein, is essential for the viral attachment to the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening 312 controlled Chinese medicinal herbs supervised by Committee on Chinese Medicine and Pharmacy at Taiwan, we identified that three widely used Chinese medicinal herbs of the family Polygonaceae inhibited the interaction of SARS-CoV S protein and ACE2. The IC50 values for Radix et Rhizoma Rhei (the root tubers of Rheum officinale Baill.), Radix Polygoni multiflori (the root tubers of Polygonum multiflorum Thunb.), and Caulis Polygoni multiflori (the vines of P. multiflorum Thunb.) ranged from 1 to 10 μg/mL. Emodin, an anthraquinone compd. derived from genus Rheum and Polygonum, significantly blocked the S protein and ACE2 interaction in a dose-dependent manner. It also inhibited the infectivity of S protein-pseudotyped retrovirus to Vero E6 cells. These findings suggested that emodin may be considered as a potential lead therapeutic agent in the treatment of SARS.
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92
O’Keefe, B. R.; Giomarelli, B.; Barnard, D. L.; Shenoy, S. R.; Chan, P. K. S.; McMahon, J. B.; Palmer, K. E.; Barnett, B. W.; Meyerholz, D. K.; Wohlford-Lenane, C. L.; McCray, P. B. Broad-Spectrum In Vitro Activity and In Vivo Efficacy of the Antiviral Protein Griffithsin against Emerging Viruses of the Family Coronaviridae. J. Virol. 2010, 84 (5), 2511– 2521, DOI: 10.1128/JVI.02322-09
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92
Broad-spectrum in vitro activity and in vivo efficacy of the antiviral protein griffithsin against emerging viruses of the family Coronaviridae
O'Keefe Barry R; Giomarelli Barbara; Barnard Dale L; Shenoy Shilpa R; Chan Paul K S; McMahon James B; Palmer Kenneth E; Barnett Brian W; Meyerholz David K; Wohlford-Lenane Christine L; McCray Paul B Jr
Journal of virology (2010), 84 (5), 2511-21 ISSN:.
Viruses of the family Coronaviridae have recently emerged through zoonotic transmission to become serious human pathogens. The pathogenic agent responsible for severe acute respiratory syndrome (SARS), the SARS coronavirus (SARS-CoV), is a member of this large family of positive-strand RNA viruses that cause a spectrum of disease in humans, other mammals, and birds. Since the publicized outbreaks of SARS in China and Canada in 2002-2003, significant efforts successfully identified the causative agent, host cell receptor(s), and many of the pathogenic mechanisms underlying SARS. With this greater understanding of SARS-CoV biology, many researchers have sought to identify agents for the treatment of SARS. Here we report the utility of the potent antiviral protein griffithsin (GRFT) in the prevention of SARS-CoV infection both in vitro and in vivo. We also show that GRFT specifically binds to the SARS-CoV spike glycoprotein and inhibits viral entry. In addition, we report the activity of GRFT against a variety of additional coronaviruses that infect humans, other mammals, and birds. Finally, we show that GRFT treatment has a positive effect on morbidity and mortality in a lethal infection model using a mouse-adapted SARS-CoV and also specifically inhibits deleterious aspects of the host immunological response to SARS infection in mammals.
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Lee, C. Griffithsin, a Highly Potent Broad-Spectrum Antiviral Lectin from Red Algae: From Discovery to Clinical Application. Mar. Drugs 2019, 17 (10), 567, DOI: 10.3390/md17100567
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93
Griffithsin, a highly potent broad-spectrum antiviral lectin from red algae: from discovery to clinical application
Lee, Choongho
Marine Drugs (2019), 17 (10), 567CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)
Virus entry into a susceptible host cell is the first step in the formation of all viral diseases. Controlling viral infections by disrupting viral entry is advantageous for antibody-mediated neutralization by the host's immune system and as a preventive and therapeutic antiviral strategy. Recently, several plant-derived carbohydrate-binding proteins (lectins) have emerged as a new class of antiviral biologics by taking advantage of a unique glycosylation pattern only found on the surface of viruses. In particular, a red algae-derived griffithsin (GRFT) protein has demonstrated superior in vitro and in vivo antiviral activity with min. host toxicity against a variety of clin. relevant, enveloped viruses. Its in vitro antiviral profiles against human immunodeficiency virus (HIV) are also discussed followed by a description of the results from a combination study using anti-HIV drugs. The results of several studies regarding its novel antiviral mechanism of action are provided in conjunction with an explanation of viral resistance profiles to GRFT. In addn., its in vitro and in vivo host toxicity profiles are summarized with its pharmacokinetic behavior using in vivo efficacy study results. Also, a large-scale prodn. and formulation strategy, as well as a drug delivery strategy, for GRFT as a new class of broad-spectrum microbicides is discussed. Finally, results from two ongoing clin. studies examg. GRFT's effects on viruses are presented.
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Soto-Acosta, R.; Bautista-Carbajal, P.; Syed, G. H.; Siddiqui, A.; Del Angel, R. M. Nordihydroguaiaretic Acid (NDGA) Inhibits Replication and Viral Morphogenesis of Dengue Virus. Antiviral Res. 2014, 109, 132– 140, DOI: 10.1016/j.antiviral.2014.07.002
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94
Nordihydroguaiaretic acid (NDGA) inhibits replication and viral morphogenesis of dengue virus
Soto-Acosta, Ruben; Bautista-Carbajal, Patricia; Syed, Gulam H.; Siddiqui, Aleem; Del Angel, Rosa M.
Antiviral Research (2014), 109 (), 132-140CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
Dengue is the most common mosquito borne viral disease in humans. The infection with any of the 4 dengue virus serotypes (DENV) can either be asymptomatic or manifest in two clin. forms, the mild dengue fever or the more severe dengue hemorrhagic fever that may progress into dengue shock syndrome. A DENV replicative cycle relies on host lipid metab.; specifically, DENV infection modulates cholesterol and fatty acid synthesis, generating a lipid-enriched cellular environment necessary for viral replication. Thus, the aim of this work was to evaluate the anti-DENV effect of the Nordihydroguaiaretic acid (NDGA), a hypolipidemic agent with antioxidant and anti-inflammatory properties. A dose-dependent inhibition in viral yield and NS1 secretion was obsd. in supernatants of infected cells treated for 24 and 48 h with different concns. of NDGA. To evaluate the effect of NDGA in DENV replication, a DENV4 replicon transfected Vero cells were treated with different concns. of NDGA. NDGA treatment significantly reduced DENV replication, reiterating the importance of lipids in viral replication. NDGA treatment also led to redn. in no. of lipid droplets (LDs), the neutral lipid storage organelles involved in DENV morphogenesis that are known to increase in no. during DENV infection. Furthermore, NDGA treatment resulted in dissocn. of the C protein from LDs. Overall our results suggest that NDGA inhibits DENV infection by targeting genome replication and viral assembly.
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Braun, E.; Sauter, D. Furin-mediated Protein Processing in Infectious Diseases and Cancer. Clin. Transl. Immunol. 2019, 8 (8), DOI: 10.1002/cti2.1073 .
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96
Modhiran, N.; Gandhi, N. S.; Wimmer, N.; Cheung, S.; Stacey, K.; Young, P. R.; Ferro, V.; Watterson, D. Dual Targeting of Dengue Virus Virions and NS1 Protein with the Heparan Sulfate Mimic PG545. Antiviral Res. 2019, 168, 121– 127, DOI: 10.1016/j.antiviral.2019.05.004
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96
Dual targeting of dengue virus virions and NS1 protein with the heparan sulfate mimic PG545
Modhiran, Naphak; Gandhi, Neha S.; Wimmer, Norbert; Cheung, Stacey; Stacey, Katryn; Young, Paul R.; Ferro, Vito; Watterson, Daniel
Antiviral Research (2019), 168 (), 121-127CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
Dengue virus (DENV) is the most prevalent mosquito-borne flavivirus that infects humans. At present, there are no specific antiviral drugs to treat DENV infection and vaccine development has met with challenges. DENV encodes two glycosaminoglycan (GAG) binding proteins; Envelope (E) and non-structural protein 1 (NS1). While previous work has validated the use of GAG analogs as inhibitors of E mediated virus-cell attachment, their potential for antiviral intervention in NS1 protein toxicity has not yet been explored. Here, we investigate the potential of the heparan sulfate mimetic PG545 as a dual purpose compd. to target both DENV virion infectivity and NS1 function. In comparison to a non-sulfated analog, we show that PG545 potently inhibits DENV infectivity with no cytotoxic effect. Against NS1, PG545 completely blocks the induction of cellular activation and abolishes NS1-mediated disruption of endothelial monolayer integrity. Furthermore, PG545 treatment moderately improves survival from lethal DENV challenge in a murine model. At peak disease, PG545-treated mice have lower viremia, circulating NS1 and serum TNF-a. Consistent with anti-NS1 activity, PG545 treatment also reduces systemic vascular leakage caused by DENV infection in vivo. Taken together, these findings demonstrate that the dual targeting of DENV virions and NS1 using GAG analogs offers a new avenue for DENV drug development.
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97
Cui, Q.; Du, R.; Anantpadma, M.; Schafer, A.; Hou, L.; Tian, J.; Davey, R. A.; Cheng, H.; Rong, L. Identification of Ellagic Acid from Plant Rhodiola Rosea L. as an Anti-Ebola Virus Entry Inhibitor. Viruses 2018, 10 (4), 152, DOI: 10.3390/v10040152
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97
Identification of ellagic acid from plant Rhodiola rosea L. as an anti-Ebola virus entry inhibitor
Cui, Qinghua; Du, Ruikun; Anantpadma, Manu; Schafer, Adam; Hou, Lin; Tian, Jingzhen; Davey, Robert A.; Cheng, Han; Rong, Lijun
Viruses (2018), 10 (4), 152/1-152/12CODEN: VIRUBR; ISSN:1999-4915. (MDPI AG)
The recent 2014-2016 West African Ebola virus epidemic underscores the need for the development of novel anti-Ebola therapeutics, due to the high mortality rates of Ebola virus infections and the lack of FDA-approved vaccine or therapy that is available for the prevention and treatment. Traditional Chinese medicines (TCMs) represent a huge reservoir of bioactive chems. and many TCMs have been shown to have antiviral activities. 373 exts. from 128 TCMs were evaluated using a high throughput assay to screen for inhibitors of Ebola virus cell entry. Ext. of Rhodiola rosea displayed specific and potent inhibition against cell entry of both Ebola virus and Marburg virus. In addn., twenty com. compds. that were isolated from Rhodiola rosea were evaluated using the pseudotyped Ebola virus entry assay, and it was found that ellagic acid and gallic acid, which are two structurally related compds., are the most effective ones. The activity of the ext. and the two pure compds. were validated using infectious Ebola virus. The time-of-addn. expts. suggest that, mechanistically, the Rhodiola rosea ext. and the effective compds. act at an early step in the infection cycle following initial cell attachment, but prior to viral/cell membrane fusion. Our findings provide evidence that Rhodiola rosea has potent anti-filovirus properties that may be developed as a novel anti-Ebola treatment.
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98
Cheng, H.; Lear-Rooney, C. M.; Johansen, L.; Varhegyi, E.; Chen, Z. W.; Olinger, G. G.; Rong, L. Inhibition of Ebola and Marburg Virus Entry by G Protein-Coupled Receptor Antagonists. J. Virol. 2015, 89 (19), 9932– 9938, DOI: 10.1128/JVI.01337-15
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98
Inhibition of Ebola and Marburg virus entry by G protein-coupled receptor antagonists
Cheng, Han; Lear-Rooney, Calli M.; Johansen, Lisa; Varhegyi, Elizabeth; Chen, Zheng W.; Olinger, Gene G.; Rong, Lijun
Journal of Virology (2015), 89 (19), 9932-9938CODEN: JOVIAM; ISSN:1098-5514. (American Society for Microbiology)
Filoviruses, consisting of Ebola virus (EBOV) and Marburg virus (MARV), are among the most lethal infectious threats to mankind. Infections by these viruses can cause severe hemorrhagic fevers in humans and nonhuman primates with high mortality rates. Since there is currently no vaccine or antiviral therapy approved for humans, there is an urgent need to develop prophylactic and therapeutic options for use during filoviral outbreaks and bioterrorist attacks. One of the ideal targets against filoviral infection and diseases is at the entry step, which is mediated by the filoviral glycoprotein (GP). In this report, we screened a chem. library of small mols. and identified numerous inhibitors, which are known G protein-coupled receptor (GPCR) antagonists targeting different GPCRs, including histamine receptors, 5-HT (serotonin) receptors, muscarinic acetylcholine receptor, and adrenergic receptor. These inhibitors can effectively block replication of both infectious EBOV and MARV, indicating a broad antiviral activity of the GPCR antagonists. The time-of-addn. expt. and microscopic studies suggest that GPCR antagonists block filoviral entry at a step following the initial attachment but prior to viral/cell membrane fusion. These results strongly suggest that GPCRs play a crit. role in filoviral entry and GPCR antagonists can be developed as an effective anti-EBOV/MARV therapy.
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99
Si, L.; Meng, K.; Tian, Z.; Sun, J.; Li, H.; Zhang, Z.; Soloveva, V.; Li, H.; Fu, G.; Xia, Q.; Xiao, S.; Zhang, L.; Zhou, D. Triterpenoids Manipulate a Broad Range of Virus-Host Fusion via Wrapping the HR2 Domain Prevalent in Viral Envelopes. Sci. Adv. 2018, 4 (11), eaau8408, DOI: 10.1126/sciadv.aau8408
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There is no corresponding record for this reference.
100
Kononova, A. A.; Sokolova, A. S.; Cheresiz, S. V.; Yarovaya, O. I.; Nikitina, R. A.; Chepurnov, A. A.; Pokrovsky, A. G.; Salakhutdinov, N. F. N-Heterocyclic Borneol Derivatives as Inhibitors of Marburg Virus Glycoprotein-Mediated VSIV Pseudotype Entry. MedChemComm 2017, 8 (12), 2233– 2237, DOI: 10.1039/C7MD00424A
[Crossref], [PubMed], [CAS], Google Scholar
100
N-Heterocyclic borneol derivatives as inhibitors of Marburg virus glycoprotein-mediated VSIV pseudotype entry
Kononova, A. A.; Sokolova, A. S.; Cheresiz, S. V.; Yarovaya, O. I.; Nikitina, R. A.; Chepurnov, A. A.; Pokrovsky, A. G.; Salakhutdinov, N. F.
MedChemComm (2017), 8 (12), 2233-2237CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
There is currently no approved antiviral therapy for treatment of Marburg virus disease (MVD). Although filovirus infection outbreaks are quite rare, the high mortality rates in such outbreaks make the development of anti-filoviral drugs an important goal of medical chem. and virol. Here, we performed screening of a large library of natural derivs. for their virus entry inhibition activity using pseudotype systems. The bornyl ester derivs. contg. satd. N-heterocycles exhibited the highest antiviral activity. It is supposed that compds. with specific inhibitory activity toward MarV-GP-dependent virus entry will inhibit the rVSIV-ΔG-MarV-GP pseudotype much more efficiently than the control rVSIV-ΔG-G pseudotype. At the same time, the compds. similarly inhibiting both pseudotypes will likely affect rVSIV capsid replication or the cellular mechanisms common to the entry of both viruses. Borneol itself is not active against both pseudotypes and is nontoxic, whereas its derivs. have varying toxicity and antiviral activity. Among low-toxic borneol derivs., six compds. turned out to be relatively specific inhibitors of MarV-GP-mediated infection (SC > 10). Of them, compd. 6 contg. a methylpiperidine moiety exhibited the highest virus-specific activity. Notably, the virus-specific activity of this compd. is twice as high as that of the ref.
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Boyd, M. R. Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating protein that binds viral surface envelope glycoprotein gp120: potential applications to microbicide development. Antimicrob. Agents Chemother. 1997, 41, 1521– 1530, DOI: 10.1128/AAC.41.7.1521
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101
Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating protein that binds viral surface envelope glycoprotein gp120: potential applications to microbicide development
Boyd, Michael R.; Gustafson, Kirk R.; Mcmahon, James B.; Shoemaker, Robert H.; O'Keefe, Barry R.; Mori, Toshiyuki; Gulakowski, Robert J.; Wu, Lin; Rivera, Maria I.; Laurencot, Carolyn M.; Currens, Michael J.; Cardellina, John H., II; Buckheit, Robert W., Jr.; Nara, Peter L.; Pannell, Lewis K.; Sowder, Raymond C., II; Henderson, Louis E.
Antimicrobial Agents and Chemotherapy (1997), 41 (7), 1521-1530CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
We have isolated and sequenced a novel 11-kDa virucidal protein, named cyanovirin-N (CV-N), from cultures of the cyanobacterium (blue-green alga) Nostoc ellipsosporum. We also have produced CV-N recombinantly by expression of a corresponding DNA sequence in Escherichia coli. Low nanomolar concns. of either natural or recombinant CV-N irreversibly inactivate diverse lab. strains and primary isolates of human immunodeficiency virus (HIV) type 1 as well as strains of HIV type 2 and simian immunodeficiency virus. In addn., CV-N aborts cell-to-cell fusion and transmission of HIV-1 infection. Continuous, 2-day exposures of uninfected CEM-SS cells or peripheral blood lymphocytes to high concns. (e.g., 9000 nM) of CV-N were not lethal to these representative host cell types. The antiviral activity of CV-N is due, at least in part, to unique, high-affinity interactions of CV-N with the viral surface envelope glycoprotein gp120. The biol. activity of CV-N is highly resistant to physicochem. denaturation, further enhancing its potential as an anti-HIV microbicide.
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102
Barrientos, L. G. Cyanovirin-N binds to the viral surface glycoprotein, GP1,2 and inhibits infectivity of Ebola virus. Antiviral Res. 2003, 58, 47– 56, DOI: 10.1016/S0166-3542(02)00183-3
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102
Cyanovirin-N binds to the viral surface glycoprotein, GP1,2 and inhibits infectivity of Ebola virus
Barrientos, Laura G.; O'Keefe, Barry R.; Bray, Mike; Sanchez, Anthony; Gronenborn, Angela M.; Boyd, Michael R.
Antiviral Research (2003), 58 (1), 47-56CODEN: ARSRDR; ISSN:0166-3542. (Elsevier Science B.V.)
Ebola virus (Ebo) causes severe hemorrhagic fever and high mortality in humans. There are currently no effective therapies. Here, the authors have explored potential anti-Ebo activity of the human immunodeficiency virus (HIV)-inactivating protein cyanovirin-N (CV-N). CV-N is known to potently inhibit the infectivity of a broad spectrum of HIV strains at the level of viral entry. This involves CV-N binding to N-linked high-mannose oligossacharides on the viral glycoprotein gp120. The Ebola envelope contains somewhat similar oligosaccharide constituents, suggesting possible susceptibility to inhibition by CV-N. Our initial results revealed that CV-N had both in vitro and in vivo antiviral activity against the Zaire strain of the Ebola virus (Ebo-Z). Addn. of CV-N to the cell culture medium at the time of Ebo-Z infection inhibited the development of viral cytopathic effects (CPEs). CV-N also delayed the death of Ebo-Z-infected mice, both when given as a series of daily s.c. injections and when the virus was incubated ex vivo together with CV-N before inoculation into the mice. Furthermore, similar to earlier results with HIV gp120, CV-N bound with considerable affinity to the Ebola surface envelope glycoprotein, GP1,2. Competition expts. with free oligosaccharides were consistent with the view that carbohydrate-mediated CV-N/GP1,2 interactions involve oligosaccharides residing on the Ebola viral envelope. Overall, these studies broaden the range of viruses known to be inhibited by CV-N, and further implicate carbohydrate moieties on viral surface proteins as common viral mol. targets for this novel protein.
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103
Báez-Santos, Y. M.; St. John, S. E.; Mesecar, A. D. The SARS-Coronavirus Papain-like Protease: Structure, Function and Inhibition by Designed Antiviral Compounds. Antiviral Res. 2015, 115, 21– 38, DOI: 10.1016/j.antiviral.2014.12.015
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103
The SARS-coronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds
Baez-Santos, Yahira M.; St. John, Sarah E.; Mesecar, Andrew D.
Antiviral Research (2015), 115 (), 21-38CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
A review. Over 10 years have passed since the deadly human coronavirus that causes severe acute respiratory syndrome (SARS-CoV) emerged from the Guangdong Province of China. Despite the fact that the SARS-CoV pandemic infected over 8500 individuals, claimed over 800 lives and cost billions of dollars in economic loss worldwide, there still are no clin. approved antiviral drugs, vaccines or monoclonal antibody therapies to treat SARS-CoV infections. The recent emergence of the deadly human coronavirus that causes Middle East respiratory syndrome (MERS-CoV) is a sobering reminder that new and deadly coronaviruses can emerge at any time with the potential to become pandemics. Therefore, the continued development of therapeutic and prophylactic countermeasures to potentially deadly coronaviruses is warranted. The coronaviral proteases, papain-like protease (PLpro) and 3C-like protease (3CLpro), are attractive antiviral drug targets because they are essential for coronaviral replication. Although the primary function of PLpro and 3CLpro are to process the viral polyprotein in a coordinated manner, PLpro has the addnl. function of stripping ubiquitin and ISG15 from host-cell proteins to aid coronaviruses in their evasion of the host innate immune responses. Therefore, targeting PLpro with antiviral drugs may have an advantage in not only inhibiting viral replication but also inhibiting the dysregulation of signaling cascades in infected cells that may lead to cell death in surrounding, uninfected cells. This review provides an up-to-date discussion on the SARS-CoV papain-like protease including a brief overview of the SARS-CoV genome and replication followed by a more in-depth discussion on the structure and catalytic mechanism of SARS-CoV PLpro, the multiple cellular functions of SARS-CoV PLpro, the inhibition of SARS-CoV PLpro by small mol. inhibitors, and the prospect of inhibiting papain-like protease from other coronaviruses. This paper forms part of a series of invited articles in Antiviral Research on "From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses.".
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104
Jo, S.; Kim, S.; Shin, D. H.; Kim, M.-S. Inhibition of SARS-CoV 3CL Protease by Flavonoids. J. Enzyme Inhib. Med. Chem. 2020, 35 (1), 145– 151, DOI: 10.1080/14756366.2019.1690480
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104
Inhibition of SARS-CoV 3CL protease by flavonoids
Jo, Seri; Kim, Suwon; Shin, Dong Hae; Kim, Mi-Sun
Journal of Enzyme Inhibition and Medicinal Chemistry (2020), 35 (1), 145-151CODEN: JEIMAZ; ISSN:1475-6366. (Taylor & Francis Ltd.)
There were severe panics caused by severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) and Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV). Therefore, researches targeting these viruses have been required. Coronaviruses (CoVs) have been rising targets of some flavonoids. The antiviral activity of some flavonoids against CoVs is presumed directly caused by inhibiting 3C-like protease (3CLpro). Here, the authors applied a flavonoid library to systematically probe inhibitory compds. against SARS-CoV 3CLpro. Herbacetin, rhoifolin and pectolinarin were found to efficiently block the enzymic activity of SARS-CoV 3CLpro. The interaction of the three flavonoids was confirmed using a tryptophan-based fluorescence method, too. An induced-fit docking anal. indicated that S1, S2 and S3' sites are involved in binding with flavonoids. The comparison with previous studies showed that Triton X-100 played a crit. role in objecting false pos. or overestimated inhibitory activity of flavonoids. With the systematic anal., the three flavonoids are suggested to be templates to design functionally improved inhibitors.
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105
Wu, C.-Y.; Jan, J.-T.; Ma, S.-H.; Kuo, C.-J.; Juan, H.-F.; Cheng, Y.-S. E.; Hsu, H.-H.; Huang, H.-C.; Wu, D.; Brik, A.; Liang, F.-S.; Liu, R.-S.; Fang, J.-M.; Chen, S.-T.; Liang, P.-H.; Wong, C.-H. Small Molecules Targeting Severe Acute Respiratory Syndrome Human Coronavirus. Proc. Natl. Acad. Sci. U. S. A. 2004, 101 (27), 10012– 10017, DOI: 10.1073/pnas.0403596101
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105
Small molecules targeting severe acute respiratory syndrome human coronavirus
Wu, Chung-Yi; Jan, Jia-Tsrong; Ma, Shiou-Hwa; Kuo, Chih-Jung; Juan, Hsueh-Fen; Cheng, Yih-Shyun E.; Hsu, Hsien-Hua; Huang, Hsuan-Cheng; Wu, Douglass; Brik, Ashraf; Liang, Fu-Sen; Liu, Rai-Shung; Fang, Jim-Min; Chen, Shui-Tein; Liang, Po-Huang; Wong, Chi-Huey
Proceedings of the National Academy of Sciences of the United States of America (2004), 101 (27), 10012-10017CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
Severe acute respiratory syndrome (SARS) is an infectious disease caused by a novel human coronavirus. Currently, no effective antiviral agents exist against this type of virus. A cell-based assay, with SARS virus and Vero E6 cells, was developed to screen existing drugs, natural products, and synthetic compds. to identify effective anti-SARS agents. Of > 10,000 agents tested, ≈50 compds. were found active at 10 μM; among these compds., two are existing drugs (Reserpine and Aescin) and several are in clin. development. These 50 active compds. were tested again, and compds. 2-6, 10, and 13 showed active at 3 μM. The 50% inhibitory concns. for the inhibition of viral replication (EC50) and host growth (CC50) were then measured and the selectivity index (SI = CC50/EC50) was detd. The EC50, based on ELISA, and SI for Reserpine, Aescin, and Valinomycin are 3.4 μM (SI = 7.3), 6.0 μM (SI = 2.5), and 0.85 μM (SI = 80), resp. Addnl. studies were carried out to further understand the mode of action of some active compds., including ELISA, Western blot anal., immunofluorescence and flow cytometry assays, and inhibition against the 3CL protease and viral entry. Of particular interest are the two anti-HIV agents, one as an entry blocker and the other as a 3CL protease inhibitor (Ki = 0.6 μM).
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106
Cho, J. K.; Curtis-Long, M. J.; Lee, K. H.; Kim, D. W.; Ryu, H. W.; Yuk, H. J.; Park, K. H. Geranylated Flavonoids Displaying SARS-CoV Papain-like Protease Inhibition from the Fruits of Paulownia Tomentosa. Bioorg. Med. Chem. 2013, 21 (11), 3051– 3057, DOI: 10.1016/j.bmc.2013.03.027
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106
Geranylated flavonoids displaying SARS-CoV papain-like protease inhibition from the fruits of Paulownia tomentosa
Cho, Jung Keun; Curtis-Long, Marcus J.; Lee, Kon Ho; Kim, Dae Wook; Ryu, Hyung Won; Yuk, Heung Joo; Park, Ki Hun
Bioorganic & Medicinal Chemistry (2013), 21 (11), 3051-3057CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
SARS-CoV papain-like protease (PLpro) is an important antiviral target due to its key roles in SARS virus replication. The MeOH exts. of the fruits of the Paulownia tree yielded many small mols. capable of targeting PLpro. Five of these compds. were new geranylated flavonoids, tomentin A, tomentin B, tomentin C, tomentin D, tomentin E (1-5). Structure anal. of new compds. (1-5) by NMR showed that they all contain a 3,4-dihydro-2H-pyran moiety. This chemotype is very rare and is derived from cyclization of a geranyl group with a phenol functionality. Most compds. (1-12) inhibited PLpro in a dose dependent manner with IC50's raging between 5.0 and 14.4 μM. All new compds. having the dihydro-2H-pyran group showed better inhibition than their parent compds. (1 vs 11, 2 vs 9, 4 vs 12, 5 vs 6). In kinetic studies, 1-12 emerged to be reversible, mixed inhibitors.
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107
Park, J.-Y.; Jeong, H. J.; Kim, J. H.; Kim, Y. M.; Park, S.-J.; Kim, D.; Park, K. H.; Lee, W. S.; Ryu, Y. B. Diarylheptanoids from Alnus Japonica Inhibit Papain-Like Protease of Severe Acute Respiratory Syndrome Coronavirus. Biol. Pharm. Bull. 2012, 35, advpub, DOI: 10.1248/bpb.b12-00623
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There is no corresponding record for this reference.
108
Park, J.-Y.; Kim, J. H.; Kim, Y. M.; Jeong, H. J.; Kim, D. W.; Park, K. H.; Kwon, H.-J.; Park, S.-J.; Lee, W. S.; Ryu, Y. B. Tanshinones as Selective and Slow-Binding Inhibitors for SARS-CoV Cysteine Proteases. Bioorg. Med. Chem. 2012, 20 (19), 5928– 5935, DOI: 10.1016/j.bmc.2012.07.038
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108
Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases
Park, Ji-Young; Kim, Jang Hoon; Kim, Young Min; Jeong, Hyung Jae; Kim, Dae Wook; Park, Ki Hun; Kwon, Hyung-Jun; Park, Su-Jin; Lee, Woo Song; Ryu, Young Bae
Bioorganic & Medicinal Chemistry (2012), 20 (19), 5928-5935CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
In the search for anti-SARS-CoV, tanshinones derived from Salvia miltiorrhiza were found to be specific and selective inhibitors for the SARS-CoV 3CLpro and PLpro, viral cysteine proteases. A literature search for studies involving the seven isolated tanshinone hits showed that at present, none have been identified as coronaviral protease inhibitors. We have identified that all of the isolated tanshinones are good inhibitors of both cysteine proteases. However, their activity was slightly affected by subtle changes in structure and targeting enzymes. All isolated compds. (1-7) act as time dependent inhibitors of PLpro, but no improved inhibition was obsd. following preincubation with the 3CLpro. In a detail kinetic mechanism study, all of the tanshinones except rosmariquinone (7) were identified as noncompetitive enzyme isomerization inhibitors. However, rosmariquinone (7) showed a different kinetic mechanism through mixed-type simple reversible slow-binding inhibition. Furthermore, tanshinone I (5) exhibited the most potent nanomolar level inhibitory activity toward deubiquitinating (IC50 = 0.7 μM). Addnl., the inhibition is selective because these compds. do not exert significant inhibitory effects against other proteases including chymotrysin, papain, and HIV protease. These findings provide potential inhibitors for SARS-CoV viral infection and replication.
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109
Kim, D. W.; Seo, K. H.; Curtis-Long, M. J.; Oh, K. Y.; Oh, J.-W.; Cho, J. K.; Lee, K. H.; Park, K. H. Phenolic Phytochemical Displaying SARS-CoV Papain-like Protease Inhibition from the Seeds of Psoralea Corylifolia. J. Enzyme Inhib. Med. Chem. 2014, 29 (1), 59– 63, DOI: 10.3109/14756366.2012.753591
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109
Phenolic phytochemical displaying SARS-CoV papain-like protease inhibition from the seeds of Psoralea corylifolia
Kim, Dae Wook; Seo, Kyung Hye; Curtis-Long, Marcus J.; Oh, Kyeong Yeol; Oh, Jong-Won; Cho, Jung Keun; Lee, Kon Ho; Park, Ki Hun
Journal of Enzyme Inhibition and Medicinal Chemistry (2014), 29 (1), 59-63CODEN: JEIMAZ; ISSN:1475-6366. (Informa Healthcare)
Severe acute respiratory syndrome coronavirus (SARS-CoV) papain-like protease (PLpro) is a key enzyme that plays an important role in SARS virus replication. The ethanol ext. of the seeds of Psoralea corylifolia showed high activity against the SARS-CoV PLpro with an IC50 of value of 15 μg/mL. Due to its potency, subsequent bioactivity-guided fractionation of the ethanol ext. led to six arom. compds. (1-6), which were identified as bavachinin (1), neobavaisoflavone (2), isobavachalcone (3), 4'-O-methylbavachalcone (4), psoralidin (5) and corylifol A (6). All isolated flavonoids (1-6) inhibited PLpro in a dose-dependent manner with IC50 ranging between 4.2 and 38.4 μM. Lineweaver-Burk and Dixon plots and their secondary replots indicated that inhibitors (1-6) were mixed inhibitors of PLpro. The anal. of KI and KIS values proved that the two most promising compds. (3 and 5) had reversible mixed type I mechanisms.
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110
Sayed, A. M.; Khattab, A. R.; AboulMagd, A. M.; Hassan, H. M.; Rateb, M. E.; Zaid, H.; Abdelmohsen, U. R. Nature as a Treasure Trove of Potential Anti-SARS-CoV Drug Leads: A Structural/Mechanistic Rationale. RSC Adv. 2020, 10 (34), 19790– 19802, DOI: 10.1039/D0RA04199H
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110
Nature as a treasure trove of potential anti-SARS-CoV drug leads: a structural/mechanistic rationale
Sayed, Ahmed M.; Khattab, Amira R.; AboulMagd, Asmaa M.; Hassan, Hossam M.; Rateb, Mostafa E.; Zaid, Hala; Abdelmohsen, Usama Ramadan
RSC Advances (2020), 10 (34), 19790-19802CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
A review. The novel Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is a potential factor for fatal illness and a tremendous concern for global public health. The COVID-19 pandemic has entered a dangerous new phase. In the context of drug discovery, the structurally-unique and chem.-diverse natural products have been valuable sources for drug leads. In this review, we report for potential candidates derived from natural sources with well-reported in vitro efficacy against SARS-CoV during the last decade. Addnl., a library of 496 phenolic metabolites was subjected to a computer-aided virtual screening against the active site of the recently reported SARS-CoV Main protease (Mpro). Anal. of physicochem. properties of these natural products has been carried out and presented for all the tested phenolic metabolites. Only three of the top candidates, viz. acetylglucopetunidin (31), isoxanthohumol (32) and ellagic acid (33), which are widely available in many edible fruits, obey both Lipinski's and Veber's rules of drug-likeness and thus possess high degrees of predicted bioavailability. These natural products are suggested as potential drug candidates for the development of anti-SARS-CoV-2 therapeutics in the near future.
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Luo, D.; Vasudevan, S. G.; Lescar, J. The Flavivirus NS2B–NS3 Protease–Helicase as a Target for Antiviral Drug Development. Antiviral Res. 2015, 118, 148– 158, DOI: 10.1016/j.antiviral.2015.03.014
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The flavivirus NS2B-NS3 protease-helicase as a target for antiviral drug development
Luo, Dahai; Vasudevan, Subhash G.; Lescar, Julien
Antiviral Research (2015), 118 (), 148-158CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
The flavivirus NS3 protein is assocd. with the endoplasmic reticulum membrane via its close interaction with the central hydrophilic region of the NS2B integral membrane protein. The multiple roles played by the NS2B-NS3 protein in the virus life cycle makes it an attractive target for antiviral drug discovery. The N-terminal region of NS3 and its cofactor NS2B constitute the protease that cleaves the viral polyprotein. The NS3 C-terminal domain possesses RNA helicase, nucleoside and RNA triphosphatase activities and is involved both in viral RNA replication and virus particle formation. In addn., NS2B-NS3 serves as a hub for the assembly of the flavivirus replication complex and also modulates viral pathogenesis and the host immune response. Here, we review biochem. and structural advances on the NS2B-NS3 protein, including the network of interactions it forms with NS5 and NS4B and highlight recent drug development efforts targeting this protein. This article forms part of a symposium in Antiviral Research on flavivirus drug discovery.
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Bharadwaj, S.; Lee, K. E.; Dwivedi, V. D.; Yadava, U.; Panwar, A.; Lucas, S. J.; Pandey, A.; Kang, S. G. Discovery of Ganoderma Lucidum Triterpenoids as Potential Inhibitors against Dengue Virus NS2B-NS3 Protease. Sci. Rep. 2019, 9 (1), 19059, DOI: 10.1038/s41598-019-55723-5
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112
Discovery of Ganoderma lucidum triterpenoids as potential inhibitors against Dengue virus NS2B-NS3 protease
Bharadwaj, Shiv; Lee, Kyung Eun; Dwivedi, Vivek Dhar; Yadava, Umesh; Panwar, Aleksha; Lucas, Stuart. J.; Pandey, Amit; Kang, Sang Gu
Scientific Reports (2019), 9 (1), 19059CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
Dengue virus (DENV) infection causes serious health problems in humans for which no drug is currently available. Recently, DENV NS2B-NS3 protease has been proposed as a primary target for anti-dengue drug discovery due to its important role in new virus particle formation by conducting DENV polyprotein cleavage. Triterpenoids from the medicinal fungus Ganoderma lucidum have been suggested as pharmacol. bioactive compds. and tested as anti-viral agents against various viral pathogens including human immunodeficiency virus. However, no reports are available concerning the anti-viral activity of triterpenoids from Ganoderma lucidum against DENV. Therefore, we employed a virtual screening approach to predict the functional triterpenoids from Ganoderma lucidum as potential inhibitors of DENV NS2B-NS3 protease, followed by an in-vitro assay. From in-silico anal. of twenty-two triterpenoids of Ganoderma lucidum, four triterpenoids, viz.Ganodermanontriol (-6.291 kcal/mol), Lucidumol A (-5.993 kcal/mol), Ganoderic acid C2 (-5.948 kcal/mol) and Ganosporeric acid A (-5.983 kcal/mol) were predicted to be viral protease inhibitors by comparison to ref. inhibitor 1,8-Dihydroxy-4,5-dinitroanthraquinone (-5.377 kcal/mol). These results were further studied for binding affinity and stability using the mol. mechanics/generalized Born surface area method and Mol. Dynamics simulations, resp. Also, in-vitro viral infection inhibition suggested that Ganodermanontriol is a potent bioactive triterpenoid.
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Sheahan, T. P.; Sims, A. C.; Zhou, S.; Graham, R. L.; Pruijssers, A. J.; Agostini, M. L.; Leist, S. R.; Schäfer, A.; Dinnon, K. H.; Stevens, L. J.; Chappell, J. D.; Lu, X.; Hughes, T. M.; George, A. S.; Hill, C. S.; Montgomery, S. A.; Brown, A. J.; Bluemling, G. R.; Natchus, M. G.; Saindane, M.; Kolykhalov, A. A.; Painter, G.; Harcourt, J.; Tamin, A.; Thornburg, N. J.; Swanstrom, R.; Denison, M. R.; Baric, R. S. An Orally Bioavailable Broad-Spectrum Antiviral Inhibits SARS-CoV-2 in Human Airway Epithelial Cell Cultures and Multiple Coronaviruses in Mice. Sci. Transl. Med. 2020, 12, eabb5883, DOI: 10.1126/scitranslmed.abb5883
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There is no corresponding record for this reference.
114
Yu, M.-S.; Lee, J.; Lee, J. M.; Kim, Y.; Chin, Y.-W.; Jee, J.-G.; Keum, Y.-S.; Jeong, Y.-J. Identification of Myricetin and Scutellarein as Novel Chemical Inhibitors of the SARS Coronavirus Helicase, NsP13. Bioorg. Med. Chem. Lett. 2012, 22 (12), 4049– 4054, DOI: 10.1016/j.bmcl.2012.04.081
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114
Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13
Yu, Mi-Sun; Lee, June; Lee, Jin Moo; Kim, Younggyu; Chin, Young-Won; Jee, Jun-Goo; Keum, Young-Sam; Jeong, Yong-Joo
Bioorganic & Medicinal Chemistry Letters (2012), 22 (12), 4049-4054CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
Severe acute respiratory syndrome (SARS) is an infectious disease with a strong potential for transmission upon close personal contact and is caused by the SARS-coronavirus (CoV). However, there are no natural or synthetic compds. currently available that can inhibit SARS-CoV. We examd. the inhibitory effects of 64 purified natural compds. against the activity of SARS helicase, nsP13, and the hepatitis C virus (HCV) helicase, NS3h, by conducting fluorescence resonance energy transfer (FRET)-based double-strand (ds) DNA unwinding assay or by using a colorimetry-based ATP hydrolysis assay. While none of the compds., examd. in our study inhibited the DNA unwinding activity or ATPase activity of human HCV helicase protein, we found that myricetin and scutellarein potently inhibit the SARS-CoV helicase protein in vitro by affecting the ATPase activity, but not the unwinding activity, nsP13. In addn., we obsd. that myricetin and scutellarein did not exhibit cytotoxicity against normal breast epithelial MCF10A cells. Our study demonstrates for the first time that selected naturally-occurring flavonoids, including myricetin and scultellarein might serve as SARS-CoV chem. inhibitors.
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Botta, L.; Rivara, M.; Zuliani, V.; Radi, M. Drug Repurposing Approaches to Fight Dengue Virus Infection and Related Diseases. Front. Biosci., Landmark Ed. 2018, 23, 997– 1019, DOI: 10.2741/4630
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115
Drug repurposing approaches to fight Dengue virus infection and related diseases
Botta, Lorenzo; Rivara, Mirko; Zuliani, Valentina; Radi, Marco
Frontiers in Bioscience, Landmark Edition (2018), 23 (6), 997-1019CODEN: FRBIF6; ISSN:1093-4715. (Frontiers in Bioscience)
Dengue is a mosquito-borne viral disease caused by four antigenically distinct serotypes of Dengue Virus (DENV), namely DENV1-4 and is currently considered the most important arthropodborn viral disease in the world. An effective antiviral therapy to treat Dengue Virus infection is still missing and a no. of replicative cycle inhibitors are currently under study. Considering the rapid spreading of DENV and the common timeframe required for bringing a new drug on the market, the repurposing of approved drugs used for different diseases to identify novel inhibitors of this pathogen represents an attractive approach for a rapid therapeutic intervention. Herein, we will describe the most recent drug repurposing approaches to fight DENV infection and their implications in antiviral drug-discovery.
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Shimizu, H.; Saito, A.; Mikuni, J.; Nakayama, E. E.; Koyama, H.; Honma, T.; Shirouzu, M.; Sekine, S.; Shioda, T. Discovery of a Small Molecule Inhibitor Targeting Dengue Virus NS5 RNA-Dependent RNA Polymerase. PLoS Neglected Trop. Dis. 2019, 13 (11), e0007894, DOI: 10.1371/journal.pntd.0007894
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116
Discovery of a small molecule inhibitor targeting dengue virus NS5 RNA-dependent RNA polymerase
Shimizu, Heaki; Saito, Akatsuki; Mikuni, Junko; Nakayama, Emi E.; Koyama, Hiroo; Honma, Teruki; Shirouzu, Mikako; Sekine, Shun-ichi; Shioda, Tatsuo
PLoS Neglected Tropical Diseases (2019), 13 (11), e0007894/1-e0007894/21CODEN: PNTDAM; ISSN:1935-2735. (Public Library of Science)
Dengue is a mosquito-borne viral infection that has spread globally in recent years. Around half of the world's population, esp. in the tropics and subtropics, is at risk of infection. Every year, 50-100 million clin. cases are reported, and more than 500,000 patients develop the symptoms of severe dengue infection: dengue haemorrhagic fever and dengue shock syndrome, which threaten life in Asia and Latin America. No antiviral drug for dengue is available. The dengue virus (DENV) non-structural protein 5 (NS5), which possesses the RNA-dependent RNA polymerase (RdRp) activity and is responsible for viral replication and transcription, is an attractive target for anti-dengue drug development. In the present study, 16,240 small-mol. compds. in a fragment library were screened for their capabilities to inhibit the DENV type 2 (DENV2) RdRp activities in vitro. Based on in cellulo antiviral and cytotoxity assays, we selected the compd. RK-0404678 with the EC50 value of 6.0 μM for DENV2. Crystallog. analyses revealed two unique binding sites for RK-0404678 within the RdRp, which are conserved in flavivirus NS5 proteins. No resistant viruses emerged after nine rounds of serial passage of DENV2 in the presence of RK-0404678, suggesting the high genetic barrier of this compd. to the emergence of a resistant virus. Collectively, RK-0404678 and its binding sites provide a new framework for antiviral drug development.
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Hamill, R. L.; Hoehn, M. M. A9145, A new adenine-containing antifungal antibiotic I. Discovery and isolation. J. Antibiot. 1973, 26 (8), 463– 465, DOI: 10.7164/antibiotics.26.463
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117
A 9145, a new adenine-containing antifungal antibiotic. I. Discovery and isolation
Hamill, Robert L.; Hoehn, Marvin M.
Journal of Antibiotics (1973), 26 (8), 463-5CODEN: JANTAJ; ISSN:0021-8820.
A9145 (I) is a new, water-sol. antifungal antibiotic produced by a strain of Streptomyces griseolus (NRRL 3739). This basic antibiotic has an apparent mol. wt. of about 510, contains adenine and a possible sugar moiety, and forms cryst. org. and inorg. salts. I is active against Candida species, Saccharomyces pastorianus, plant disease fungi and Trypanosoma species. I has an LD50 (s.c.) of 185 mg/kg in mice.
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118
Krafcikova, P.; Silhan, J.; Nencka, R.; Boura, E. Structural Analysis of the SARS-CoV-2 Methyltransferase Complex Involved in RNA Cap Creation Bound to Sinefungin. Nat. Commun. 2020, 11 (1), 3717, DOI: 10.1038/s41467-020-17495-9
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118
Structural analysis of the SARS-CoV-2 methyltransferase complex involved in RNA cap creation bound to sinefungin
Krafcikova, Petra; Silhan, Jan; Nencka, Radim; Boura, Evzen
Nature Communications (2020), 11 (1), 3717CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
Abstr.: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. 2'-O-RNA methyltransferase (MTase) is one of the enzymes of this virus that is a potential target for antiviral therapy as it is crucial for RNA cap formation; an essential process for viral RNA stability. This MTase function is assocd. with the nsp16 protein, which requires a cofactor, nsp10, for its proper activity. Here we show the crystal structure of the nsp10-nsp16 complex bound to the pan-MTase inhibitor sinefungin in the active site. Our structural comparisons reveal low conservation of the MTase catalytic site between Zika and SARS-CoV-2 viruses, but high conservation of the MTase active site between SARS-CoV-2 and SARS-CoV viruses; these data suggest that the prepn. of MTase inhibitors targeting several coronaviruses - but not flaviviruses - should be feasible. Together, our data add to important information for structure-based drug discovery.
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Hercik, K.; Brynda, J.; Nencka, R.; Boura, E. Structural Basis of Zika Virus Methyltransferase Inhibition by Sinefungin. Arch. Virol. 2017, 162 (7), 2091– 2096, DOI: 10.1007/s00705-017-3345-x
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119
Structural basis of Zika virus methyltransferase inhibition by sinefungin
Hercik, Kamil; Brynda, Jiri; Nencka, Radim; Boura, Evzen
Archives of Virology (2017), 162 (7), 2091-2096CODEN: ARVIDF; ISSN:0304-8608. (Springer-Verlag GmbH)
Zika virus is considered a major global threat to human kind. Here, we present a crystal structure of one of its essential enzymes, the methyltransferase, with the inhibitor sinefungin. This structure, together with previously solved structures with bound substrates, will provide the information needed for rational inhibitor design. Based on the structural data we suggest the modification of the adenine moiety of sinefungin to increase selectivity and to covalently link it to a GTP analog, to increase the affinity of the synthesized compds.
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Noble, C. G.; Li, S.-H.; Dong, H.; Chew, S. H.; Shi, P.-Y. Crystal Structure of Dengue Virus Methyltransferase without S-Adenosyl-L-Methionine. Antiviral Res. 2014, 111, 78– 81, DOI: 10.1016/j.antiviral.2014.09.003
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120
Crystal structure of dengue virus methyltransferase without S-adenosyl-L-methionine
Noble, Christian G.; Li, Shi-Hua; Dong, Hongping; Chew, Sock Hui; Shi, Pei-Yong
Antiviral Research (2014), 111 (), 78-81CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
Flavivirus methyltransferase is a genetically-validated antiviral target. Crystal structures of almost all available flavivirus methyltransferases contain S-adenosyl-L-methionine (SAM), the Me donor mol. that co-purifies with the enzymes. This raises a possibility that SAM is an integral structural component required for the folding of dengue virus (DENV) methyltransferase. Here we exclude this possibility by solving the crystal structure of DENV methyltransferase without SAM. The SAM ligand was removed from the enzyme through a urea-mediated denaturation-and-renaturation protocol. The crystal structure of the SAM-depleted enzyme exhibits a vacant SAM-binding pocket, with a conformation identical to that of the SAM-enzyme co-crystal structure. Functionally, equiv. enzymic activities (N-7 methylation, 2'-O methylation, and GMP-enzyme complex formation) were detected for the SAM-depleted and SAM-contg. recombinant proteins. These results clearly indicate that the SAM mol. is not an essential component for the correct folding of DENV methyltransferase. Furthermore, the results imply a potential antiviral approach to search for inhibitors that can bind to the SAM-binding pocket and compete against SAM binding. To demonstrate this potential, we have soaked crystals of DENV methyltransferase without a bound SAM with the natural product Sinefungin and show that preformed crystals are capable of binding ligands in this pocket.
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De Clercq, E. Ebola Virus (EBOV) Infection: Therapeutic Strategies. Biochem. Pharmacol. 2015, 93 (1), 1– 10, DOI: 10.1016/j.bcp.2014.11.008
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Ebola virus (EBOV) infection: Therapeutic strategies
De Clercq, Erik
Biochemical Pharmacology (Amsterdam, Netherlands) (2015), 93 (1), 1-10CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)
A review. Within less than a year after its epidemic started (in Dec. 2013) in Guinea, Ebola virus (EBOV), a member of the filoviridae, has spread over a no. of West-African countries (Guinea, Sierra Leone and Liberia) and gained allures that have been unprecedented except by human immunodeficiency virus (HIV). Although EBOV is highly contagious and transmitted by direct contact with body fluids, it could be counteracted by the adequate chemoprophylactic and -therapeutic interventions: vaccines, antibodies, siRNAs (small interfering RNAs), interferons and chem. substances, i.e. neplanocin A derivs. (i.e. 3-deazaneplanocin A), BCX4430, favipiravir (T-705), endoplasmic reticulum (ER) α-glucosidase inhibitors and a variety of compds. that have been found to inhibit EBOV infection blocking viral entry or by a mode of action that still has to be resolved. Much has to be learned from the mechanism of action of the compds. active against VSV (vesicular stomatitis virus), a virus belonging to the rhabdoviridae, that in its mode of replication could be exemplary for the replication of filoviridae. BCX44303-Deazaneplanocin AFavipiravirFiloviridae.
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Oestereich, L.; Lüdtke, A.; Wurr, S.; Rieger, T.; Muñoz-Fontela, C.; Günther, S. Successful Treatment of Advanced Ebola Virus Infection with T-705 (Favipiravir) in a Small Animal Model. Antiviral Res. 2014, 105, 17– 21, DOI: 10.1016/j.antiviral.2014.02.014
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122
Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model
Oestereich, Lisa; Ludtke, Anja; Wurr, Stephanie; Rieger, Toni; Munoz-Fontela, Cesar; Gunther, Stephan
Antiviral Research (2014), 105 (), 17-21CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
Outbreaks of Ebola hemorrhagic fever in sub-Saharan Africa are assocd. with case fatality rates of up to 90%. Currently, neither a vaccine nor an effective antiviral treatment is available for use in humans. Here, we evaluated the efficacy of the pyrazinecarboxamide deriv. T-705 (favipiravir) against Zaire Ebola virus (EBOV) in vitro and in vivo. T-705 suppressed replication of Zaire EBOV in cell culture by 4 log units with an IC90 of 110 μM. Mice lacking the type I interferon receptor (IFNAR-/-) were used as in vivo model for Zaire EBOV-induced disease. Initiation of T-705 administration at day 6 post infection induced rapid virus clearance, reduced biochem. parameters of disease severity, and prevented a lethal outcome in 100% of the animals. The findings suggest that T-705 is a candidate for treatment of Ebola hemorrhagic fever.
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Warren, T. K.; Jordan, R.; Lo, M. K.; Ray, A. S.; Mackman, R. L.; Soloveva, V.; Siegel, D.; Perron, M.; Bannister, R.; Hui, H. C.; Larson, N.; Strickley, R.; Wells, J.; Stuthman, K. S.; Van Tongeren, S. A.; Garza, N. L.; Donnelly, G.; Shurtleff, A. C.; Retterer, C. J.; Gharaibeh, D.; Zamani, R.; Kenny, T.; Eaton, B. P.; Grimes, E.; Welch, L. S.; Gomba, L.; Wilhelmsen, C. L.; Nichols, D. K.; Nuss, J. E.; Nagle, E. R.; Kugelman, J. R.; Palacios, G.; Doerffler, E.; Neville, S.; Carra, E.; Clarke, M. O.; Zhang, L.; Lew, W.; Ross, B.; Wang, Q.; Chun, K.; Wolfe, L.; Babusis, D.; Park, Y.; Stray, K. M.; Trancheva, I.; Feng, J. Y.; Barauskas, O.; Xu, Y.; Wong, P.; Braun, M. R.; Flint, M.; McMullan, L. K.; Chen, S.-S.; Fearns, R.; Swaminathan, S.; Mayers, D. L.; Spiropoulou, C. F.; Lee, W. A.; Nichol, S. T.; Cihlar, T.; Bavari, S. Therapeutic Efficacy of the Small Molecule GS-5734 against Ebola Virus in Rhesus Monkeys. Nature 2016, 531 (7594), 381– 385, DOI: 10.1038/nature17180
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123
Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys
Warren, Travis K.; Jordan, Robert; Lo, Michael K.; Ray, Adrian S.; Mackman, Richard L.; Soloveva, Veronica; Siegel, Dustin; Perron, Michel; Bannister, Roy; Hui, Hon C.; Larson, Nate; Strickley, Robert; Wells, Jay; Stuthman, Kelly S.; Van Tongeren, Sean A.; Garza, Nicole L.; Donnelly, Ginger; Shurtleff, Amy C.; Retterer, Cary J.; Gharaibeh, Dima; Zamani, Rouzbeh; Kenny, Tara; Eaton, Brett P.; Grimes, Elizabeth; Welch, Lisa S.; Gomba, Laura; Wilhelmsen, Catherine L.; Nichols, Donald K.; Nuss, Jonathan E.; Nagle, Elyse R.; Kugelman, Jeffrey R.; Palacios, Gustavo; Doerffler, Edward; Neville, Sean; Carra, Ernest; Clarke, Michael O.; Zhang, Lijun; Lew, Willard; Ross, Bruce; Wang, Queenie; Chun, Kwon; Wolfe, Lydia; Babusis, Darius; Park, Yeojin; Stray, Kirsten M.; Trancheva, Iva; Feng, Joy Y.; Barauskas, Ona; Xu, Yili; Wong, Pamela; Braun, Molly R.; Flint, Mike; McMullan, Laura K.; Chen, Shan-Shan; Fearns, Rachel; Swaminathan, Swami; Mayers, Douglas L.; Spiropoulou, Christina F.; Lee, William A.; Nichol, Stuart T.; Cihlar, Tomas; Bavari, Sina
Nature (London, United Kingdom) (2016), 531 (7594), 381-385CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
The most recent Ebola virus outbreak in West Africa, which was unprecedented in the no. of cases and fatalities, geog. distribution, and no. of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clin. efficacy. Here we report the discovery of a novel small mol. GS-5734, a monophosphoramidate prodrug of an adenosine analog, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacol. active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. I.v. administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily i.v. administration of 10 mg kg-1 GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clin. disease signs and pathophysiol. markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-mol. antiviral compd. against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufg., and clin. studies investigating the drug safety and pharmacokinetics are ongoing.
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Warren, T. K.; Wells, J.; Panchal, R. G.; Stuthman, K. S.; Garza, N. L.; Van Tongeren, S. A.; Dong, L.; Retterer, C. J.; Eaton, B. P.; Pegoraro, G.; Honnold, S.; Bantia, S.; Kotian, P.; Chen, X.; Taubenheim, B. R.; Welch, L. S.; Minning, D. M.; Babu, Y. S.; Sheridan, W. P.; Bavari, S. Protection against Filovirus Diseases by a Novel Broad-Spectrum Nucleoside Analogue BCX4430. Nature 2014, 508 (7496), 402– 405, DOI: 10.1038/nature13027
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124
Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430
Warren, Travis K.; Wells, Jay; Panchal, Rekha G.; Stuthman, Kelly S.; Garza, Nicole L.; Van Tongeren, Sean A.; Dong, Lian; Retterer, Cary J.; Eaton, Brett P.; Pegoraro, Gianluca; Honnold, Shelley; Bantia, Shanta; Kotian, Pravin; Chen, Xilin; Taubenheim, Brian R.; Welch, Lisa S.; Minning, Dena M.; Babu, Yarlagadda S.; Sheridan, William P.; Bavari, Sina
Nature (London, United Kingdom) (2014), 508 (7496), 402-405CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
Filoviruses are emerging pathogens and causative agents of viral haemorrhagic fever. Case fatality rates of filovirus disease outbreaks are among the highest reported for any human pathogen, exceeding 90% (ref. 1). Licensed therapeutic or vaccine products are not available to treat filovirus diseases. Candidate therapeutics previously shown to be efficacious in non-human primate disease models are based on virus-specific designs and have limited broad-spectrum antiviral potential. Here we show that BCX4430, a novel synthetic adenosine analog, inhibits infection of distinct filoviruses in human cells. Biochem., reporter-based and primer-extension assays indicate that BCX4430 inhibits viral RNA polymerase function, acting as a non-obligate RNA chain terminator. Post-exposure i.m. administration of BCX4430 protects against Ebola virus and Marburg virus disease in rodent models. Most importantly, BCX4430 completely protects cynomolgus macaques from Marburg virus infection when administered as late as 48 h after infection. In addn., BCX4430 exhibits broad-spectrum antiviral activity against numerous viruses, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses and flaviviruses. This is the first report, to our knowledge, of non-human primate protection from filovirus disease by a synthetic drug-like small mol. We provide addnl. pharmacol. characterizations supporting the potential development of BCX4430 as a countermeasure against human filovirus diseases and other viral diseases representing major public health threats.
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Daino, G. L.; Frau, A.; Sanna, C.; Rigano, D.; Distinto, S.; Madau, V.; Esposito, F.; Fanunza, E.; Bianco, G.; Taglialatela-Scafati, O.; Zinzula, L.; Maccioni, E.; Corona, A.; Tramontano, E. Identification of Myricetin as an Ebola Virus VP35–Double-Stranded RNA Interaction Inhibitor through a Novel Fluorescence-Based Assay. Biochemistry 2018, 57 (44), 6367– 6378, DOI: 10.1021/acs.biochem.8b00892
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125
Identification of myricetin as an Ebola virus VP35-double-stranded RNA interaction inhibitor through a novel fluorescence-based assay
Daino, Gian Luca; Frau, Aldo; Sanna, Cinzia; Rigano, Daniela; Distinto, Simona; Madau, Veronica; Esposito, Francesca; Fanunza, Elisa; Bianco, Giulia; Taglialatela-Scafati, Orazio; Zinzula, Luca; Maccioni, Elias; Corona, Angela; Tramontano, Enzo
Biochemistry (2018), 57 (44), 6367-6378CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
Ebola virus (EBOV) is a filovirus that causes a severe and rapidly progressing hemorrhagic syndrome; a recent epidemic illustrated the urgent need for novel therapeutic agents because no drugs have been approved for treatment of Ebola virus. A key contribution to the high lethality obsd. during EBOV outbreaks comes from viral evasion of the host antiviral innate immune response in which viral protein VP35 plays a crucial role, blocking interferon type I prodn., first by masking the viral double-stranded RNA (dsRNA) and preventing its detection by the pattern recognition receptor RIG-I. Aiming to identify inhibitors of the interaction of VP35 with the viral dsRNA, counteracting the VP35 viral innate immune evasion, we established a new methodol. for high-yield recombinant VP35 (rVP35) expression and purifn. and a novel and robust fluorescence-based rVP35-RNA interaction assay (Z' factor of 0.69). Taking advantage of such newly established methods, we screened a small library of Sardinian natural exts., identifying Limonium morisianum as the most potent inhibitor ext. A bioguided fractionation led to the identification of myricetin as the component that can inhibit rVP35-dsRNA interaction with an IC50 value of 2.7 μM. Mol. docking studies showed that myricetin interacts with the highly conserved region of the VP35 RNA binding domain, laying the basis for further structural optimization of potent inhibitors of VP35-dsRNA interaction.
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Kamitani, W.; Narayanan, K.; Huang, C.; Lokugamage, K.; Ikegami, T.; Ito, N.; Kubo, H.; Makino, S. Severe Acute Respiratory Syndrome Coronavirus Nsp1 Protein Suppresses Host Gene Expression by Promoting Host MRNA Degradation. Proc. Natl. Acad. Sci. U. S. A. 2006, 103 (34), 12885– 12890, DOI: 10.1073/pnas.0603144103
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126
Severe acute respiratory syndrome coronavirus nsp1 protein suppresses host gene expression by promoting host mRNA degradation
Kamitani, Wataru; Narayanan, Krishna; Huang, Cheng; Lokugamage, Kumari; Ikegami, Tetsuro; Ito, Naoto; Kubo, Hideyuki; Makino, Shinji
Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (34), 12885-12890CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
Severe acute respiratory syndrome (SARS) coronavirus (SCoV) causes a recently emerged human disease assocd. with pneumonia. The 5' end two-thirds of the single-stranded pos.-sense viral genomic RNA, gene 1, encodes 16 mature proteins. Expression of nsp1, the most N-terminal gene 1 protein, prevented Sendai virus-induced endogenous IFN-β mRNA accumulation without inhibiting dimerization of IFN regulatory factor 3, a protein that is essential for activation of the IFN-β promoter. Furthermore, nsp1 expression promoted degrdn. of expressed RNA transcripts and host endogenous mRNAs, leading to a strong host protein synthesis inhibition. SCoV replication also promoted degrdn. of expressed RNA transcripts and host mRNAs, suggesting that nsp1 exerted its mRNA destabilization function in infected cells. In contrast to nsp1-induced mRNA destabilization, no degrdn. of the 28S and 18S rRNAs occurred in either nsp1-expressing cells or SCoV-infected cells. These data suggested that, in infected cells, nsp1 promotes host mRNA degrdn. and thereby suppresses host gene expression, including proteins involved in host innate immune functions. SCoV nsp1-mediated promotion of host mRNA degrdn. may play an important role in SCoV pathogenesis.
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Shi, C.-S.; Nabar, N. R.; Huang, N.-N.; Kehrl, J. H. SARS-Coronavirus Open Reading Frame-8b Triggers Intracellular Stress Pathways and Activates NLRP3 Inflammasomes. Cell Death Discovery 2019, 5 (1), 1– 12, DOI: 10.1038/s41420-019-0230-2
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127
Hyperglycemia exacerbates acetaminophen-induced acute liver injury by promoting liver-resident macrophage proinflammatory response via AMPK/PI3K/AKT-mediated oxidative stress
Wang, Qi; Wei, Song; Zhou, Haoming; Shen, Gefenqiang; Gan, Xiaojie; Zhou, Shun; Qiu, Jiannan; Shi, Chenyu; Lu, Ling
Cell Death Discovery (2019), 5 (1), 1-12CODEN: CDDEB5; ISSN:2058-7716. (Nature Research)
Although diabetes mellitus/hyperglycemia is a risk factor for acute liver injury, the underlying mechanism remains largely unknown. Liver-resident macrophages (Kupffer cells, KCs) and oxidative stress play crit. roles in the pathogenesis of toxin-induced liver injury. Here, we evaluated the role of oxidative stress in regulating KC polarization against acetaminophen (APAP)-mediated acute liver injury in a streptozotocin-induced hyperglycemic murine model. Compared to the controls, hyperglycemic mice exhibited a significant increase in liver injury and intrahepatic inflammation. KCs obtained from hyperglycemic mice secreted higher levels of the proinflammatory factors, such as TNF-α and IL-6, lower levels of the anti-inflammatory factor IL-10. Furthermore, enhanced oxidative stress was revealed by increased levels of reactive oxygen species (ROS) in KCs from hyperglycemic mice post APAP treatment. In addn., ROS inhibitor NAC resulted in a significant decrease of ROS prodn. in hyperglycemic KCs from mice posttreated with APAP. We also analyzed the role of hyperglycemia in macrophage M1/M2 polarization. Interestingly, we found that hyperglycemia promoted M1 polarization, but inhibited M2 polarization of KCs obtained from APAP-exposed livers, as evidenced by increased MCP-1 and inducible NO synthase (iNOS) gene induction but decreased Arg-1 and CD206 gene induction accompanied by increased STAT1 activation and decreased STAT6 activation. NAC restored Arg-1, CD206 gene induction, and STAT6 activation. To explore the mechanism how hyperglycemia regulates KCs polarization against APAP-induced acute liver injury, we examd. the AMPK/PI3K/AKT signaling pathway and found decreased AMPK activation and increased AKT activation in liver and KCs from hyperglycemic mice post APAP treatment. AMPK activation by its agonist AICAR or PI3K inhibition by its antagonist LY294002 inhibited ROS prodn. in KCs from hyperglycemic mice post APAP treatment and significantly attenuated APAP-induced liver injury in the hyperglycemic mice, compared to the control mice. Our results demonstrated that hyperglycemia exacerbated APAP-induced acute liver injury by promoting liver-resident macrophage proinflammatory response via AMPK/PI3K/AKT-mediated oxidative stress.
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McBride, R.; Fielding, B. C. The Role of Severe Acute Respiratory Syndrome (SARS)-Coronavirus Accessory Proteins in Virus Pathogenesis. Viruses 2012, 4 (11), 2902– 2923, DOI: 10.3390/v4112902
[Crossref], [PubMed], [CAS], Google Scholar
128
The role of severe acute respiratory syndrome (SARS)-coronavirus accessory proteins in virus pathogenesis
McBride, Ruth; Fielding, Burtram C.
Viruses (2012), 4 (), 2902-2923CODEN: VIRUBR; ISSN:1999-4915. (MDPI AG)
A review. A respiratory disease caused by a novel coronavirus, termed the severe acute respiratory syndrome coronavirus (SARS-CoV), was first reported in China in late 2002. The subsequent efficient human-to-human transmission of this virus eventually affected more than 30 countries worldwide, resulting in a mortality rate of ∼10% of infected individuals. The spread of the virus was ultimately controlled by isolation of infected individuals and there has been no infections reported since Apr. 2004. However, the natural reservoir of the virus was never identified and it is not known if this virus will re-emerge and, therefore, research on this virus continues. The SARS-CoV genome is about 30 kb in length and is predicted to contain 14 functional open reading frames (ORFs). The genome encodes for proteins that are homologous to known coronavirus proteins, such as the replicase proteins (ORFs 1a and 1b) and the four major structural proteins: nucleocapsid (N), spike (S), membrane (M) and envelope (E). SARS-CoV also encodes for eight unique proteins, called accessory proteins, with no known homologues. This review will summarize the current knowledge on SARS-CoV accessory proteins and will include: (i) expression and processing; (ii) the effects on cellular processes; and (iii) functional studies.
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Whitby, K.; Pierson, T. C.; Geiss, B.; Lane, K.; Engle, M.; Zhou, Y.; Doms, R. W.; Diamond, M. S. Castanospermine, a Potent Inhibitor of Dengue Virus Infection In Vitro and In Vivo. J. Virol. 2005, 79 (14), 8698– 8706, DOI: 10.1128/JVI.79.14.8698-8706.2005
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129
Castanospermine, a potent inhibitor of dengue virus infection in vitro and in vivo
Whitby, Kevin; Pierson, Theodore C.; Geiss, Brian; Lane, Kelly; Engle, Michael; Zhou, Yi; Doms, Robert W.; Diamond, Michael S.
Journal of Virology (2005), 79 (14), 8698-8706CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
Previous studies have suggested that α-glucosidase inhibitors such as castanospermine and deoxynojirimycin inhibit dengue virus type 1 infection by disrupting the folding of the structural proteins prM and E, a step crucial to viral secretion. We extend these studies by evaluating the inhibitory activity of castanospermine against a panel of clin. important flaviviruses including all four serotypes of dengue virus, yellow fever virus, and West Nile virus. Using in vitro assays we demonstrated that infections by all serotypes of dengue virus were inhibited by castanospermine. In contrast, yellow fever virus and West Nile virus were partially and almost completely resistant to the effects of the drug, resp. Castanospermine inhibited dengue virus infection at the level of secretion and infectivity of viral particles. Importantly, castanospermine prevented mortality in a mouse model of dengue virus infection, with doses of 10, 50, and 250 mg/kg of body wt. per day being highly effective at promoting survival (P ≤ 0.0001). Correspondingly, castanospermine had no adverse or protective effect on West Nile virus mortality in an analogous mouse model. Overall, our data suggest that castanospermine has a strong antiviral effect on dengue virus infection and warrants further development as a possible treatment in humans.
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Watanabe, S.; Rathore, A. P. S.; Sung, C.; Lu, F.; Khoo, Y. M.; Connolly, J.; Low, J.; Ooi, E. E.; Lee, H. S.; Vasudevan, S. G. Dose- and Schedule-Dependent Protective Efficacy of Celgosivir in a Lethal Mouse Model for Dengue Virus Infection Informs Dosing Regimen for a Proof of Concept Clinical Trial. Antiviral Res. 2012, 96 (1), 32– 35, DOI: 10.1016/j.antiviral.2012.07.008
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130
Dose- and schedule-dependent protective efficacy of celgosivir in a lethal mouse model for dengue virus infection informs dosing regimen for a proof of concept clinical trial
Watanabe, Satoru; Rathore, Abhay P. S.; Sung, Cynthia; Lu, Fan; Khoo, Yok Moi; Connolly, John; Low, Jenny; Ooi, Eng Eong; Lee, How Sung; Vasudevan, Subhash G.
Antiviral Research (2012), 96 (1), 32-35CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
Celgosivir (6-O-butanoyl castanospermine), a pro-drug of the naturally occurring castanospermine, is an inhibitor of α-glucosidase I and II that is found to be a potent inhibitor of several enveloped viruses including all four serotypes of dengue virus. We showed previously that the compd. fully protected AG129 mice from lethal infection with a mouse adapted dengue virus at a dose of 50 mg/kg twice daily (BID) for 5 days and was effective even after 48 h delayed treatment. Here we show that the protection by celgosivir is dose- and schedule-dependent and that a twice-a-day regimen of 50, 25 or 10 mg/kg is more protective than a single daily dose of 100 mg/kg. Treatment with 50 mg/kg BID castanospermine had comparable efficacy as 25 mg/kg BID celgosivir, suggesting that celgosivir is approx. twice as potent as castanospermine with respect to in vivo antiviral efficacy. Pharmacokinetics (PK) studies of celgosivir in mice showed that it rapidly metabolized to castanospermine. Simulation of the PK data with the survival data for the various doses of celgosivir tested suggests that the steady-state min. concn. is a crit. parameter to note in choosing dose and schedule. These results influenced the selection of the dose regimen for a proof-of-concept clin. trial of celgosivir as a treatment against dengue fever.
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Shen, L. W.; Mao, H. J.; Wu, Y. L.; Tanaka, Y.; Zhang, W. TMPRSS2: A Potential Target for Treatment of Influenza Virus and Coronavirus Infections. Biochimie 2017, 142, 1– 10, DOI: 10.1016/j.biochi.2017.07.016
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131
TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections
Shen, Li Wen; Mao, Hui Juan; Wu, Yan Ling; Tanaka, Yoshimasa; Zhang, Wen
Biochimie (2017), 142 (), 1-10CODEN: BICMBE; ISSN:0300-9084. (Elsevier Masson SAS)
Influenza virus and coronavirus epidemics or pandemics have occurred in succession worldwide throughout the early 21st century. These epidemics or pandemics pose a major threat to human health. Here, we outline a crit. role of the host cell protease TMPRSS2 in influenza virus and coronavirus infections and highlight an antiviral therapeutic strategy targeting TMPRSS2.
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Dana, D.; Pathak, S. K. A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L. Molecules 2020, 25 (3), 698, DOI: 10.3390/molecules25030698
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132
A review of small molecule inhibitors and functional probes of human cathepsin L
Dana, Dibyendu; Pathak, Sanjai K.
Molecules (2020), 25 (3), 698CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
A review. Human cathepsin L belongs to the cathepsin family of proteolytic enzymes with primarily an endopeptidase activity. Although its primary functions were originally thought to be only of a housekeeping enzyme that degraded intracellular and endocytosed proteins in lysosome, numerous recent studies suggest that it plays many crit. and specific roles in diverse cellular settings. Not surprisingly, the dysregulated function of cathepsin L has manifested itself in several human diseases, making it an attractive target for drug development. Unfortunately, several redundant and isoform-specific functions have recently emerged, adding complexities to the drug discovery process. To address this, a series of chem. biol. tools have been developed that helped define cathepsin L biol. with exquisite precision in specific cellular contexts. This review elaborates on the recently developed small mol. inhibitors and probes of human cathepsin L, outlining their mechanisms of action, and describing their potential utilities in dissecting unknown function.
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Vidal-Albalat, A.; González, F. V. In Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier, 2016; Vol. 50, Chapter 6, pp 179– 213.
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134
Mori, Y.; Yamashita, T.; Tanaka, Y.; Tsuda, Y.; Abe, T.; Moriishi, K.; Matsuura, Y. Processing of Capsid Protein by Cathepsin L Plays a Crucial Role in Replication of Japanese Encephalitis Virus in Neural and Macrophage Cells. J. Virol. 2007, 81 (16), 8477– 8487, DOI: 10.1128/JVI.00477-07
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134
Processing of capsid protein by cathepsin L plays a crucial role in replication of Japanese encephalitis virus in neural and macrophage cells
Mori, Yoshio; Yamashita, Tetsuo; Tanaka, Yoshinori; Tsuda, Yoshimi; Abe, Takayuki; Moriishi, Kohji; Matsuura, Yoshiharu
Journal of Virology (2007), 81 (16), 8477-8487CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
The flavivirus capsid protein not only is a component of nucleocapsids but also plays a role in viral replication. In this study, the authors found a small capsid protein in cells infected with Japanese encephalitis virus (JEV) but not in the viral particles. The small capsid protein was shown to be generated by processing with host cysteine protease cathepsin L. An in vitro cleavage assay revealed that cathepsin L cleaves the capsid protein between amino acid residues Lys18 and Arg19, which are well conserved among the mosquito-borne flaviviruses. A mutant JEV resistant to the cleavage of the capsid protein by cathepsin L was generated from an infectious cDNA clone of JEV by introducing a substitution in the cleavage site. The mutant JEV exhibited growth kinetics similar to those of the wild-type JEV in monkey (Vero), mosquito (C6/36), and porcine (PK15) cell lines, whereas replication of the mutant JEV in mouse macrophage (RAW264.7) and neuroblastoma (N18) cells was impaired. Furthermore, the neurovirulence and neuroinvasiveness of the mutant JEV to mice were lower than those of the wild-type JEV. These results suggest that the processing of the JEV capsid protein by cathepsin L plays a crucial role in the replication of JEV in neural and macrophage cells, which leads to the pathogenesis of JEV infection.
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Puerta-Guardo, H.; Glasner, D. R.; Harris, E. Dengue Virus NS1 Disrupts the Endothelial Glycocalyx, Leading to Hyperpermeability. PLoS Pathog. 2016, 12 (7), e1005738, DOI: 10.1371/journal.ppat.1005738
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135
Dengue virus NS1 disrupts the endothelial glycocalyx, leading to hyperpermeability
Puerta-Guardo, Henry; Glasner, Dustin R.; Harris, Eva
PLoS Pathogens (2016), 12 (7), e1005738/1-e1005738/29CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
Dengue is the most prevalent arboviral disease in humans and a major public health problem worldwide. Systemic plasma leakage, leading to hypovolemic shock and potentially fatal complications, is a crit. determinant of dengue severity. Recently, we and others described a novel pathogenic effect of secreted dengue virus (DENV) non-structural protein 1 (NS1) in triggering hyperpermeability of human endothelial cells in vitro and systemic vascular leakage in vivo. NS1 was shown to activate toll-like receptor 4 signaling in primary human myeloid cells, leading to secretion of pro-inflammatory cytokines and vascular leakage. However, distinct endothelial cell-intrinsic mechanisms of NS1-induced hyperpermeability remained to be defined. The endothelial glycocalyx layer (EGL) is a network of membrane-bound proteoglycans and glycoproteins lining the vascular endothelium that plays a key role in regulating endothelial barrier function. Here, we demonstrate that DENV NS1 disrupts the EGL on human pulmonary microvascular endothelial cells, inducing degrdn. of sialic acid and shedding of heparan sulfate proteoglycans. This effect is mediated by NS1-induced expression of sialidases and heparanase, resp. NS1 also activates cathepsin L, a lysosomal cysteine proteinase, in endothelial cells, which activates heparanase via enzymic cleavage. Specific inhibitors of sialidases, heparanase, and cathepsin L prevent DENV NS1-induced EGL disruption and endothelial hyperpermeability. All of these effects are specific to NS1 from DENV1-4 and are not induced by NS1 from West Nile virus, a related flavivirus. Together, our data suggest an important role for EGL disruption in DENV NS1-mediated endothelial dysfunction during severe dengue disease.
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Miller, B.; Friedman, A. J.; Choi, H.; Hogan, J.; McCammon, J. A.; Hook, V.; Gerwick, W. H. The Marine Cyanobacterial Metabolite Gallinamide A Is a Potent and Selective Inhibitor of Human Cathepsin L. J. Nat. Prod. 2014, 77 (1), 92– 99, DOI: 10.1021/np400727r
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136
The marine cyanobacterial metabolite gallinamide A is a potent and selective inhibitor of human cathepsin L
Miller, Bailey; Friedman, Aaron J.; Choi, Hyukjae; Hogan, James; McCammon, J. Andrew; Hook, Vivian; Gerwick, William H.
Journal of Natural Products (2014), 77 (1), 92-99CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
Marine natural products can be potent inhibitors of proteases, an important drug target class in human diseases. Marine cyanobacterial exts. were assessed for inhibitory activity to human cathepsin L. The active component gallinamide A potently and selectively inhibited the human cysteine protease cathepsin L in vitro. With 30-min preincubation, gallinamide A had IC50 = 5.0 nM and the kinetic anal. showed inhibition const. ki = 9000±260 M-1 s-1. Preincubation-diln. and activity-probe expts. revealed an irreversible mode of inhibition. Comparison of IC50 values showed 28- to 320-fold greater selectivity toward cathepsin L than closely related human cysteine proteases cathepsin V or B. Mol. docking and mol. dynamics simulations were used to det. the positioning of gallinamide A in the active site of cathepsin L. These data resulted in the identification of a pose characterized by high stability, consistent hydrogen bond network, and the reactive Michael acceptor enamide of gallinamide A positioned near the active site cysteine of the protease, leading to the proposed mechanism of covalent inhibition. These data reveal and characterize the novel activity of gallinamide A as a potent inhibitor of human cathepsin L.
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Brosius, A. D.; Overman, L. E. Aloperine: Stereocontrolled Synthesis of Two Stereoisomers and Determination of Absolute Configuration. J. Org. Chem. 1997, 62 (3), 440– 441, DOI: 10.1021/jo9621231
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137
Aloperine: Stereocontrolled Synthesis of Two Stereoisomers and Determination of Absolute Configuration
Brosius, Arthur D.; Overman, Larry E.
Journal of Organic Chemistry (1997), 62 (3), 440-441CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Racemic diastereoisomers of aloperine I (R = α-H, β-H) were prepd starting from 1-(3-cyclohexenylmethyl)-3,4-dihydro-(1H)-pyridin-2-one (II) via the use of iodine to control the stereoselectivity of N-acyliminium ion-alkene cyclization. Pyridinone II was stereoselectively cyclized with Bu4NI to form III, which could be converted to isomers I. The abs. configuration of the natural enantiomer of aloperine was reported to be 6R,7R,9R,11S.
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Fusetani, N.; Fujita, M.; Nakao, Y.; Matsunaga, S.; van Soest, R. W. M. Tokaramide A,a New Cathepsin B Inhibitor from the Marine Sponge Theonella Aff. Mirabilis. Bioorg. Med. Chem. Lett. 1999, 9 (24), 3397– 3402, DOI: 10.1016/S0960-894X(99)00618-6
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138
Tokaramide A, a new cathepsin B inhibitor from the marine sponge Theonella aff. mirabilis
Fusetani, Nobuhiro; Fujita, Masaki; Nakao, Yoichi; Matsunaga, Shigeki; Van Soest, Rob W. M.
Bioorganic & Medicinal Chemistry Letters (1999), 9 (24), 3397-3402CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)
A new cathepsin B inhibitor, tokaramide A (I) has been isolated from the marine sponge Theonella aff. mirabilis. Its structure was detd. by spectroscopic and chem. methods. Tokaramide A inhibits cathepsin B with an IC50 value of 29.0 ng/mL.
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Nakao, Y.; Fujita, M.; Warabi, K.; Matsunaga, S.; Fusetani, N. Miraziridine A, a Novel Cysteine Protease Inhibitor from the Marine Sponge Theonella Aff. Mirabilis1. J. Am. Chem. Soc. 2000, 122 (42), 10462– 10463, DOI: 10.1021/ja001859j
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139
Miraziridine A, a novel cysteine protease inhibitor from the marine sponge Theonella aff. mirabilis
Nakao, Yoichi; Fujita, Masaki; Warabi, Kaoru; Matsunaga, Shigeki; Fusetani, Nobuhiro
Journal of the American Chemical Society (2000), 122 (42), 10462-10463CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
This work describes the isolation and structure elucidation of miraziridine A from T. mirabilis and its cathepsin B inhibitory activity.
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140
Zhang, X.; Liu, Q.; Zhang, N.; Li, Q.; Liu, Z.; Li, Y.; Gao, L.; Wang, Y.; Deng, H.; Song, D. Discovery and Evolution of Aloperine Derivatives as Novel Anti-Filovirus Agents through Targeting Entry Stage. Eur. J. Med. Chem. 2018, 149, 45– 55, DOI: 10.1016/j.ejmech.2018.02.061
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140
Discovery and evolution of aloperine derivatives as novel anti-filo virus agents through targeting entry stage
Zhang, Xin; Liu, Qiang; Zhang, Na; Li, Qian-Qian; Liu, Zhan-Dong; Li, Ying-Hong; Gao, Li-Mei; Wang, You-Chun; Deng, Hong-Bin; Song, Dan-Qing
European Journal of Medicinal Chemistry (2018), 149 (), 45-55CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
Preventing filoviruses in the entry stage is an attractive antiviral strategy. Taking aloperine, a Chinese natural herb with an endocyclic skeleton, as the lead, 23 new aloperine derivs. were synthesized and evaluated for their anti-filovirus activities including ebola virus (EBOV) and marburg virus (MARV) using pseudotyped virus model. Structure-activity relationship (SAR) anal. indicated that the introduction of a 12N-dichlorobenzyl group was beneficial for the potency. Compd. 2e (12N-3',4'-dichlorobenzylaloperine dihydrochloride) exhibited the most potent anti-EBOV and anti-MARV effects both in vitro and in vivo. It also displayed a good pharmacokinetic and safety profile in vivo, indicating an ideal druglike feature. The primary mechanism study showed that 2e could block a late stage of viral entry, mainly through inhibiting cysteine cathepsin B activity of host components. The authors consider compd. 2e to be a promising broad-spectrum anti-filovirus agent with the advantages of a unique chem. scaffold and a specific biol. mechanism.
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141
Hanada, K.; Tamai, M.; Yamagishi, M.; Ohmura, S.; Sawada, J.; Tanaka, I. Isolation and Characterization of E–64, a New Thiol Protease Inhibitor. Agric. Biol. Chem. 1978, 42 (3), 523– 528, DOI: 10.1271/bbb1961.42.523
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141
Studies on thiol protease inhibitors. Part I. Isolation and characterization of E-64, a new thiol protease inhibitor
Hanada, Kazunori; Tamai, Masaharu; Yamagishi, Michio; Ohmura, Sadafumi; Sawada, Jiro; Tanaka, Ichiro
Agricultural and Biological Chemistry (1978), 42 (3), 523-8CODEN: ABCHA6; ISSN:0002-1369.
A new thiol protease inhibitor, named E-64, was isolated from the ext. of a solid culture of Aspergillus japonicus TPR-64 freshly isolated from soil. E-64 was obtained as white needles and the empirical formula was estd. to be C15N5H27O5. This was neutral in its electrophoretic behavior and proved to be a specific and strong inhibitor toward thiol proteases such as papain and cathepsin B. They combine equimolecularly and irreversibly.
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142
Tamai, M.; Matsumoto, K.; Omura, S.; Koyama, I.; Ozawa, Y.; Hanada, K. In Vitro and in Vivo Inhibition of Cysteine Proteinases by Est, a New Analog of E-64. J. Pharmacobio-Dyn. 1986, 9 (8), 672– 677, DOI: 10.1248/bpb1978.9.672
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142
In vitro and in vivo inhibition of cysteine proteinases by EST, a new analog of E-64
Tamai, Masaharu; Matsumoto, Kazuko; Omura, Sadafumi; Koyama, Ikuo; Ozawa, Yasuo; Hanada, Kazunori
Journal of Pharmacobio-Dynamics (1986), 9 (8), 672-7CODEN: JOPHDQ; ISSN:0386-846X.
The in vitro and in vivo inhibitory activities of EST (I; R = Et) and E-64c (I; R = H), both analogs of E-64, against cysteine proteinases such as cathepsin B, cathepsin H, and papain were studied. Following their synthesis, both EST and E-64c demonstrated a specificity for these cysteine proteinases, however, E-64c was 100-1000 times stronger than EST in the in vitro inhibition of these enzymes. However when they were administered orally to hamsters, the inhibitory activity of EST against cathepsins in skeletal muscle, heart, and liver was much greater than that obsd. with E-64c. E-64c, but no unchanged EST, was found in the plasma of treated hamsters, indicating a conversion of EST to E-64c. EST, in contrast to E-64c, was readily absorbed through the intestinal membrane due to its greater lipophilicity. Thus, EST is a useful oral prodrug for E-64c. The therapeutic use of oral EST as a specific inhibitor of cysteine proteinases for the treatment of muscular dystrophy is discussed.
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143
Murata, M.; Miyashita, S.; Yokoo, C.; Tamai, M.; Hanada, K.; Hatayama, K.; Towatari, T.; Nikawa, T.; Katunuma, N. Novel Epoxysuccinyl Peptides Selective Inhibitors of Cathepsin B, in Vitro. FEBS Lett. 1991, 280 (2), 307– 310, DOI: 10.1016/0014-5793(91)80318-W
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143
Novel epoxysuccinyl peptides. Selective inhibitors of cathepsin B, in vitro
Murata, Mitsuo; Miyashita, Satsuki; Yokoo, Chihiro; Tamai, Masaharu; Hanada, Kazunori; Hatayama, Katsuo; Towatari, Takae; Nikawa, Takeshi; Katunuma, Nobuhiko
FEBS Letters (1991), 280 (2), 307-10CODEN: FEBLAL; ISSN:0014-5793.
A series of new epoxysuccinyl peptides were designed and synthesized to develop a specific inhibitor of cathepsin B. Of these compds., N-(L-3-trans-ethoxycarbonyloxirane-2-carbonyl)-L-isoleucyl-L-proline (compd. CA-030) and N-(L-3-trans-propylcarbamoyloxirane-2-carbonyl)-L-isoleucyl-L-proline (compd. CA-074) were the most potent and specific inhibitors of cathepsin B in vitro. The carboxyl group of proline and the Et ester group or n-propylamide group in the oxirane ring were necessary, the Et ester group or the n-propylamide group being particularly effective for distinguishing cathepsin B from other cysteine proteinases such as cathepsins L and H, and calpains.
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144
Smith, S. A.; Nivarthi, U. K.; de Alwis, R.; Kose, N.; Sapparapu, G.; Bombardi, R.; Kahle, K. M.; Pfaff, J. M.; Lieberman, S.; Doranz, B. J.; de Silva, A. M.; Crowe, J. E. Dengue Virus PrM-Specific Human Monoclonal Antibodies with Virus Replication-Enhancing Properties Recognize a Single Immunodominant Antigenic Site. J. Virol. 2016, 90 (2), 780– 789, DOI: 10.1128/JVI.01805-15
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144
Dengue virus prM-specific human monoclonal antibodies with virus replication-enhancing properties recognize a single immunodominant antigenic site
Smith, Scott A.; Nivarthi, Usha K.; de Alwis, Ruklanthi; Kose, Nurgun; Sapparapu, Gopal; Bombardi, Robin; Kahle, Kristen M.; Pfaff, Jennifer M.; Lieberman, Sherri; Doranz, Benjamin J.; de Silva, Aravinda M.; Crowe, James E., Jr.
Journal of Virology (2016), 90 (2), 780-789CODEN: JOVIAM; ISSN:1098-5514. (American Society for Microbiology)
The proposed antibody-dependent enhancement (ADE) mechanism for severe dengue virus (DENV) disease suggests that nonneutralizing serotype cross-reactive antibodies generated during a primary infection facilitate entry into Fc receptor bearing cells during secondary infection, resulting in enhanced viral replication and severe disease. One group of cross-reactive antibodies that contributes considerably to this serum profile target the premembrane (prM) protein. We report here the isolation of a large panel of naturally occurring human monoclonal antibodies (MAbs) obtained from subjects following primary DENV serotype 1, 2, or 3 or secondary natural DENV infections or following primary DENV serotype 1 live attenuated virus vaccination to det. the antigenic landscape on the prM protein that is recognized by human antibodies. We isolated 25 prM-reactive human MAbs, encoded by diverse antibody-variable genes. Competition-binding studies revealed that all of the antibodies bound to a single major antigenic site on prM. Alanine scanning-based shotgun mutagenesis epitope mapping studies revealed diverse patterns of fine specificity of various clones, suggesting that different antibodies use varied binding poses to recognize several overlapping epitopes within the immunodominant site. Several of the antibodies interacted with epitopes on both prM and E protein residues. Despite the diverse genetic origins of the antibodies and differences in the fine specificity of their epitopes, each of these prM-reactive antibodies was capable of enhancing the DENV infection of Fc receptor-bearing cells.
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145
Dalbey, R. E.; von Heijne, G. Signal Peptidases in Prokaryotes and Eukaryotes - a New Protease Family. Trends Biochem. Sci. 1992, 17 (11), 474– 478, DOI: 10.1016/0968-0004(92)90492-R
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145
Signal peptidases in prokaryotes and eukaryotes - a new protease family
Dalbey, Ross E.; Von Heijne, Gunnar
Trends in Biochemical Sciences (1992), 17 (11), 474-8CODEN: TBSCDB; ISSN:0968-0004.
A review, with 30 refs., on signal peptidases, the family of proteinases involved in removing targeting peptides from preproteins. These peptidases play central roles in the secretory pathway, as well as in the delivery of proteins to the mitochondrial intermembrane space and to the lumen to thylakoids. The catalytic mechanism of preprotein cleavage has long been an enigma, but recent data from site-directed mutagenesis and sequence studies suggest that signal peptidases may constitute a new type of serine protease, mechanistically related to the β-lactamases. Emphasis is given to membrane topol., substrate specificity, sequence homol. and mechanism of catalysis of signal peptidases.
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146
Estoppey, D.; Lee, C. M.; Janoschke, M.; Lee, B. H.; Wan, K. F.; Dong, H.; Mathys, P.; Filipuzzi, I.; Schuhmann, T.; Riedl, R.; Aust, T.; Galuba, O.; McAllister, G.; Russ, C.; Spiess, M.; Bouwmeester, T.; Bonamy, G. M. C.; Hoepfner, D. The Natural Product Cavinafungin Selectively Interferes with Zika and Dengue Virus Replication by Inhibition of the Host Signal Peptidase. Cell Rep. 2017, 19 (3), 451– 460, DOI: 10.1016/j.celrep.2017.03.071
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146
The Natural Product Cavinafungin Selectively Interferes with Zika and Dengue Virus Replication by Inhibition of the Host Signal Peptidase
Estoppey, David; Lee, Chia Min; Janoschke, Marco; Lee, Boon Heng; Wan, Kah Fei; Dong, Hongping; Mathys, Philippe; Filipuzzi, Ireos; Schuhmann, Tim; Riedl, Ralph; Aust, Thomas; Galuba, Olaf; McAllister, Gregory; Russ, Carsten; Spiess, Martin; Bouwmeester, Tewis; Bonamy, Ghislain M. C.; Hoepfner, Dominic
Cell Reports (2017), 19 (3), 451-460CODEN: CREED8; ISSN:2211-1247. (Cell Press)
Flavivirus infections by Zika and dengue virus impose a significant global healthcare threat with no US Food and Drug Administration (FDA)-approved vaccination or specific antiviral treatment available. Here, we present the discovery of an anti-flaviviral natural product named cavinafungin. Cavinafungin is a potent and selectively active compd. against Zika and all four dengue virus serotypes. Unbiased, genome-wide genomic profiling in human cells using a novel CRISPR/Cas9 protocol identified the endoplasmic-reticulum-localized signal peptidase as the efficacy target of cavinafungin. Orthogonal profiling in S. cerevisiae followed by the selection of resistant mutants pinpointed the catalytic subunit of the signal peptidase SEC11 as the evolutionary conserved target. Biochem. anal. confirmed a rapid block of signal sequence cleavage of both host and viral proteins by cavinafungin. This study provides an effective compd. against the eukaryotic signal peptidase and independent confirmation of the recently identified crit. role of the signal peptidase in the replicative cycle of flaviviruses.
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147
Wu, S.-F.; Lee, C.-J.; Liao, C.-L.; Dwek, R. A.; Zitzmann, N.; Lin, Y.-L. Antiviral Effects of an Iminosugar Derivative on Flavivirus Infections. J. Virol. 2002, 76 (8), 3596– 3604, DOI: 10.1128/JVI.76.8.3596-3604.2002
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147
Antiviral effects of an iminosugar derivative on flavivirus infections
Wu, Shu-Fen; Lee, Chyan-Jang; Liao, Ching-Len; Dwek, Raymond A.; Zitzmann, Nicole; Lin, Yi-Ling
Journal of Virology (2002), 76 (8), 3596-3604CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
Endoplasmic reticulum (ER) α-glucosidase inhibitors, which block the trimming step of N-linked glycosylation, have been shown to eliminate the prodn. of several ER-budding viruses. Here we investigated the effects of one such inhibitor, N-nonyl-deoxynojirimycin (NN-DNJ), a 9-carbon alkyl iminosugar deriv., on infection by Japanese encephalitis virus (JEV) and dengue virus serotype 2 (DEN-2). In the presence of NN-DNJ, JEV and DEN-2 infections were suppressed in a dose-dependent manner. This inhibitory effect appeared to influence DEN-2 infection more than JEV infection, since lower concns. of NN-DNJ substantially blocked DEN-2 replication. Secretion of the flaviviral glycoproteins E and NS1 was greatly reduced, and levels of DEN-2 viral RNA replication measured by fluorogenic reverse transcription-PCR were also decreased, by NN-DNJ. Notably, the viral glycoproteins, prM, E, and NS1 were found to assoc. transiently with the ER chaperone calnexin, and this interaction was affected by NN-DNJ, suggesting a potential role of calnexin in the folding of flaviviral glycoproteins. Addnl., in a mouse model of lethal challenge by JEV infection, oral delivery of NN-DNJ reduced the mortality rate. These findings show that NN-DNJ has an antiviral effect on flavivirus infection, likely through interference with virus replication at the posttranslational modification level, occurring mainly in the ER.
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148
Yagi, M.; Kouno, T.; Aoyagi, Y.; Murai, H. The Structure of Moranoline, a Piperidine Alkaloid from Morus Species. Nippon Nogei Kagaku Kaishi 1976, 50 (11), 571– 572, DOI: 10.1271/nogeikagaku1924.50.11_571
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148
The structure of moranoline, a piperidine alkaloid from Morus species
Yagi, Masahiro; Kouno, Tatsuhiko; Aoyagi, Yoshiaki; Murai, Hiromu
Nippon Nogei Kagaku Kaishi (1976), 50 (11), 571-2CODEN: NNKKAA; ISSN:0002-1407.
A new piperidine alkaloid, moranoline (I), m.p. 204-5°, C6H13NO4, was isolated from Morus. The structure of moranoline was detd. as (2R,3R,4R,5S)-2-hydroxymethyl-3,4,5-trihydroxypiperidine by spectral anal.
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149
Yu, W.; Gill, T.; Wang, L.; Du, Y.; Ye, H.; Qu, X.; Guo, J.-T.; Cuconati, A.; Zhao, K.; Block, T. M.; Xu, X.; Chang, J. Design, Synthesis, and Biological Evaluation of N-Alkylated Deoxynojirimycin (DNJ) Derivatives for the Treatment of Dengue Virus Infection. J. Med. Chem. 2012, 55 (13), 6061– 6075, DOI: 10.1021/jm300171v
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149
Design, Synthesis, and Biological Evaluation of N-Alkylated Deoxynojirimycin (DNJ) Derivatives for the Treatment of Dengue Virus Infection
Yu, Wenquan; Gill, Tina; Wang, Lijuan; Du, Yanming; Ye, Hong; Qu, Xiaowang; Guo, Ju-Tao; Cuconati, Andrea; Zhao, Kang; Block, Timothy M.; Xu, Xiaodong; Chang, Jinhong
Journal of Medicinal Chemistry (2012), 55 (13), 6061-6075CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
We recently described the discovery of oxygenated N-alkyl deoxynojirimycin (DNJ) deriv. I [R = C(OH)Et2] with antiviral activity against dengue virus (DENV) infection both in vitro and in vivo. This imino sugar was promising but had an EC50 against DENV in BHK cells of 6.5 μM, which limited its use in in vivo. I [R = C(OH)Et2] presented structural opportunities for activity relationship anal., which we exploited and report here. These structure-activity relationship studies led to analogs, e.g. I (R = OC6H4-2,5-difluoro) with nano-molar antiviral activity (EC50 = 0.3-0.5 μM) against DENV infection, while maintaining low cytotoxicity (CC50 > 500 μM, SI > 1000). In male Sprague-Dawley rats, compd. I (R = OC6H4-2,5-difluoro) was well tolerated at a dose up to 200 mg/kg and displayed desirable PK profiles, with significantly improved bioavailability (F = 92 ± 4%).
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150
Wang, H.; Shen, Y.; Zhao, L.; Ye, Y. 1-Deoxynojirimycin and its Derivatives: A Mini Review of the Literature. Curr. Med. Chem. 2020, 27, 1– 15, DOI: 10.2174/0929867327666200114112728
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151
Chang, J.; Warren, T. K.; Zhao, X.; Gill, T.; Guo, F.; Wang, L.; Comunale, M. A.; Du, Y.; Alonzi, D. S.; Yu, W.; Ye, H.; Liu, F.; Guo, J.-T.; Mehta, A.; Cuconati, A.; Butters, T. D.; Bavari, S.; Xu, X.; Block, T. M. Small Molecule Inhibitors of ER α-Glucosidases Are Active against Multiple Hemorrhagic Fever Viruses. Antiviral Res. 2013, 98 (3), 432– 440, DOI: 10.1016/j.antiviral.2013.03.023
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151
Small molecule inhibitors of ER α-glucosidases are active against multiple hemorrhagic fever viruses
Chang, Jinhong; Warren, Travis K.; Zhao, Xuesen; Gill, Tina; Guo, Fang; Wang, Lijuan; Comunale, Mary Ann; Du, Yanming; Alonzi, Dominic S.; Yu, Wenquan; Ye, Hong; Liu, Fei; Guo, Ju-Tao; Mehta, Anand; Cuconati, Andrea; Butters, Terry D.; Bavari, Sina; Xu, Xiaodong; Block, Timothy M.
Antiviral Research (2013), 98 (3), 432-440CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
Host cellular endoplasmic reticulum α-glucosidases I and II are essential for the maturation of viral glycosylated envelope proteins that use the calnexin mediated folding pathway. Inhibition of these glycan processing enzymes leads to the misfolding and degrdn. of these viral glycoproteins and subsequent redn. in virion secretion. We previously reported that, CM-10-18, an imino sugar α-glucosidase inhibitor, efficiently protected the lethality of dengue virus infection of mice. In the current study, through an extensive structure-activity relationship study, we have identified three CM-10-18 derivs. that demonstrated superior in vitro antiviral activity against representative viruses from four viral families causing hemorrhagic fever. Moreover, the three novel imino sugars significantly reduced the mortality of two of the most pathogenic hemorrhagic fever viruses, Marburg virus and Ebola virus, in mice. Our study thus proves the concept that imino sugars are promising drug candidates for the management of viral hemorrhagic fever caused by variety of viruses.
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152
Zhang, X. G.; Mason, P. W.; Dubovi, E. J.; Xu, X.; Bourne, N.; Renshaw, R. W.; Block, T. M.; Birk, A. V. Antiviral Activity of Geneticin against Dengue Virus. Antiviral Res. 2009, 83 (1), 21– 27, DOI: 10.1016/j.antiviral.2009.02.204
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152
Antiviral activity of geneticin against dengue virus
Zhang, Xianchao G.; Mason, Peter W.; Dubovi, Edward J.; Xu, Xiaodong; Bourne, Nigel; Renshaw, Randall W.; Block, Timothy M.; Birk, Alexander V.
Antiviral Research (2009), 83 (1), 21-27CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
The aminoglycoside, geneticin (G418), was recently shown to have antiviral activity against bovine viral diarrhea virus (BVDV). Since BVDV, dengue virus (DENV) and yellow fever virus (YFV) all belong to the Flaviviridae family, it seemed possible that a common step in their life cycle might be affected by this aminoglycoside. Here it is shown that geneticin prevented the cytopathic effect (CPE) resulting from DENV-2 infection of BHK cells, in a dose-dependent manner with an 50% effective concn. (EC50) value of 3 ± 0.4 μg/mL. Geneticin had no detectable effect on CPE caused by YFV in BHK cells. Geneticin also inhibited DENV-2 viral yield with an EC50 value of 2 ± 0.1 μg/mL and an EC90 value of 20 ± 2 μg/mL. With a CC50 value of 165 ± 5 μg/mL, the selectivity index of anti-DENV activity of geneticin in BHK cells was established to be 66. Furthermore, 25 μg/mL of geneticin nearly completely blocked plaque formation induced by DENV-2, but not YFV. In addn., geneticin, inhibited DENV-2 viral RNA replication and viral translation. Gentamicin, kanamycin, and the guanidinylated geneticin showed no anti-DENV activity. Neomycin and paromomycin demonstrated weak antiviral activity at high concns. Finally, aminoglycoside-3'-phosphotransferase activity of neomycin-resistant gene abolished antiviral activity of geneticin.
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153
Hwang, B. Y.; Su, B.-N.; Chai, H.; Mi, Q.; Kardono, L. B. S.; Afriastini, J. J.; Riswan, S.; Santarsiero, B. D.; Mesecar, A. D.; Wild, R.; Fairchild, C. R.; Vite, G. D.; Rose, W. C.; Farnsworth, N. R.; Cordell, G. A.; Pezzuto, J. M.; Swanson, S. M.; Kinghorn, A. D. Silvestrol and Episilvestrol, Potential Anticancer Rocaglate Derivatives from Aglaia Silvestris. J. Org. Chem. 2004, 69 (10), 3350– 3358, DOI: 10.1021/jo040120f
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153
Silvestrol and episilvestrol, potential anticancer rocaglate derivatives from Aglaia silvestris
Hwang, Bang Yeon; Su, Bao-Ning; Chai, Heebyung; Mi, Qiuwen; Kardono, Leonardus B. S.; Afriastini, Johar J.; Riswan, Soedarsono; Santarsiero, Bernard D.; Mesecar, Andrew D.; Wild, Robert; Fairchild, Craig R.; Vite, Gregory D.; Rose, William C.; Farnsworth, Norman R.; Cordell, Geoffrey A.; Pezzuto, John M.; Swanson, Steven M.; Kinghorn, A. Douglas
Journal of Organic Chemistry (2004), 69 (10), 3350-3358CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Two cytotoxic rocaglate derivs. possessing an unusual dioxanyloxy unit, silvestrol (I) and episilvestrol (II), were isolated from the fruits and twigs of Aglaia silvestris by bioassay-guided fractionation monitored with a human oral epidermoid carcinoma (KB) cell line. Addnl., two new baccharane-type triterpenoids, 17,24-epoxy-25-hydroxybaccharan-3-one (III) and 17,24-epoxy-25-hydroxy-3-oxobaccharan-21-oic acid (IV), as well as eleven known compds., 1β,6α-dihydroxy-4(15)-eudesmene (5), ferulic acid (6), grasshopper ketone (7), apigenin, cabraleone, chrysoeriol, 1β,4β-dihydroxy-6α,15α-epoxyeudesmane, 4-hydroxy-3-methoxyacetophenone, 4-hydroxyphenethyl alc., ocotillone, and β-sitosterol 3-O-β-D-glucopyranoside, were also isolated and characterized. The structures of compds. (I-IV) were elucidated by spectroscopic studies and by chem. transformation. The abs. stereochem. of silvestrol was established by a X-ray diffraction study of its di-p-bromobenzoate deriv., and the structure of 3 was also confirmed by single-crystal X-ray diffraction. The isolates and chem. transformation products were evaluated for cytotoxicity against several human cancer cell lines, and silvestrol and episilvestrol exhibited potent in vitro cytotoxic activity. Silvestrol was further evaluated in vivo in the hollow fiber test and in the murine P-388 leukemia model.
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154
Biedenkopf, N.; Lange-Grünweller, K.; Schulte, F. W.; Weißer, A.; Müller, C.; Becker, D.; Becker, S.; Hartmann, R. K.; Grünweller, A. The Natural Compound Silvestrol Is a Potent Inhibitor of Ebola Virus Replication. Antiviral Res. 2017, 137, 76– 81, DOI: 10.1016/j.antiviral.2016.11.011
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154
The natural compound silvestrol is a potent inhibitor of Ebola virus replication
Biedenkopf, Nadine; Lange-Gruenweller, Kerstin; Schulte, Falk W.; Weisser, Aileen; Mueller, Christin; Becker, Dirk; Becker, Stephan; Hartmann, Roland K.; Gruenweller, Arnold
Antiviral Research (2017), 137 (), 76-81CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
The DEAD-box RNA helicase eIF4A, which is part of the heterotrimeric translation initiation complex in eukaryotes, is an important novel drug target in cancer research because its helicase activity is required to unwind extended and highly structured 5'-UTRs of several proto-oncogenes. Silvestrol, a natural compd. isolated from the plant Aglaia foveolata, is a highly efficient, non-toxic and specific inhibitor of eIF4A. Importantly, 5'-capped viral mRNAs often contain structured 5'-UTRs as well, which may suggest a dependence on eIF4A for their translation by the host protein synthesis machinery. In view of the recent Ebola virus (EBOV) outbreak in West Africa, the identification of potent antiviral compds. is urgently required. Since Ebola mRNAs are 5'-capped and harbor RNA secondary structures in their extended 5'-UTRs, we initiated a BSL4 study to analyze silvestrol in EBOV-infected Huh-7 cells and in primary human macrophages for its antiviral activity. We obsd. that silvestrol inhibits EBOV infection at low nanomolar concns., as inferred from large redns. of viral titers. This correlated with an almost complete disappearance of EBOV proteins, comparable in effect to the translational shutdown of expression of the proto-oncoprotein PIM1, a cellular kinase known to be affected by silvestrol. Effective silvestrol concns. were non-toxic in the tested cell systems. Thus, silvestrol appears to be a promising first-line drug for the treatment of acute EBOV and possibly other viral infections.
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155
Werner, G.; Hagenmaier, H.; Albert, K.; Kohlshorn, H. The Structure of the Bafilomycins, a New Group of Macrolide Antibiotics. Tetrahedron Lett. 1983, 24 (47), 5193– 5196, DOI: 10.1016/S0040-4039(00)88394-X
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155
The structure of the bafilomycins, a new group of macrolide antibiotics
Werner, Gerhard; Hagenmaier, Hanspaul; Albert, Klaus; Kohlshorn, Heinz; Drautz, Hannelore
Tetrahedron Letters (1983), 24 (47), 5193-6CODEN: TELEAY; ISSN:0040-4039.
Bafilomycins A1 (I), A2, B2, C1, and C2 were isolated from EtOAc ext. of the culture medium of Streptomyces griseus subspecies sulfurus by column chromatog. on silica gel with CHCl3-MeOH (9:1). Each component was further purified by multiple column chromatog. on silica gel. Structures of these 16-membered lactone macrolide antibiotics were detd. mainly by spectroscopic studies; physicochem. properties of these antibiotics are given.
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156
Yonezawa, A.; Cavrois, M.; Greene, W. C. Studies of Ebola Virus Glycoprotein-Mediated Entry and Fusion by Using Pseudotyped Human Immunodeficiency Virus Type 1 Virions: Involvement of Cytoskeletal Proteins and Enhancement by Tumor Necrosis Factor Alpha. J. Virol. 2005, 79 (2), 918– 926, DOI: 10.1128/JVI.79.2.918-926.2005
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156
Studies of Ebola virus glycoprotein-mediated entry and fusion by using pseudotyped human immunodeficiency virus type 1 virions: Involvement of cytoskeletal proteins and enhancement by tumor necrosis factor alpha
Yonezawa, Akihito; Cavrois, Marielle; Greene, Warner C.
Journal of Virology (2005), 79 (2), 918-926CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
The Ebola filoviruses are aggressive pathogens that cause severe and often lethal hemorrhagic fever syndromes in humans and nonhuman primates. To date, no effective therapies have been identified. To analyze the entry and fusion properties of Ebola virus, the authors adapted a human immunodeficiency virus type 1 (HIV-1) virion-based fusion assay by substituting Ebola virus glycoprotein (GP) for the HIV-1 envelope. Fusion was detected by cleavage of the fluorogenic substrate CCF2 by β-lactamase-Vpr incorporated into virions and released as a result of virion fusion. Entry and fusion induced by the Ebola virus GP occurred with much slower kinetics than with vesicular stomatitis virus G protein (VSV-G) and were blocked by depletion of membrane cholesterol and by inhibition of vesicular acidification with bafilomycin A1. These properties confirmed earlier studies and validated the assay for exploring other properties of Ebola virus GP-mediated entry and fusion. Entry and fusion of Ebola virus GP pseudotypes, but not VSV-G or HIV-1 Env pseudotypes, were impaired in the presence of the microtubule-disrupting agent nocodazole but were enhanced in the presence of the microtubule-stabilizing agent paclitaxel (Taxol). Agents that impaired microfilament function, including cytochalasin B, cytochalasin D, latrunculin A, and jasplakinolide, also inhibited Ebola virus GP-mediated entry and fusion. Together, these findings suggest that both microtubules and microfilaments may play a role in the effective trafficking of vesicles contg. Ebola virions from the cell surface to the appropriate acidified vesicular compartment where fusion occurs. In terms of Ebola virus GP-mediated entry and fusion to various target cells, primary macrophages proved highly sensitive, while monocytes from the same donors displayed greatly reduced levels of entry and fusion. The authors further obsd. that tumor necrosis factor alpha, which is released by Ebola virus-infected monocytes/macrophages, enhanced Ebola virus GP-mediated entry and fusion to human umbilical vein endothelial cells. Thus, Ebola virus infection of one target cell may induce biol. changes that facilitate infection of secondary target cells that play a key role in filovirus pathogenesis. Finally, these studies indicate that pseudotyping in the HIV-1 virion-based fusion assay may be a valuable approach to the study of entry and fusion properties mediated through the envelopes of other viral pathogens.
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157
Aldridge, D. C.; Armstrong, J. J.; Speake, R. N.; Turner, W. B. The Cytochalasins, a New Class of Biologically Active Mould Metabolites. Chem. Commun. 1967, 26– 27, DOI: 10.1039/c19670000026
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157
Cytochalasins, a new class of biologically active mold metabolites
Aldridge, D. C.; Armstrong, J. J.; Speake, Roy N.; Turner, William Brian
Chemical Communications (London) (1967), (1), 26-7CODEN: CCOMA8; ISSN:0009-241X.
A new class of mold products was isolated for which the name cytochalasins (cyto = cell, chalasis = relaxation) was proposed. Four cytochalasins (A and B from Helminthosporium dematioideum and C and D from Metarrhizium amisopliae) were isolated. Structures (Ia) and (IIb) have been suggested for cytochalasin A (C29H35NO5) and cytochalasin B (C29H37NO5), resp. The relation between cytochalasins A and B was established by oxidn. of the latter to the former with MnO2. Cytochalasins C and D are isomers, C30H37NO6, whose relation to each other has not been established.
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158
Kashman, Y.; Groweiss, A.; Shmueli, U. Latrunculin, a New 2-Thiazolidinone Macrolide from the Marine Sponge Latrunculia Magnifica. Tetrahedron Lett. 1980, 21 (37), 3629– 3632, DOI: 10.1016/0040-4039(80)80255-3
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158
Latrunculin, a new 2-thiazolidinone macrolide from the marine sponge Latrunculia magnifica
Kashman, Y.; Groweiss, A.; Shmueli, U.
Tetrahedron Letters (1980), 21 (37), 3629-32CODEN: TELEAY; ISSN:0040-4039.
L. magnifica, Yielded 3 new thiazolidinone macrolide toxins, named latrunculin-A (I), -B (II), and -C (a stereoisomer of I); structures were detd. by chem. and spectral anal. with special ref. to x-ray diffraction data of a cryst. deriv. of I. The biogenesis of the latrunculins, a new class of 14- and 16-membered macrolides to which the 2-thiazolidinone moiety is attached, is proposed.
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159
Crews, P.; Manes, L. V.; Boehler, M. Jasplakinolide, a Cyclodepsipeptide from the Marine Sponge, Jaspis SP. Tetrahedron Lett. 1986, 27 (25), 2797– 2800, DOI: 10.1016/S0040-4039(00)84645-6
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159
Jasplakinolide, a cyclodepsipeptide from the marine sponge, Jaspis sp
Crews, Phillip; Manes, Lawrence V.; Boehler, Mark
Tetrahedron Letters (1986), 27 (25), 2797-800CODEN: TELEAY; ISSN:0040-4039.
Jasplakinolide (I), which has antifungal and anthelminthic bioactivity, was isolated from the soft sponge Jaspis and its structure was detd. as a cyclodepsipeptide comprised of 3 amino acids and an oxy-trimethyl-nonanoyl group by using NMR and mass spectrometry.
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160
Beck, S.; Henß, L.; Weidner, T.; Herrmann, J.; Müller, R.; Chao, Y.-K.; Grimm, C.; Weber, C.; Sliva, K.; Schnierle, B. S. Identification of Entry Inhibitors of Ebola Virus Pseudotyped Vectors from a Myxobacterial Compound Library. Antiviral Res. 2016, 132, 85– 91, DOI: 10.1016/j.antiviral.2016.05.017
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160
Identification of entry inhibitors of Ebola virus pseudotyped vectors from a myxobacterial compound library
Beck, Simon; Henss, Lisa; Weidner, Tatjana; Herrmann, Jennifer; Mueller, Rolf; Chao, Yu-Kai; Grimm, Christian; Weber, Christopher; Sliva, Katja; Schnierle, Barbara S.
Antiviral Research (2016), 132 (), 85-91CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
Myxobacteria produce secondary metabolites many of which were described to have various biol. effects including anti-fungal, anti-bacterial and anti-viral activity. The majority of these metabolites are novel scaffolds with unique modes-of-action and hence might be potential leads for drug discovery. Here, we tested a myxobacterial natural product library for compds. with inhibitory activity against Ebola virus (EBOV). The assay was performed with a surrogate system using Ebola envelope glycoprotein (GP) pseudotyped lentiviral vectors. EBOV specificity was proven by counter-screening with vesicular stomatitis virus G protein pseudotyped vectors. Two compds. were identified that preferentially inhibited EBOV GP mediated cell entry: Chondramides that act on the actin skeleton but might be too toxic and noricumazole A, a potassium channel inhibitor, which might constitute a novel pathway to inhibit Ebola virus cell entry.
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161
Kunze, B.; Jansen, R.; Sasse, F.; Höfle, G.; Reichenbach, H. Chondramides A-D, New Antifungal and Cytostatic Depsipeptides from Chondromyces Crocatus (Myxobacteria). J. Antibiot. 1995, 48 (11), 1262– 1266, DOI: 10.7164/antibiotics.48.1262
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161
Antibiotics from gliding bacteria. 71. Chondramides A-D, new antifungal and cytostatic depsipeptides from Chondromyces crocatus (Myxobacteria): production, physico-chemical and biological properties
Kunze, Brigitte; Jansen, Rolf; Sasse, Florenz; Hoefle, Gerhard; Reichenbach, Hans
Journal of Antibiotics (1995), 48 (11), 1262-6CODEN: JANTAJ; ISSN:0021-8820. (Japan Antibiotics Research Association)
Novel depsipeptides, named chondramides were produced at levels up to 4.3 mg/L by several myxobacteria of the genus Chondromyces. The compds. are structurally closely related to jaspamide/jasplakinolide from marine sponges of the genus Jaspis. Initially the chondramides were detected in acetone exts. of the biomass of Chondromyces crocatus, strain Cm c2. So far, four structural variants could be characterized, the chondramides A-D. They inhibited the growth of a few yeasts and showed high cytostatic activity against cultivated human and animal cells.
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162
Herrmann, J.; Hüttel, S.; Müller, R. Discovery and Biological Activity of New Chondramides from Chondromyces Sp. ChemBioChem 2013, 14 (13), 1573– 1580, DOI: 10.1002/cbic.201300140
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162
Discovery and Biological Activity of New Chondramides from Chondromyces sp.
Herrmann, Jennifer; Huettel, Stephan; Mueller, Rolf
ChemBioChem (2013), 14 (13), 1573-1580CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
Myxobacteria have proven to be highly valuable sources of natural products, as they produce a variety of secondary metabolites with unique structures and often new modes of action. In this study, high-content screening is demonstrated to be a convenient tool for bioactivity-guided isolation of natural products from crude bacterial exts. By the application of focused, image-based screens we were able to identify over 30 novel chondramide derivs. from Chondromyces sp. MSr9030, some of which were present in only minute amts. These cyclic depsipeptides were shown to target actin filaments with a similar binding mode to that of the mushroom toxin phalloidin. Fermns. of the myxobacterial strain were carried out under improved cultivation conditions, and supplementation of the culture broth with potassium bromide afforded the prodn. of brominated analogs that are superior (in terms of biol. activity) to all chondramides described to date. Initial biol. profiling of 11 new derivs. in comparison to the ref. compds. (chondramides A-C) showed that bromo-chondramide C3 and propionyl-bromo-chondramide C3 are the most active in cell-based studies, with GI50 values on human cancer cell lines in the low nanomolar range. Given that these brominated C3 analogs were also less potent on noncancerous human cells (by a factor of 2 to 4 in comparison to cancer cell lines), our results can aid further structure-activity relationship-guided development of chondramides, either as mol. probes or pharmaceutical agents.
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163
Fan, H.-H.; Wang, L.-Q.; Liu, W.-L.; An, X.-P.; Liu, Z.-D.; He, X.-Q.; Song, L.-H.; Tong, Y.-G. Repurposing of Clinically Approved Drugs for Treatment of Coronavirus Disease 2019 in a 2019-Novel Coronavirus-Related Coronavirus Model. Chin. Med. J. (Engl.) 2020, 133 (9), 1051– 1056, DOI: 10.1097/CM9.0000000000000797
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163
Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus-related coronavirus model
Fan Hua-Hao; Wang Li-Qin; Liu Wen-Li; An Xiao-Ping; Liu Zhen-Dong; He Xiao-Qi; Song Li-Hua; Tong Yi-Gang
Chinese medical journal (2020), 133 (9), 1051-1056 ISSN:.
BACKGROUND: Medicines for the treatment of 2019-novel coronavirus (2019-nCoV) infections are urgently needed. However, drug screening using live 2019-nCoV requires high-level biosafety facilities, which imposes an obstacle for those institutions without such facilities or 2019-nCoV. This study aims to repurpose the clinically approved drugs for the treatment of coronavirus disease 2019 (COVID-19) in a 2019-nCoV-related coronavirus model. METHODS: A 2019-nCoV-related pangolin coronavirus GX_P2V/pangolin/2017/Guangxi was described. Whether GX_P2V uses angiotensin-converting enzyme 2 (ACE2) as the cell receptor was investigated by using small interfering RNA (siRNA)-mediated silencing of ACE2. The pangolin coronavirus model was used to identify drug candidates for treating 2019-nCoV infection. Two libraries of 2406 clinically approved drugs were screened for their ability to inhibit cytopathic effects on Vero E6 cells by GX_P2V infection. The anti-viral activities and anti-viral mechanisms of potential drugs were further investigated. Viral yields of RNAs and infectious particles were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and plaque assay, respectively. RESULTS: The spike protein of coronavirus GX_P2V shares 92.2% amino acid identity with that of 2019-nCoV isolate Wuhan-hu-1, and uses ACE2 as the receptor for infection just like 2019-nCoV. Three drugs, including cepharanthine (CEP), selamectin, and mefloquine hydrochloride, exhibited complete inhibition of cytopathic effects in cell culture at 10 μmol/L. CEP demonstrated the most potent inhibition of GX_P2V infection, with a concentration for 50% of maximal effect [EC50] of 0.98 μmol/L. The viral RNA yield in cells treated with 10 μmol/L CEP was 15,393-fold lower than in cells without CEP treatment ([6.48 ± 0.02] × 10vs. 1.00 ± 0.12, t = 150.38, P < 0.001) at 72 h post-infection (p.i.). Plaque assays found no production of live viruses in media containing 10 μmol/L CEP at 48 h p.i. Furthermore, we found CEP had potent anti-viral activities against both viral entry (0.46 ± 0.12, vs.1.00 ± 0.37, t = 2.42, P < 0.05) and viral replication ([6.18 ± 0.95] × 10vs. 1.00 ± 0.43, t = 3.98, P < 0.05). CONCLUSIONS: Our pangolin coronavirus GX_P2V is a workable model for 2019-nCoV research. CEP, selamectin, and mefloquine hydrochloride are potential drugs for treating 2019-nCoV infection. Our results strongly suggest that CEP is a wide-spectrum inhibitor of pan-betacoronavirus, and further study of CEP for treatment of 2019-nCoV infection is warranted.
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Li, S.; Chen, C.; Zhang, H.; Guo, H.; Wang, H.; Wang, L.; Zhang, X.; Hua, S.; Yu, J.; Xiao, P. Identification of Natural Compounds with Antiviral Activities against SARS-Associated Coronavirus. Antiviral Res. 2005, 67 (1), 18– 23, DOI: 10.1016/j.antiviral.2005.02.007
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164
Identification of natural compounds with antiviral activities against SARS-associated coronavirus
Li, Shi-you; Chen, Cong; Zhang, Hai-qing; Guo, Hai-yan; Wang, Hui; Wang, Lin; Zhang, Xiang; Hua, Shi-neng; Yu, Jun; Xiao, Pei-gen; Li, Rong-song; Tan, Xuehai
Antiviral Research (2005), 67 (1), 18-23CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
More than 200 Chinese medicinal herb exts. were screened for antiviral activities against Severe Acute Respiratory Syndrome-assocd. coronavirus (SARS-CoV) using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay for virus-induced cytopathic effect (CPE). Four of these exts. showed moderate to potent antiviral activities against SARS-CoV with 50% effective concn. (EC50) ranging from 2.4±0.2 to 88.2±7.7 μg/mL. Out of the four, Lycoris radiata was most potent. To identify the active component, L. radiata ext. was subjected to further fractionation, purifn., and CPE/MTS assays. This process led to the identification of a single substance lycorine as an anti-SARS-CoV component with an EC50 value of 15.7±1.2 nM. This compd. has a CC50 value of 14980.0±912.0 nM in cytotoxicity assay and a selective index (SI) greater than 900. The results suggested that four herbal exts. and the compd. lycorine are candidates for the development of new anti-SARS-CoV drugs in the treatment of SARS.
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Lane, T.; Anantpadma, M.; Freundlich, J. S.; Davey, R. A.; Madrid, P. B.; Ekins, S. The Natural Product Eugenol Is an Inhibitor of the Ebola Virus In Vitro. Pharm. Res. 2019, 36 (7), 104, DOI: 10.1007/s11095-019-2629-0
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165
The Natural Product Eugenol Is an Inhibitor of the Ebola Virus In Vitro
Lane Thomas; Ekins Sean; Anantpadma Manu; Davey Robert A; Anantpadma Manu; Davey Robert A; Freundlich Joel S; Madrid Peter B
Pharmaceutical research (2019), 36 (7), 104 ISSN:.
PURPOSE: Since the 2014 Ebola virus (EBOV) outbreak in West Africa there has been considerable effort towards developing drugs to treat Ebola virus disease and yet to date there is no FDA approved treatment. This is important as at the time of writing this manuscript there is an ongoing outbreak in the Democratic Republic of the Congo which has killed over 1000. METHODS: We have evaluated a small number of natural products, some of which had shown antiviral activity against other pathogens. This is exemplified with eugenol, which is found in high concentrations in multiple essential oils, and has shown antiviral activity against feline calicivirus, tomato yellow leaf curl virus, Influenza A virus, Herpes Simplex virus type 1 and 2, and four airborne phages. RESULTS: Four compounds possessed EC50 values less than or equal to 11 μM. Of these, eugenol, had an EC50 of 1.3 μM against EBOV and is present in several plants including clove, cinnamon, basil and bay. Eugenol is much smaller and structurally unlike any compound that has been previously identified as an inhibitor of EBOV, therefore it may provide new mechanistic insights. CONCLUSION: This compound is readily accessible in bulk quantities, is inexpensive, and has a long history of human consumption, which endorses the idea for further assessment as an antiviral therapeutic. This work also suggests that a more exhaustive assessment of natural product libraries against EBOV and other viruses is warranted to improve our ability to identify compounds that are so distinct from FDA approved drugs.
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Caly, L.; Druce, J. D.; Catton, M. G.; Jans, D. A.; Wagstaff, K. M. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in Vitro. Antiviral Res. 2020, 178, 104787, DOI: 10.1016/j.antiviral.2020.104787
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The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro
Caly, Leon; Druce, Julian D.; Catton, Mike G.; Jans, David A.; Wagstaff, Kylie M.
Antiviral Research (2020), 178 (), 104787CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
Although several clin. trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addn. to Vero-hSLAM cells 2 h post infection with SARS-CoV-2 able to effect ∼5000-fold redn. in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.
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Chaccour, C.; Hammann, F.; Ramon-Garcia, S.; Rabinovich, N. R. Ivermectin and COVID-19: Keeping Rigor in Times of Urgency. Am. J. Trop. Med. Hyg. 2020, 102, 1156– 1157, DOI: 10.4269/ajtmh.20-0271
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Chaccour Carlos; Rabinovich N Regina; Chaccour Carlos; Chaccour Carlos; Hammann Felix; Ramon-Garcia Santiago; Ramon-Garcia Santiago; Rabinovich N Regina
The American journal of tropical medicine and hygiene (2020), 102 (6), 1156-1157 ISSN:.
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Gaurav Joshi, Jayant Sindhu, Shikha Thakur, Abhilash Rana, Geetika Sharma, Mayank, Ramarao Poduri. Recent efforts for drug identification from phytochemicals against SARS-CoV-2: Exploration of the chemical space to identify druggable leads. Food and Chemical Toxicology 2021, 152 , 112160. https://doi.org/10.1016/j.fct.2021.112160

Abstract
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Figure 1
Figure 1. Life cycle of coronaviruses as represented by the SARS-CoV-1/2 and MERS-CoV viruses. The Roman numerals in the figure refer to entries in Table 2. The “T” symbol indicates a target with potential for developing an inhibitor.
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Figure 2
Figure 2. Life cycle of Flaviviridae as represented by the dengue virus. The Roman numerals in the figure refer to entries in Table 3. The “T” symbol indicates a target with potential for developing an inhibitor.
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Figure 3
Figure 3. Life cycle of filoviruses as represented by the Ebola virus. The Roman numerals in the figure refer to the entries in Table 4. The “T” symbol indicates a target with potential for developing an inhibitor.
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Figure 4
Figure 4. Schematic diagrams for the genomes of coronavirus SARS-CoV-2 (Coronaviridae), Dengue virus (Flaviviridae), and Ebola virus (Filoviridae). The genomes of Coronaviridae and Flaviviridae are composed of single-strand positive-sense RNA, whereas those of the Filoviridae are composed of a single strand of negative-sense RNA. Genes labeled by Roman numerals encode potential druggable protein targets mentioned in this review and accord with the same Roman numerals used in Figures 1–3 and Tables 2–4. Capsid protein (pink), spike protein (red), polymerase (brown), enzyme (orange), structural protein (green), envelope protein (yellow), cofactor/activator (blue), others/undefined protein (gray).
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Figure 5
Figure 5. Inhibitors of viral structural proteins of (A) Coronaviridae, (B) Flaviviridae, or (C) Filoviridae. The following are natural products: griffithsin (PDB: 2GTY), emodin, nordihydroguaiaretic acid, ellagic acid, gallic acid, cyanovirin-N (11, PDB: 2EZM), and natural product derivatives: PG545, 8, 9, 10.
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Figure 6
Figure 6. Inhibitors of viral proteases 3CLpro (A), PLpro (B), or NS3 (C). The following are natural products: herbacetin, pectolinarin, rhoifolin, tomentin B, hirsutenone, cryptotanshinone, psoralidin, ganodermanotriol, ivermectin, and natural product derivatives: rupintrivir.
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Figure 7
Figure 7. Inhibitors of viral replicase complex component RdRp. Shown here are compounds that are inhibitors of Coronaviridae, Flaviviridae, Filoviridae, or multiple families. The following are natural products: mycophenolic acid and sinefungin, and natural product derivatives: Remdesivir, Favipiravir, Ribavirin, Galdesivir, β-d-N4-hydroxycytidine, BCX4430.
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Figure 8
Figure 8. Inhibitors of viral helicase. All of these are natural products.
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Figure 9
Figure 9. Inhibitors of selected accessory proteins. Celgosivir is a derivative of the natural product castanospermine.
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Figure 10
Figure 10. Inhibitors of host cysteine proteases cathepsin L/B or serine proteases TMPRSS2/4. The following are natural products: aprotinin, gallinamide A, nicolaiodesin C, grassypeptolide, leupeptin, tokoramide A, miraziridine A, E-64d, and natural product derivatives: 43, CA074.
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Figure 11
Figure 11. Inhibitors of other selected targets with activity to RNA viruses. All of these compounds are natural products.
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Figure 12
Figure 12. Inhibitors with demonstrated antiviral activity without a known target or mechanism of action. All of these compounds are natural products.
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  Deutsch, Liat; Houri, Inbal; Ben-Ari, Ziv; Shlomai, Amir; Veitsman, Ella; Cohen-Ezra, Oranit; Issachar, Assaf; Mor, Orna; Gozlan, Yael; Bruck, Rafael; Menachem, Yoram; Zelber-Sagi, Shira; Katchman, Helena; Shibolet, Oren
  BMC Infectious Diseases (2020), 20 (1), 264CODEN: BIDMBJ; ISSN:1471-2334. (BioMed Central Ltd.)
  Abstr.: Background: Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma. Treatment with first generation protease inhibitors (PI) + peg-interferon (pegIFN) and ribavirin (RBV) achieved sustained virol. response (SVR) rates of 65-75% but was assocd. with multiple side effects. The aim of this study was to evaluate safety and efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir (3D) ± RBV in HCV genotype 1 patients that failed previous treatment with first generation PIs. Methods: An investigator-initiated, open-label, multi-center clin. trial. HCV Genotype 1 patients who were previously null/partial responders or relapsers to telaprevir, boceprevir or simepravir+pegIFN/RBV and met eligibility criteria were included. 3D ± RBV were administrated for 12 or 24 wk according to label. The primary outcome was antiviral response (SVR12); Secondary outcomes were patient reported outcomes, adverse events and resistance assocd. variants. Results: Thirty-nine patients initiated treatment according to study protocol (59% men, age 54.0 ± 8.7 years, BMI 28.7 ± 4.5 kg/m2). Thirty-seven (94.9%) completed the study. Thirty-five patients had genotype 1b (9 cirrhotics) and 4 had genotype 1a (2 cirrhotics). Intention-to-treat SVR12 was 92.3% and per-protocol SVR12 was 97.3%. The rate of advanced fibrosis (FibroScan score F3-4) declined from 46.2 to 25.7% (P = 0.045). Abnormal ALT levels declined from 84.6 to 8.6% (P < 0.001). Seven patients (17.9%) experienced serious adverse events (3 Psychiatric admissions, 1 pneumonia, 1 ankle fracture, 2 palpitations), and 12 patients (30.8%) experienced self-reported adverse events, mostly weakness. Conclusion: 3D ± RBV is safe and effective in achieving SVR among patients with HCV genotype 1 who failed previous first-generation PI treatment. Trial registration: NCT02646111 (submitted to ClinicalTrials.gov, Dec. 28, 2015).
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16. 16
  Pol, S.; Lagaye, S. The Remarkable History of the Hepatitis C Virus. Genes Immun. 2019, 20 (5), 436– 446, DOI: 10.1038/s41435-019-0066-z
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  16
  The remarkable history of the hepatitis C virus
  Pol Stanislas; Pol Stanislas; Pol Stanislas; Pol Stanislas; Lagaye Sylvie; Pol Stanislas; Lagaye Sylvie
  Genes and immunity (2019), 20 (5), 436-446 ISSN:.
  The infection with the hepatitis C virus (HCV) is an example of the translational research success. The reciprocal interactions between clinicians and scientists have allowed in 30 years the initiation of empirical treatments by interferon, the discovery of the virus, the development of serological and virological tools for diagnosis but also for prognosis (the non-invasive biochemical or morphological fibrosis tests, the predictors of the specific immune response including genetic IL28B polymorphisms). Finally, well-tolerated and effective treatments with oral antivirals inhibiting HCV non-structural viral proteins involved in viral replication have been marketed this last decade, allowing the cure of all infected subjects. HCV chronic infection, which is a public health issue, is a hepatic disease, which may lead to a cirrhosis and an hepatocellular carcinoma (HCC) but also a systemic disease with extra-hepatic manifestations either associated with a cryoglobulinemic vasculitis or chronic inflammation. The HCV infection is the only chronic viral infection, which may be cured: the so-called sustained virologic response, defined by undetectable HCV RNA 12 weeks after the end of the treatment, significantly reduces the risk of morbidity and mortality associated with hepatic and extra-hepatic manifestations, which are mainly reversible. The history of HCV ends with the pangenotypic efficacy of the multiple combinations, easy to use for 8-12 weeks with one to three pills per day and little problems of tolerance. This explains the short 30 years from the virus discovery to the viral hepatitis elimination policy proposed by the World Health Organization (WHO) in 2016.
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17. 17
  Perlman, S. Another Decade, Another Coronavirus. N. Engl. J. Med. 2020, 382 (8), 760– 762, DOI: 10.1056/NEJMe2001126
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  17
  Another Decade, Another Coronavirus
  Perlman Stanley
  The New England journal of medicine (2020), 382 (8), 760-762 ISSN:.
  There is no expanded citation for this reference.
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18. 18
  Dong, E.; Du, H.; Gardner, L. An Interactive Web-Based Dashboard to Track COVID-19 in Real Time. Lancet Infect. Dis. 2020, 20 (5), 533– 534, DOI: 10.1016/S1473-3099(20)30120-1
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  18
  An interactive web-based dashboard to track COVID-19 in real time
  Dong, Ensheng; Du, Hongru; Gardner, Lauren
  Lancet Infectious Diseases (2020), 20 (5), 533-534CODEN: LIDABP; ISSN:1473-3099. (Elsevier Ltd.)
  The authors describe the development of an online interactive dashboard, hosted by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University, Baltimore, MD, USA, to visualize and track reported cases of coronavirus disease 2019 (COVID-19) in real time. The dashboard, first shared publicly on Jan 22, illustrates the location and no. of confirmed COVID-19 cases, deaths, and recoveries for all affected countries. It was developed to provide researchers, public health authorities, and the general public with a user-friendly tool to track the outbreak as it unfolds. All data collected and displayed are made freely available, initially through Google Sheets and now through a GitHub repository, along with the feature layers of the dashboard, which are now included in the Esri Living Atlas.
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19. 19
  Gorbalenya, A. E.; Baker, S. C.; Baric, R. S.; de Groot, R. J.; Drosten, C.; Gulyaeva, A. A.; Haagmans, B. L.; Lauber, C.; Leontovich, A. M.; Neuman, B. W.; Penzar, D.; Perlman, S.; Poon, L. L. M.; Samborskiy, D. V.; Sidorov, I. A.; Sola, I.; Ziebuhr, J. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The Species Severe Acute Respiratory Syndrome-Related Coronavirus : Classifying 2019-NCoV and Naming It SARS-CoV-2. Nat. Microbiol. 2020, 5 (4), 536– 544, DOI: 10.1038/s41564-020-0695-z
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  There is no corresponding record for this reference.
20. 20
  Weiss, S. R.; Leibowitz, J. L. Chapter 4 - Coronavirus Pathogenesis. In Advances in Virus Research; Maramorosch, K., Shatkin, A. J., Murphy, F. A., Eds.; Academic Press, 2011; Vol. 81, pp 85– 164.
  Google Scholar
  There is no corresponding record for this reference.
21. 21
  Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R.; Niu, P.; Zhan, F.; Ma, X.; Wang, D.; Xu, W.; Wu, G.; Gao, G. F.; Tan, W. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N. Engl. J. Med. 2020, 382 (8), 727– 733, DOI: 10.1056/NEJMoa2001017
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  21
  A novel coronavirus from patients with pneumonia in China, 2019
  Zhu, Na; Zhang, Dingyu; Wang, Wenling; Li, Xingwang; Yang, Bo; Song, Jingdong; Zhao, Xiang; Huang, Baoying; Shi, Weifeng; Lu, Roujian; Niu, Peihua; Zhan, Faxian; Ma, Xuejun; Wang, Dayan; Xu, Wenbo; Wu, Guizhen; Gao, George F.; Tan, Wenjie
  New England Journal of Medicine (2020), 382 (8), 727-733CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)
  In Dec. 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. Complete genome sequences of the three novel coronaviruses were submitted to GISAID (BetaCoV/Wuhan/ IVDC-HB-01/2019, accession ID: EPI_ISL_402119; BetaCoV/Wuhan/IVDC-HB-04/2020, accession ID: EPI_ISL_402120; BetaCoV/Wuhan/IVDC-HB-05/2019, accession ID: EPI_ISL_402121).
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22. 22
  Muramatsu, T.; Takemoto, C.; Kim, Y.-T.; Wang, H.; Nishii, W.; Terada, T.; Shirouzu, M.; Yokoyama, S. SARS-CoV 3CL Protease Cleaves Its C-Terminal Autoprocessing Site by Novel Subsite Cooperativity. Proc. Natl. Acad. Sci. U. S. A. 2016, 113 (46), 12997– 13002, DOI: 10.1073/pnas.1601327113
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  22
  SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity
  Muramatsu, Tomonari; Takemoto, Chie; Kim, Yong-Tae; Wang, Hongfei; Nishii, Wataru; Terada, Takaho; Shirouzu, Mikako; Yokoyama, Shigeyuki
  Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (46), 12997-13002CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  The 3C-like protease (3CLpro) of severe acute respiratory syndrome coronavirus (SARS-CoV) cleaves 11 sites in the polyproteins, including its own N- and C-terminal autoprocessing sites, by recognizing P4-P1 and P1'. In this study, we detd. the crystal structure of 3CLpro with the C-terminal prosequence and the catalytic-site C145A mutation, in which the enzyme binds the C-terminal prosequence of another mol. Surprisingly, Phe at the P3' position [Phe(P3')] is snugly accommodated in the S3' pocket. Mutations of Phe(P3') impaired the C-terminal autoprocessing, but did not affect N-terminal autoprocessing. This difference was ascribed to the P2 residue, Phe(P2) and Leu(P2), in the C- and N-terminal sites, as follows. The S3' subsite is formed by Phe(P2)-induced conformational changes of 3CLpro and the direct involvement of Phe(P2) itself. In contrast, the N-terminal prosequence with Leu(P2) does not cause such conformational changes for the S3' subsite formation. In fact, the mutation of Phe(P2) to Leu in the C-terminal autoprocessing site abolishes the dependence on Phe(P3'). These mechanisms explain why Phe is required at the P3' position when the P2 position is occupied by Phe rather than Leu, which reveals a type of subsite cooperativity. Moreover, the peptide consisting of P4-P1 with Leu(P2) inhibits protease activity, whereas that with Phe(P2) exhibits a much smaller inhibitory effect, because Phe(P3') is missing. Thus, this subsite cooperativity likely exists to avoid the autoinhibition of the enzyme by its mature C-terminal sequence, and to retain the efficient C-terminal autoprocessing by the use of Phe(P2).
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23. 23
  Zhang, T.; Wu, Q.; Zhang, Z. Probable Pangolin Origin of SARS-CoV-2 Associated with the COVID-19 Outbreak. Curr. Biol. 2020, 30 (7), 1346– 1351, DOI: 10.1016/j.cub.2020.03.022
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  23
  Probable Pangolin Origin of SARS-CoV-2 Associated with the COVID-19 Outbreak
  Zhang, Tao; Wu, Qunfu; Zhang, Zhigang
  Current Biology (2020), 30 (7), 1346-1351.e2CODEN: CUBLE2; ISSN:0960-9822. (Cell Press)
  An outbreak of coronavirus disease 2019 (COVID-19) caused by the 2019 novel coronavirus (SARS-CoV-2) began in the city of Wuhan in China and has widely spread worldwide. Currently, it is vital to explore potential intermediate hosts of SARS-CoV-2 to control COVID-19 spread. Therefore, we reinvestigated published data from pangolin lung samples from which SARS-CoV-like CoVs were detected by Liu et al. (2019). We found genomic and evolutionary evidence of the occurrence of a SARS-CoV-2-like CoV (named Pangolin-CoV) in dead Malayan pangolins (Manis javanica). Pangolin-CoV is 91.02% and 90.55% identical to SARS-CoV-2 and BatCoV RaTG13, resp., at the whole-genome level. Aside from bat CoV RaTG13, Pangolin-CoV is the most closely related CoV to SARS-CoV-2. The S1 protein of Pangolin-CoV is much more closely related to SARS-CoV-2 than to RaTG13. Five key amino acid residues involved in the interaction with human ACE2 are completely consistent between Pangolin-CoV and SARS-CoV-2, but four amino acid mutations are present in RaTG13. Both Pangolin-CoV and RaTG13 lost the putative furin recognition sequence motif at S1/S2 cleavage site that can be obsd. in the SARS-CoV-2. Conclusively, this study suggests that pangolin species are a natural reservoir of SARS-CoV-2-like CoVs.
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24. 24
  Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T. S.; Herrler, G.; Wu, N.-H.; Nitsche, A.; Müller, M. A.; Drosten, C.; Pöhlmann, S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020, 181 (2), 271– 280, DOI: 10.1016/j.cell.2020.02.052
  [Crossref], [PubMed], [CAS], Google Scholar
  24
  SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor
  Hoffmann, Markus; Kleine-Weber, Hannah; Schroeder, Simon; Krueger, Nadine; Herrler, Tanja; Erichsen, Sandra; Schiergens, Tobias S.; Herrler, Georg; Wu, Nai-Huei; Nitsche, Andreas; Mueller, Marcel A.; Drosten, Christian; Poehlmann, Stefan
  Cell (Cambridge, MA, United States) (2020), 181 (2), 271-280.e8CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
  The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clin. use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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25. 25
  Yan, R.; Zhang, Y.; Li, Y.; Xia, L.; Guo, Y.; Zhou, Q. Structural Basis for the Recognition of SARS-CoV-2 by Full-Length Human ACE2. Science 2020, 367 (6485), 1444– 1448, DOI: 10.1126/science.abb2762
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  25
  Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2
  Yan, Renhong; Zhang, Yuanyuan; Li, Yaning; Xia, Lu; Guo, Yingying; Zhou, Qiang
  Science (Washington, DC, United States) (2020), 367 (6485), 1444-1448CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
  Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious coronavirus disease 2019 (COVID-19) epidemic. Here, we present cryo-electron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter B0AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resoln. of 2.9 angstroms, with a local resoln. of 3.5 angstroms at the ACE2-RBD interface. The ACE2-B0AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues. These findings provide important insights into the mol. basis for coronavirus recognition and infection.
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26. 26
  Lu, G.; Hu, Y.; Wang, Q.; Qi, J.; Gao, F.; Li, Y.; Zhang, Y.; Zhang, W.; Yuan, Y.; Bao, J.; Zhang, B.; Shi, Y.; Yan, J.; Gao, G. F. Molecular Basis of Binding between Novel Human Coronavirus MERS-CoV and Its Receptor CD26. Nature 2013, 500 (7461), 227– 231, DOI: 10.1038/nature12328
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  26
  Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26
  Lu, Guangwen; Hu, Yawei; Wang, Qihui; Qi, Jianxun; Gao, Feng; Li, Yan; Zhang, Yanfang; Zhang, Wei; Yuan, Yuan; Bao, Jinku; Zhang, Buchang; Shi, Yi; Yan, Jinghua; Gao, George F.
  Nature (London, United Kingdom) (2013), 500 (7461), 227-231CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  The newly emergent Middle East respiratory syndrome coronavirus (MERS-CoV) can cause severe pulmonary disease in humans, representing the second example of a highly pathogenic coronavirus, the first being SARS-CoV. CD26 (also known as dipeptidyl peptidase 4, DPP4) was recently identified as the cellular receptor for MERS-CoV. The engagement of the MERS-CoV spike protein with CD26 mediates viral attachment to host cells and virus-cell fusion, thereby initiating infection. Here we delineate the mol. basis of this specific interaction by presenting the first crystal structures of both the free receptor binding domain (RBD) of the MERS-CoV spike protein and its complex with CD26. Furthermore, binding between the RBD and CD26 is measured using real-time surface plasmon resonance with a dissocn. const. of 16.7nM. The viral RBD is composed of a core subdomain homologous to that of the SARS-CoV spike protein, and a unique strand-dominated external receptor binding motif that recognizes blades IV and V of the CD26 β-propeller. The at. details at the interface between the two binding entities reveal a surprising protein-protein contact mediated mainly by hydrophilic residues. Sequence alignment indicates, among betacoronaviruses, a possible structural conservation for the region homologous to the MERS-CoV RBD core, but a high variation in the external receptor binding motif region for virus-specific pathogenesis such as receptor recognition.
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27. 27
  Wrapp, D.; Wang, N.; Corbett, K. S.; Goldsmith, J. A.; Hsieh, C.-L.; Abiona, O.; Graham, B. S.; McLellan, J. S. Cryo-EM Structure of the 2019-NCoV Spike in the Prefusion Conformation. Science 2020, 367 (6483), 1260– 1263, DOI: 10.1126/science.abb2507
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  27
  Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation
  Wrapp, Daniel; Wang, Nianshuang; Corbett, Kizzmekia S.; Goldsmith, Jory A.; Hsieh, Ching-Lin; Abiona, Olubukola; Graham, Barney S.; McLellan, Jason S.
  Science (Washington, DC, United States) (2020), 367 (6483), 1260-1263CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
  The outbreak of a novel coronavirus (2019-nCoV) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure development, we detd. a 3.5-angstrom-resoln. cryo-electron microscopy structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also provide biophys. and structural evidence that the 2019-nCoV S protein binds angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute respiratory syndrome (SARS)-CoV S. Addnl., we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two RBDs. The structure of 2019-nCoV S should enable the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis.
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28. 28
  Zang, R.; Castro, M. F. G.; McCune, B. T.; Zeng, Q.; Rothlauf, P. W.; Sonnek, N. M.; Liu, Z.; Brulois, K. F.; Wang, X.; Greenberg, H. B.; Diamond, M. S.; Ciorba, M. A.; Whelan, S. P. J.; Ding, S. TMPRSS2 and TMPRSS4 Promote SARS-CoV-2 Infection of Human Small Intestinal Enterocytes. Sci. Immunol. 2020, 5 (47), eabc3582 DOI: 10.1126/sciimmunol.abc3582 .
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  There is no corresponding record for this reference.
29. 29
  Simmons, G.; Gosalia, D. N.; Rennekamp, A. J.; Reeves, J. D.; Diamond, S. L.; Bates, P. Inhibitors of Cathepsin L Prevent Severe Acute Respiratory Syndrome Coronavirus Entry. Proc. Natl. Acad. Sci. U. S. A. 2005, 102 (33), 11876– 11881, DOI: 10.1073/pnas.0505577102
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  29
  Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry
  Simmons, Graham; Gosalia, Dhaval N.; Rennekamp, Andrew J.; Reeves, Jacqueline D.; Diamond, Scott L.; Bates, Paul
  Proceedings of the National Academy of Sciences of the United States of America (2005), 102 (33), 11876-11881CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  Severe acute respiratory syndrome (SARS) is caused by an emergent coronavirus (SARS-CoV), for which there is currently no effective treatment. SARS-CoV mediates receptor binding and entry by its spike (S) glycoprotein, and infection is sensitive to lysosomotropic agents that perturb endosomal pH. We demonstrate here that the lysosomotropic-agent-mediated block to SARS-CoV infection is overcome by protease treatment of target-cell-assocd. virus. In addn., SARS-CoV infection was blocked by specific inhibitors of the pH-sensitive endosomal protease cathepsin L. A cell-free membrane-fusion system demonstrates that engagement of receptor followed by proteolysis is required for SARS-CoV membrane fusion and indicates that cathepsin L is sufficient to activate membrane fusion by SARS-CoV S. These results suggest that SARS-CoV infection results from a unique, three-step process: receptor binding and induced conformational changes in S glycoprotein followed by cathepsin L proteolysis within endosomes. The requirement for cathepsin L proteolysis identifies a previously uncharacterized class of inhibitor for SARS-CoV infection.
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30. 30
  Gierer, S.; Bertram, S.; Kaup, F.; Wrensch, F.; Heurich, A.; Krämer-Kühl, A.; Welsch, K.; Winkler, M.; Meyer, B.; Drosten, C.; Dittmer, U.; von Hahn, T.; Simmons, G.; Hofmann, H.; Pöhlmann, S. The Spike Protein of the Emerging Betacoronavirus EMC Uses a Novel Coronavirus Receptor for Entry, Can Be Activated by TMPRSS2, and Is Targeted by Neutralizing Antibodies. J. Virol. 2013, 87 (10), 5502– 5511, DOI: 10.1128/JVI.00128-13
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  30
  The spike protein of the emerging betacoronavirus EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing antibodies
  Gierer, Stefanie; Bertram, Stephanie; Kaup, Franziska; Wrensch, Florian; Heurich, Adeline; Kraemer-Kuehl, Annika; Welsch, Kathrin; Winkler, Michael; Meyer, Benjamin; Drosten, Christian; Dittmer, Ulf; von Hahn, Thomas; Simmons, Graham; Hofmann, Heike; Poehlmann, Stefan
  Journal of Virology (2013), 87 (10), 5502-5511CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
  The novel human coronavirus EMC (hCoV-EMC), which recently emerged in Saudi Arabia, is highly pathogenic and could pose a significant threat to public health. The elucidation of hCoV-EMC interactions with host cells is crit. to our understanding of the pathogenesis of this virus and to the identification of targets for antiviral intervention. Here we investigated the viral and cellular determinants governing hCoV-EMC entry into host cells. We found that the spike protein of hCoV-EMC (EMC-S) is incorporated into lentiviral particles and mediates transduction of human cell lines derived from different organs, including the lungs, kidneys, and colon, as well as primary human macrophages. Expression of the known coronavirus receptors ACE2, CD13, and CEACAM1 did not facilitate EMC-S-driven transduction, suggesting that hCoV-EMC uses a novel receptor for entry. Directed protease expression and inhibition analyses revealed that TMPRSS2 and endosomal cathepsins activate EMC-S for virus-cell fusion and constitute potential targets for antiviral intervention. Finally, EMC-S-driven transduction was abrogated by serum from an hCoV-EMC-infected patient, indicating that EMC-S-specific neutralizing antibodies can be generated in patients. Collectively, our results indicate that hCoV-EMC uses a novel receptor for protease-activated entry into human cells and might be capable of extrapulmonary spread. In addn., they define TMPRSS2 and cathepsins B and L as potential targets for intervention and suggest that neutralizing antibodies contribute to the control of hCoV-EMC infection.
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31. 31
  Yuan, M.; Wu, N. C.; Zhu, X.; Lee, C.-C. D.; So, R. T. Y.; Lv, H.; Mok, C. K. P.; Wilson, I. A. A Highly Conserved Cryptic Epitope in the Receptor-Binding Domains of SARS-CoV-2 and SARS-CoV. Science 2020, 368, 630 DOI: 10.1126/science.abb7269 .
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  31
  A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV
  Yuan, Meng; Wu, Nicholas C.; Zhu, Xueyong; Lee, Chang-Chun D.; So, Ray T. Y.; Lv, Huibin; Mok, Chris K. P.; Wilson, Ian A.
  Science (Washington, DC, United States) (2020), 368 (6491), 630-633CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
  The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has now become a pandemic, but there is currently very little understanding of the antigenicity of the virus. We therefore detd. the crystal structure of CR3022, a neutralizing antibody previously isolated from a convalescent SARS patient, in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein at 3.1-angstrom resoln. CR3022 targets a highly conserved epitope, distal from the receptor binding site, that enables cross-reactive binding between SARS-CoV-2 and SARS-CoV. Structural modeling further demonstrates that the binding epitope can only be accessed by CR3022 when at least two RBDs on the trimeric S protein are in the "up" conformation and slightly rotated. These results provide mol. insights into antibody recognition of SARS-CoV-2.
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32. 32
  Kawase, M.; Shirato, K.; van der Hoek, L.; Taguchi, F.; Matsuyama, S. Simultaneous Treatment of Human Bronchial Epithelial Cells with Serine and Cysteine Protease Inhibitors Prevents Severe Acute Respiratory Syndrome Coronavirus Entry. J. Virol. 2012, 86 (12), 6537– 6545, DOI: 10.1128/JVI.00094-12
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  32
  Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry
  Kawase, Miyuki; Shirato, Kazuya; van der Hoek, Lia; Taguchi, Fumihiro; Matsuyama, Shutoku
  Journal of Virology (2012), 86 (12), 6537-6545CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
  The type II transmembrane protease TMPRSS2 activates the spike (S) protein of severe acute respiratory syndrome coronavirus (SARS-CoV) on the cell surface following receptor binding during viral entry into cells. In the absence of TMPRSS2, SARS-CoV achieves cell entry via an endosomal pathway in which cathepsin L may play an important role, i.e., the activation of spike protein fusogenicity. This study shows that a com. serine protease inhibitor (camostat) partially blocked infection by SARS-CoV and human coronavirus NL63 (HCoV-NL63) in HeLa cells expressing the receptor angiotensin-converting enzyme 2 (ACE2) and TMPRSS2. Simultaneous treatment of the cells with camostat and EST [(23,25)trans-epoxysuccinyl-L-leucylamindo-3-methylbutane Et ester], a cathepsin inhibitor, efficiently prevented both cell entry and the multistep growth of SARS-CoV in human Calu-3 airway epithelial cells. This efficient inhibition could be attributed to the dual blockade of entry from the cell surface and through the endosomal pathway. These observations suggest camostat as a candidate antiviral drug to prevent or depress TMPRSS2-dependent infection by SARS-CoV.
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33. 33
  Fehr, A. R.; Perlman, S. Coronaviruses: An Overview of Their Replication and Pathogenesis. In Coronaviruses: Methods and Protocols; Maier, H. J., Bickerton, E., Britton, P., Eds.; Methods in Molecular Biology; Springer: New York, NY, 2015; pp 1– 23.
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34. 34
  Yin, W.; Mao, C.; Luan, X.; Shen, D.-D.; Shen, Q.; Su, H.; Wang, X.; Zhou, F.; Zhao, W.; Gao, M.; Chang, S.; Xie, Y.-C.; Tian, G.; Jiang, H.-W.; Tao, S.-C.; Shen, J.; Jiang, Y.; Jiang, H.; Xu, Y.; Zhang, S.; Zhang, Y.; Xu, H. E. Structural Basis for Inhibition of the RNA-Dependent RNA Polymerase from SARS-CoV-2 by Remdesivir. Science 2020, 368, 1499 DOI: 10.1126/science.abc1560 .
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  Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir
  Yin, Wanchao; Mao, Chunyou; Luan, Xiaodong; Shen, Dan-Dan; Shen, Qingya; Su, Haixia; Wang, Xiaoxi; Zhou, Fulai; Zhao, Wenfeng; Gao, Minqi; Chang, Shenghai; Xie, Yuan-Chao; Tian, Guanghui; Jiang, He-Wei; Tao, Sheng-Ce; Shen, Jingshan; Jiang, Yi; Jiang, Hualiang; Xu, Yechun; Zhang, Shuyang; Zhang, Yan; Xu, H. Eric
  Science (Washington, DC, United States) (2020), 368 (6498), 1499-1504CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
  The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global crisis. Replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp) enzyme, a target of the antiviral drug remdesivir. Here, we report the cryo-electron microscopy structure of the SARS-CoV-2 RdRp, both in the apo form at 2.8-angstrom resoln. and in complex with a 50-base template-primer RNA and remdesivir at 2.5-angstrom resoln. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp, where remdesivir is covalently incorporated into the primer strand at the first replicated base pair, and terminates chain elongation. Our structures provide insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.
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35. 35
  Gordon, C. J.; Tchesnokov, E. P.; Woolner, E.; Perry, J. K.; Feng, J. Y.; Porter, D. P.; Gotte, M. Remdesivir Is a Direct-Acting Antiviral That Inhibits RNA-Dependent RNA Polymerase from Severe Acute Respiratory Syndrome Coronavirus 2 with High Potency. J. Biol. Chem. 2020, 295, 6785, DOI: 10.1074/jbc.RA120.013679
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  Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency
  Gordon, Calvin J.; Tchesnokov, Egor P.; Woolner, Emma; Perry, Jason K.; Feng, Joy Y.; Porter, Danielle P.; Gotte, Matthias
  Journal of Biological Chemistry (2020), 295 (20), 6785-6797CODEN: JBCHA3; ISSN:1083-351X. (American Society for Biochemistry and Molecular Biology)
  Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed to control this current pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of SARS-CoV-2 depends on the viral RNA-dependent RNA polymerase (RdRp), which is the likely target of the investigational nucleotide analog remdesivir (RDV). RDV shows broad-spectrum antiviral activity against RNA viruses, and previous studies with RdRps from Ebola virus and Middle East respiratory syndrome coronavirus (MERS-CoV) have revealed that delayed chain termination is RDV's plausible mechanism of action. Here, we expressed and purified active SARS-CoV-2 RdRp composed of the nonstructural proteins nsp8 and nsp12. Enzyme kinetics indicated that this RdRp efficiently incorporates the active triphosphate form of RDV (RDV-TP) into RNA. Incorporation of RDV-TP at position i caused termination of RNA synthesis at position i + 3. We obtained almost identical results with SARS-CoV, MERS-CoV, and SARS-CoV-2 RdRps. A unique property of RDV-TP is its high selectivity over incorporation of its natural nucleotide counterpart ATP. In this regard, the triphosphate forms of 2'-C-methylated compds., including sofosbuvir, approved for the management of hepatitis C virus infection, and the broad-acting antivirals favipiravir and ribavirin, exhibited significant deficits. Furthermore, we provide evidence for the target specificity of RDV, as RDV-TP was less efficiently incorporated by the distantly related Lassa virus RdRp, and termination of RNA synthesis was not obsd. These results collectively provide a unifying, refined mechanism of RDV-mediated RNA synthesis inhibition in coronaviruses and define this nucleotide analog as a direct-acting antiviral.
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36. 36
  Sanders, J. M.; Monogue, M. L.; Jodlowski, T. Z.; Cutrell, J. B. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA 2020, DOI: 10.1001/jama.2020.6019 .
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  Pillaiyar, T.; Manickam, M.; Namasivayam, V.; Hayashi, Y.; Jung, S.-H. An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy. J. Med. Chem. 2016, 59 (14), 6595– 6628, DOI: 10.1021/acs.jmedchem.5b01461
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  37
  An Overview of Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy
  Pillaiyar, Thanigaimalai; Manickam, Manoj; Namasivayam, Vigneshwaran; Hayashi, Yoshio; Jung, Sang-Hun
  Journal of Medicinal Chemistry (2016), 59 (14), 6595-6628CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Severe acute respiratory syndrome (SARS) is caused by a newly emerged coronavirus that infected more than 8000 individuals and resulted in more than 800 (10-15%) fatalities in 2003. The causative agent of SARS has been identified as a novel human coronavirus (SARS-CoV), and its viral protease, SARS-CoV 3CLpro, has been shown to be essential for replication and has hence been recognized as a potent drug target for SARS infection. Currently, there is no effective treatment for this epidemic despite the intensive research that has been undertaken since 2003 (over 3500 publications). This perspective focuses on the status of various efficacious anti-SARS-CoV 3CLpro chemotherapies discovered during the last 12 years (2003-2015) from all sources, including lab. synthetic methods, natural products, and virtual screening. We describe here mainly peptidomimetic and small mol. inhibitors of SARS-CoV 3CLpro. Attempts have been made to provide a complete description of the structural features and binding modes of these inhibitors under many conditions.
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38. 38
  Lee, H.; Lei, H.; Santarsiero, B. D.; Gatuz, J. L.; Cao, S.; Rice, A. J.; Patel, K.; Szypulinski, M. Z.; Ojeda, I.; Ghosh, A. K.; Johnson, M. E. Inhibitor Recognition Specificity of MERS-CoV Papain-like Protease May Differ from That of SARS-CoV. ACS Chem. Biol. 2015, 10 (6), 1456– 1465, DOI: 10.1021/cb500917m
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  38
  Inhibitor Recognition Specificity of MERS-CoV Papain-like Protease May Differ from That of SARS-CoV
  Lee, Hyun; Lei, Hao; Santarsiero, Bernard D.; Gatuz, Joseph L.; Cao, Shuyi; Rice, Amy J.; Patel, Kavankumar; Szypulinski, Michael Z.; Ojeda, Isabel; Ghosh, Arun K.; Johnson, Michael E.
  ACS Chemical Biology (2015), 10 (6), 1456-1465CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
  The Middle East Respiratory Syndrome coronavirus (MERS-CoV) papain-like protease (PLpro) blocking loop 2 (BL2) structure differs significantly from that of SARS-CoV PLpro, where it has been proven to play a crucial role in SARS-CoV PLpro inhibitor binding. Four SARS-CoV PLpro lead inhibitors were tested against MERS-CoV PLpro, none of which were effective against MERS-CoV PLpro. Structure and sequence alignments revealed that two residues, Y269 and Q270, responsible for inhibitor binding to SARS-CoV PLpro, were replaced by T274 and A275 in MERS-CoV PLpro, making crit. binding interactions difficult to form for similar types of inhibitors. High-throughput screening (HTS) of 25 000 compds. against both PLpro enzymes identified a small fragment-like noncovalent dual inhibitor. Mode of inhibition studies by enzyme kinetics and competition surface plasmon resonance (SPR) analyses suggested that this compd. acts as a competitive inhibitor with an IC50 of 6 μM against MERS-CoV PLpro, indicating that it binds to the active site, whereas it acts as an allosteric inhibitor against SARS-CoV PLpro with an IC50 of 11 μM. These results raised the possibility that inhibitor recognition specificity of MERS-CoV PLpro may differ from that of SARS-CoV PLpro. In addn., inhibitory activity of this compd. was selective for SARS-CoV and MERS-CoV PLpro enzymes over two human homologs, the ubiquitin C-terminal hydrolases 1 and 3 (hUCH-L1 and hUCH-L3).
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39. 39
  Salles, T. S.; da Encarnação Sá-Guimarães, T.; de Alvarenga, E. S. L.; Guimarães-Ribeiro, V.; de Meneses, M. D. F.; de Castro-Salles, P. F.; dos Santos, C. R.; do Amaral Melo, A. C.; Soares, M. R.; Ferreira, D. F.; Moreira, M. F. History, Epidemiology and Diagnostics of Dengue in the American and Brazilian Contexts: A Review. Parasites Vectors 2018, 11 (1), 264, DOI: 10.1186/s13071-018-2830-8
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  History, epidemiology and diagnostics of dengue in the American and Brazilian contexts: a review
  Salles Tiago Souza; da Encarnacao Sa-Guimaraes Thayane; de Alvarenga Evelyn Seam Lima; Guimaraes-Ribeiro Victor; do Amaral Melo Ana Claudia; Soares Marcia Regina; Moreira Monica Ferreira; Salles Tiago Souza; de Meneses Marcelo Damiao Ferreira; Ferreira Davis Fernandes; de Castro-Salles Patricia Faria; Dos Santos Carlucio Rocha; do Amaral Melo Ana Claudia; Moreira Monica Ferreira; Ferreira Davis Fernandes
  Parasites & vectors (2018), 11 (1), 264 ISSN:.
  Dengue virus (DENV), an arbovirus transmitted by mosquitoes, has become a major threat to American human life, reaching approximately 23 million cases from 1980 to 2017. Brazil is among the countries most affected by this terrible viral disease, with 13.6 million cases. DENV has four different serotypes, DENV1-4, which show a broad clinical spectrum. Dengue creates a staggering epidemiological and economic burden for endemic countries. Without a specific therapy and with a commercial vaccine that presents some problems relative to its full effectiveness, initiatives to improve vector control strategies, early disease diagnostics and the development of vaccines and antiviral drugs are priorities. In this study, we present the probable origins of dengue in America and the trajectories of its spread. Overall, dengue diagnostics are costly, making the monitoring of dengue epidemiology more difficult and affecting physicians' therapeutic decisions regarding dengue patients, especially in developing countries. This review also highlights some recent and important findings regarding dengue in Brazil and the Americas. We also summarize the existing DENV polymerase chain reaction (PCR) diagnostic tests to provide an improved reference since these tests are useful and accurate at discriminating DENV from other flaviviruses that co-circulate in the Americas. Additionally, these DENV PCR assays ensure virus serotyping, enabling epidemiologic monitoring.
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40. 40
  Michelitsch, A.; Tews, B. A.; Klaus, C.; Bestehorn-Willmann, M.; Dobler, G.; Beer, M.; Wernike, K. In Vivo Characterization of Tick-Borne Encephalitis Virus in Bank Voles (Myodes Glareolus). Viruses 2019, 11 (11), 1069, DOI: 10.3390/v11111069
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  40
  In vivo characterization of Tick-borne encephalitis virus in bank voles (Myodes glareolus)
  Michelitsch, Anna; Tews, Birke Andrea; Klaus, Christine; Bestehorn-Willmann, Malena; Dobler, Gerhard; Beer, Martin; Wernike, Kerstin
  Viruses (2019), 11 (11), 1069CODEN: VIRUBR; ISSN:1999-4915. (MDPI AG)
  Tick-borne encephalitis is the most important tick-transmitted zoonotic virus infection in Eurasia, causing severe neurol. symptoms in humans. The causative agent, the tick-borne encephalitis virus (TBEV), circulates between ticks and a variety of mammalian hosts. To study the interaction between TBEV and one of its suspected reservoir hosts, bank voles of the Western evolutionary lineage were inoculated s.c. with either one of eight TBEV strains or the related attenuated Langat virus, and were euthanized after 28 days. In addn., a subset of four strains was characterized in bank voles of the Carpathian linage. Six bank voles were inoculated per strain, and were housed together in groups of three with one uninfected in-contact animal each. Generally, most bank voles did not show any clin. signs1 over the course of infection. However, one infected bank vole died and three had to be euthanized prematurely, all of which had been inoculated with the identical TBEV strain (Battaune 17-H9, isolated in 2017 in Germany from a bank vole). All inoculated animals seroconverted, while none of the in-contact animals did. Viral RNA was detected via real-time RT-PCR in the whole blood samples of 31 out of 74 inoculated and surviving bank voles. The corresponding serum sample remained PCR-neg. in nearly all cases (29/31). In addn., brain and/or spine samples tested pos. in 11 cases, mostly correlating with a pos. whole blood sample. Our findings suggest a good adaptation of TBEV to bank voles, combining in most cases a low virulence phenotype with detectable virus replication and hinting at a reservoir host function of bank voles for TBEV.
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41. 41
  Aguas, R.; Dorigatti, I.; Coudeville, L.; Luxemburger, C.; Ferguson, N. M. Cross-Serotype Interactions and Disease Outcome Prediction of Dengue Infections in Vietnam. Sci. Rep. 2019, 9 (1), 9395, DOI: 10.1038/s41598-019-45816-6
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  Cross-serotype interactions and disease outcome prediction of dengue infections in Vietnam
  Aguas R; Dorigatti I; Ferguson N M; Aguas R; Aguas R; Coudeville L; Luxemburger C
  Scientific reports (2019), 9 (1), 9395 ISSN:.
  Dengue pathogenesis is extremely complex. Dengue infections are thought to induce life-long immunity from homologous challenges as well as a multi-factorial heterologous risk enhancement. Here, we use the data collected from a prospective cohort study of dengue infections in schoolchildren in Vietnam to disentangle how serotype interactions modulate clinical disease risk in the year following serum collection. We use multinomial logistic regression to correlate the yearly neutralizing antibody measurements obtained with each infecting serotype in all dengue clinical cases collected over the course of 6 years (2004-2009). This allowed us to extrapolate a fully discretised matrix of serotype interactions, revealing clear signals of increased risk of clinical illness in individuals primed with a previous dengue infection. The sequences of infections which produced a higher risk of dengue fever upon secondary infection are: DEN1 followed by DEN2; DEN1 followed by DEN4; DEN2 followed by DEN3; and DEN4 followed by DEN3. We also used this longitudinal data to train a machine learning algorithm on antibody titre differences between consecutive years to unveil asymptomatic dengue infections and estimate asymptomatic infection to clinical case ratios over time, allowing for a better characterisation of the population's past exposure to different serotypes.
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42. 42
  Hadfield, J.; Brito, A. F.; Swetnam, D. M.; Vogels, C. B. F.; Tokarz, R. E.; Andersen, K. G.; Smith, R. C.; Bedford, T.; Grubaugh, N. D. Twenty Years of West Nile Virus Spread and Evolution in the Americas Visualized by Nextstrain. PLoS Pathog. 2019, 15 (10), e1008042, DOI: 10.1371/journal.ppat.1008042
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  Twenty years of west nile virus spread and evolution in the americas visualized by nextstrain
  Hadfield, James; Brito, Anderson F.; Swetnam, Daniele M.; Vogels, Chantal B. F.; Tokarz, Ryan E.; Andersen, Kristian G.; Smith, Ryan C.; Bedford, Trevor; Grubaugh, Nathan D.
  PLoS Pathogens (2019), 15 (10), e1008042CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
  It has been 20 years since West Nile virus first emerged in the Americas, and since then, little progress has been made to control outbreaks caused by this virus. After its first detection in New York in 1999, West Nile virus quickly spread across the continent, causing an epidemic of human disease and massive bird die-offs. Now the virus has become endemic to the United States, where an estd. 7 million human infections have occurred, making it the leading mosquito-borne virus infection and the most common cause of viral encephalitis in the country. To bring new attention to one of the most important mosquito-borne viruses in the Americas, we provide an interactive review using Nextstrain: a visualization tool for real-time tracking of pathogen evolution. Nextstrain utilizes a growing database of more than 2,000 West Nile virus genomes and harnesses the power of phylogenetics for students, educators, public health workers, and researchers to visualize key aspects of virus spread and evolution. Using Nextstrain, we use virus genomics to investigate the emergence of West Nile virus in the U S, followed by its rapid spread, evolution in a new environment, establishment of endemic transmission, and subsequent international spread. For each figure, we include a link to Nextstrain to allow the readers to directly interact with and explore the underlying data in new ways. We also provide a brief online narrative that parallels this review to further explain the data and highlight key epidemiol. and evolutionary features. Mirroring the dynamic nature of outbreaks, the Nextstrain links provided within this paper are constantly updated as new West Nile virus genomes are shared publicly, helping to stay current with the research. Overall, our review showcases how genomics can track West Nile virus spread and evolution, as well as potentially uncover novel targeted control measures to help alleviate its public health burden.
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43. 43
  https://www.cdc.gov/westnile/healthcareproviders/healthCareProviders-TreatmentPrevention.html.
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  Rodrigues, L. C. Microcephaly and Zika Virus Infection. Lancet 2016, 387 (10033), 2070– 2072, DOI: 10.1016/S0140-6736(16)00742-X
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  Microcephaly and Zika virus infection
  Rodrigues Laura C
  Lancet (London, England) (2016), 387 (10033), 2070-2072 ISSN:.
  There is no expanded citation for this reference.
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  Turtle, L.; Solomon, T. Japanese Encephalitis — the Prospects for New Treatments. Nat. Rev. Neurol. 2018, 14 (5), 298– 313, DOI: 10.1038/nrneurol.2018.30
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  Japanese encephalitis - the prospects for new treatments
  Turtle Lance; Solomon Tom; Turtle Lance; Solomon Tom
  Nature reviews. Neurology (2018), 14 (5), 298-313 ISSN:.
  Japanese encephalitis is a mosquito-borne disease that occurs in Asia and is caused by Japanese encephalitis virus (JEV), a member of the genus Flavivirus. Although many flaviviruses can cause encephalitis, JEV causes particularly severe neurological manifestations. The virus causes loss of more disability-adjusted life years than any other arthropod-borne virus owing to the frequent neurological sequelae of the condition. Despite substantial advances in our understanding of Japanese encephalitis from in vitro studies and animal models, studies of pathogenesis and treatment in humans are lagging behind. Few mechanistic studies have been conducted in humans, and only four clinical trials of therapies for Japanese encephalitis have taken place in the past 10 years despite an estimated incidence of 69,000 cases per year. Previous trials for Japanese encephalitis might have been too small to detect important benefits of potential treatments. Many potential treatment targets exist for Japanese encephalitis, and pathogenesis and virological studies have uncovered mechanisms by which these drugs could work. In this Review, we summarize the epidemiology, clinical features, prevention and treatment of Japanese encephalitis and focus on potential new therapeutic strategies, based on repurposing existing compounds that are already suitable for human use and could be trialled without delay. We use our newly improved understanding of Japanese encephalitis pathogenesis to posit potential treatments and outline some of the many challenges that remain in tackling the disease in humans.
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46. 46
  https://www.cdc.gov/japaneseencephalitis/vaccine/index.html.
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  Velay, A.; Paz, M.; Cesbron, M.; Gantner, P.; Solis, M.; Soulier, E.; Argemi, X.; Martinot, M.; Hansmann, Y.; Fafi-Kremer, S. Tick-Borne Encephalitis Virus: Molecular Determinants of Neuropathogenesis of an Emerging Pathogen. Crit. Rev. Microbiol. 2019, 45 (4), 472– 493, DOI: 10.1080/1040841X.2019.1629872
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  Tick-borne encephalitis virus: molecular determinants of neuropathogenesis of an emerging pathogen
  Velay Aurelie; Paz Magali; Cesbron Marlene; Gantner Pierre; Solis Morgane; Fafi-Kremer Samira; Velay Aurelie; Gantner Pierre; Solis Morgane; Soulier Eric; Fafi-Kremer Samira; Argemi Xavier; Hansmann Yves; Martinot Martin
  Critical reviews in microbiology (2019), 45 (4), 472-493 ISSN:.
  Tick-borne encephalitis virus (TBEV) is a zoonotic agent causing severe encephalitis. The transmission cycle involves the virus, the Ixodes tick vector, and a vertebrate reservoir, such as small mammals (rodents, or shrews). Humans are accidentally involved in this transmission cycle. Tick-borne encephalitis (TBE) has been a growing public health problem in Europe and Asia over the past 30 years. The mechanisms involved in the development of TBE are very complex and likely multifactorial, involving both host and viral factors. The purpose of this review is to provide an overview of the current literature on TBE neuropathogenesis in the human host and to demonstrate the emergence of common themes in the molecular pathogenesis of TBE in humans. We discuss and review data on experimental study models and on both viral (molecular genetics of TBEV) and host (immune response, and genetic background) factors involved in TBE neuropathogenesis in the context of human infection.
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48. 48
  Hui, L.; Nie, Y.; Li, S.; Guo, M.; Yang, W.; Huang, R.; Chen, J.; Liu, Y.; Lu, X.; Chen, Z.; Yang, Q.; Wu, Y. Matrix Metalloproteinase 9 Facilitates Zika Virus Invasion of the Testis by Modulating the Integrity of the Blood-Testis Barrier. PLoS Pathog. 2020, 16 (4), e1008509, DOI: 10.1371/journal.ppat.1008509
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  Matrix metalloproteinase 9 facilitates Zika virus invasion of the testis by modulating the integrity of the blood-testis barrier
  Hui, Lixia; Nie, Yiwen; Li, Shihua; Guo, Moujian; Yang, Wei; Huang, Rui; Chen, Junsen; Liu, Yingxia; Lu, Xuancheng; Chen, Zhen; Yang, Qingyu; Wu, Ying
  PLoS Pathogens (2020), 16 (4), e1008509/1-e1008509/22CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
  Zika virus (ZIKV) is a unique flavivirus with high tropism to the testes. ZIKV can persist in human semen for months and can cause testicular damage in male mice. However, the mechanisms through which ZIKV enters the testes remain unclear. In this study, we revealed that matrix metalloproteinase 9 (MMP9) was upregulated by ZIKV infection in cell culture and in A129 mice. Furthermore, using an in vitro Sertoli cell barrier model and MMP9-/- mice, we found that ZIKV infection directly affected the permeability of the bloodtestis barrier (BTB), and knockout or inhibition of MMP9 reduced the effects of ZIKV on the Sertoli cell BTB, highlighting its role in ZIKV-induced disruption of the BTB. Interestingly, the protein levels of MMP9 were elevated by ZIKV nonstructural protein 1 (NS1) in primary mouse Sertoli cells (mSCs) and other cell lines. Moreover, the interaction between NS1 and MMP9 induced the K63-linked polyubiquitination of MMP9, which enhanced the stability of MMP9. The upregulated MMP9 level led to the degrdn. of essential proteins involved in the maintenance of the BTB, such as tight junction proteins (TJPs) and type IV collagens. Collectively, we concluded that ZIKV infection promoted the expression of MMP9 which was further stabilized by NS1 induced K63-linked polyubiquitination to affect the TJPs/ type IV collagen network, thereby disrupting the BTB and facilitating ZIKV entry into the testes.
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49. 49
  Wang, P.; Dai, J.; Bai, F.; Kong, K.-F.; Wong, S. J.; Montgomery, R. R.; Madri, J. A.; Fikrig, E. Matrix Metalloproteinase 9 Facilitates West Nile Virus Entry into the Brain. J. Virol. 2008, 82 (18), 8978– 8985, DOI: 10.1128/JVI.00314-08
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  Matrix metalloproteinase 9 facilitates West Nile virus entry into the brain
  Wang, Penghua; Dai, Jianfeng; Bai, Fengwei; Kong, Kok-Fai; Wong, Susan J.; Montgomery, Ruth R.; Madri, Joseph A.; Fikrig, Erol
  Journal of Virology (2008), 82 (18), 8978-8985CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
  West Nile virus (WNV) is the most-common cause of mosquito-borne encephalitis in the United States. Invasion of the brain by WNV is influenced by viral and host factors, and the mol. mechanism underlying disruption of the blood-brain barrier is likely multifactorial. Here we show that matrix metalloproteinase 9 (MMP9) is involved in WNV entry into the brain by enhancing blood-brain barrier permeability. Murine MMP9 expression was induced in the circulation shortly after WNV infection, and the protein levels remained high even when viremia subsided. In the murine brain, MMP9 expression and its enzymic activity were upregulated and MMP9 was shown to partly localize to the blood vessels. Interestingly, we also found that cerebrospinal fluid from patients suffering from WNV contained increased MMP9 levels. The peripheral viremia and expression of host cytokines were not altered in MMP9-/- mice; however, these animals were protected from lethal WNV challenge. The resistance of MMP9-/- mice to WNV infection correlated with an intact blood-brain barrier since IgG, Evans blue leakage into brain, and type IV collagen degrdn. were markedly reduced in the MMP9-/- mice compared with their levels in controls. Consistent with this, the brain viral loads, selected inflammatory cytokines, and leukocyte infiltrates were significantly reduced in the MMP9-/- mice compared to their levels in wild-type mice. These data suggest that MMP9 plays a role in mediating WNV entry into the central nervous system and that strategies to interrupt this process may influence the course of West Nile encephalitis.
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50. 50
  Glasner, D. R.; Ratnasiri, K.; Puerta-Guardo, H.; Espinosa, D. A.; Beatty, P. R.; Harris, E. Dengue Virus NS1 Cytokine-Independent Vascular Leak Is Dependent on Endothelial Glycocalyx Components. PLoS Pathog. 2017, 13 (11), e1006673, DOI: 10.1371/journal.ppat.1006673
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  Dengue virus NS1 cytokine-independent vascular leak is dependent on endothelial glycocalyx components
  Glasner, Dustin R.; Ratnasiri, Kalani; Puerta-Guardo, Henry; Espinosa, Diego A.; Robert Beatty, P.; Harris, Eva
  PLoS Pathogens (2017), 13 (11), e1006673/1-e1006673/22CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
  Dengue virus (DENV) is the most prevalent, medically important mosquito-borne virus. Disease ranges from uncomplicated dengue to life-threatening disease, characterized by endothelial dysfunction and vascular leakage. Previously, we demonstrated that DENV nonstructural protein 1 (NS1) induces endothelial hyperpermeability in a systemic mouse model and human pulmonary endothelial cells, where NS1 disrupts the endothelial glycocalyx-like layer. NS1 also triggers release of inflammatory cytokines from PBMCs via TLR4. Here, we examd. the relative contributions of inflammatory mediators and endothelial cell-intrinsic pathways. In vivo, we demonstrated that DENV NS1 but not the closely-related West Nile virus NS1 triggers localized vascular leak in the dorsal dermis of wild-type C57BL/6 mice. In vitro, we showed that human dermal endothelial cells exposed to DENV NS1 do not produce inflammatory cytokines (TNF-a, IL-6, IL-8) and that blocking these cytokines does not affect DENV NS1-induced endothelial hyperpermeability. Further, we demonstrated that DENV NS1 induces vascular leak in TLR4- or TNF-a receptor-deficient mice at similar levels to wild-type animals. Finally, we blocked DENV NS1-induced vascular leak in vivo using inhibitors targeting mols. involved in glycocalyx disruption. Taken together, these data indicate that DENV NS1-induced endothelial cell-intrinsic vascular leak is independent of inflammatory cytokines but dependent on endothelial glycocalyx components.
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51. 51
  Gopala Reddy, S. B.; Chin, W.-X.; Shivananju, N. S. Dengue Virus NS2 and NS4: Minor Proteins, Mammoth Roles. Biochem. Pharmacol. 2018, 154, 54– 63, DOI: 10.1016/j.bcp.2018.04.008
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  Dengue virus NS2 and NS4: Minor proteins, mammoth roles
  Gopala Reddy, Sindhoora Bhargavi; Chin, Wei-Xin; Shivananju, Nanjunda Swamy
  Biochemical Pharmacology (Amsterdam, Netherlands) (2018), 154 (), 54-63CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)
  A review. Despite the ever-increasing global incidence of dengue fever, there are no specific chemotherapy regimens for its treatment. Structural studies on dengue virus (DENV) proteins have revealed potential drug targets. Major DENV proteins such as the envelope protein and non-structural (NS) proteins 3 and 5 have been extensively investigated in antiviral studies, but with limited success in vitro. However, the minor NS proteins NS2 and NS4 have remained relatively underreported. Emerging evidence indicating their indispensable roles in virus propagation and host immunomodulation should encourage us to target these proteins for drug discovery. This review covers current knowledge on DENV NS2 and NS4 proteins from structural and functional perspectives and assesses their potential as targets for antiviral design. Antiviral targets in NS2A include surface-exposed transmembrane regions involved in pathogenesis, while those in NS2B include protease-binding sites in a conserved hydrophilic domain. Ideal drug targets in NS4A include helix α4 and the PEPEKQR sequence, which are essential for NS4A-2K cleavage and NS4A-NS4B assocn., resp. In NS4B, the cytoplasmic loop connecting helixes α5 and α7 is an attractive target for antiviral design owing to its role in dimerization and NS4B-NS3 interaction. Findings implicating NS2A, NS2B, and NS4A in membrane-modulation and viroporin-like activities indicate an opportunity to target these proteins by disrupting their assocn. with membrane lipids. Despite the lack of 3D structural data, recent topol. findings and progress in structure-prediction methods should be sufficient impetus for targeting NS2 and NS4 for drug design.
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52. 52
  Bautista-Carbajal, P.; Soto-Acosta, R.; Angel-Ambrocio, A. H.; Cervantes-Salazar, M.; Loranca-Vega, C. I.; Herrera-Martínez, M.; del Angel, R. M. The Calmodulin Antagonist W-7 (N-(6-Aminohexyl)-5-Chloro-1-Naphthalenesulfonamide Hydrochloride) Inhibits DENV Infection in Huh-7 Cells. Virology 2017, 501, 188– 198, DOI: 10.1016/j.virol.2016.12.004
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  The calmodulin antagonist W-7 (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride) inhibits DENV infection in Huh-7 cells
  Bautista-Carbajal, Patricia; Soto-Acosta, Ruben; Angel-Ambrocio, Antonio H.; Cervantes-Salazar, Margot; Loranca-Vega, Circe I.; Herrera-Martinez, Mayra; del Angel, Rosa M.
  Virology (2017), 501 (), 188-198CODEN: VIRLAX; ISSN:0042-6822. (Elsevier B.V.)
  Dengue virus (DENV) replicative cycle occurs in the endoplasmic reticulum where calcium ions play an important role in cell signaling. Calmodulin (CaM) is the primary sensor of intracellular Ca2+ levels in eukaryotic cells. In this paper, the effect of the calmodulin antagonist W-7 in DENV infection in Huh-7 cells was evaluated. W7 inhibited viral yield, NS1 secretion and viral RNA and protein synthesis. Moreover, luciferase activity, encoded by a DENV replicon, was also reduced. A decrease in the replicative complexes formation was clearly obsd. in W7 treated cells. Docking simulations suggest 2 possible mechanisms of action for W7: the direct inhibition of NS2B-NS3 activity and/or inhibition of the interaction between NS2A with Ca2+-CaM complex. This last possibility was supported by the in vitro interaction obsd. between recombinant NS2A and CaM. These results indicate that Ca2+-CaM plays an important role in DENV replication.
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53. 53
  Falgout, B.; Pethel, M.; Zhang, Y. M.; Lai, C. J. Both Nonstructural Proteins NS2B and NS3 Are Required for the Proteolytic Processing of Dengue Virus Nonstructural Proteins. J. Virol. 1991, 65 (5), 2467– 2475, DOI: 10.1128/JVI.65.5.2467-2475.1991
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  Both nonstructural proteins NS2B and NS3 are required for the proteolytic processing of dengue virus nonstructural proteins
  Falgout, Barry; Pethel, Michele; Zhang, Yi Ming; Lai, Ching Juh
  Journal of Virology (1991), 65 (5), 2467-75CODEN: JOVIAM; ISSN:0022-538X.
  The cleavages at the junctions of the flavivirus nonstructural (NS) proteins NS2A/NS2B, NS2B/NS3, NS3/NS4A, and NS4B/NS5 share an amino acid sequence motif and are presumably catalyzed by a virus-encoded protease. Recombinant vaccinia viruses expressing various portions of the NS region of the dengue virus type 4 polyprotein were constructed. By analyzing immune ppts. of 35S-labeled lysates of recombinant virus-infected cells, the NS2A/NS2B, NS2B/NS3, and NS3/NS4A cleavages could be monitored. A polyprotein composed of NS2A, NS2B, and the N-terminal 184 amino acids of NS3 was cleaved at the NS2A/NS2B and NS2B/NS3 junctions, whereas a similar polyprotein contg. only the first 77 amino acids of NS3 was not cleaved. This finding is consistent with the proposal that the N-terminal 180 amino acids of NS3 constitute a protease domain. Polyproteins contg. NS2A and NS3 with large in-frame deletions of NS2B were not cleaved at the NS2A/NS2B or NS2B/NS3 junctions. Coinfection with a recombinant expressing NS2B complemented these NS2B deletions for NS2B/NS3 cleavage and probably also for NS2A/NS2B cleavage. Thus, NS2B is also required for the NS2A/NS2B and NS2B/NS3 cleavages and can act in trans. Other expts. showed that NS2B was needed, apparently in cis, for NS3/NS4A cleavage and for a series of internal cleavages in NS3. Indirect evidence that NS3 can also act in trans was obtained. Models are discussed for a two-component protease activity requiring both NS2B and NS3.
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54. 54
  Timiri, A. K.; Sinha, B. N.; Jayaprakash, V. Progress and Prospects on DENV Protease Inhibitors. Eur. J. Med. Chem. 2016, 117, 125– 143, DOI: 10.1016/j.ejmech.2016.04.008
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  Progress and prospects on DENV protease inhibitors
  Timiri, Ajay Kumar; Sinha, Barij Nayan; Jayaprakash, Venkatesan
  European Journal of Medicinal Chemistry (2016), 117 (), 125-143CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
  New treatments are desperately required to combat increasing rate of dengue fever cases reported in tropical and sub-tropical parts of the world. Among the ten proteins (structural and non-structural) encoded by dengue viral genome, NS2B-NS3 protease is an ideal target for drug discovery. It is responsible for the processing of poly protein that is required for genome replication of the virus. Moreover, inhibitors designed against proteases were found successful in Human Immuno-deficiency Virus (HIV) and Hepatitis C Virus (HCV). Complete mol. mechanism and a survey of inhibitors reported against dengue protease will be helpful in designing effective and potent inhibitors. This review provides an insight on mol. mechanism of dengue virus protease and covers up-to-date information on different inhibitors reported against dengue proteases with medicinal chem. perspective.
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  Miller, S.; Sparacio, S.; Bartenschlager, R. Subcellular Localization and Membrane Topology of the Dengue Virus Type 2 Non-Structural Protein 4B. J. Biol. Chem. 2006, 281 (13), 8854– 8863, DOI: 10.1074/jbc.M512697200
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  Subcellular Localization and Membrane Topology of the Dengue Virus Type 2 Non-structural Protein 4Bd2
  Miller, Sven; Sparacio, Sandra; Bartenschlager, Ralf
  Journal of Biological Chemistry (2006), 281 (13), 8854-8863CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
  Dengue virus (DV) is a member of the family Flavoviridae: these pos. strand RNA viruses encode a polyprotein that is processed in case of DV into 10 proteins. Although for most of these proteins distinct functions have been defined, this is less clear for the highly hydrophobic non-structural protein (NS) 4B. Despite its possible role as an antagonist of the interferon-induced antiviral response, this protein may play an addnl. more direct role for viral replication. In this study we detd. the subcellular localization, membrane assocn., and membrane topol. of DV NS4B. We found that NS4B resides primarily in cytoplasmic foci originating from the endoplasmic reticulum. NS4B colocalizes with NS3 and double-stranded RNA, an intermediate of viral replication, arguing that NS4B is part of the membrane-bound viral replication complex. Biochem. anal. revealed that NS4B is an integral membrane protein, and that its preceding 2K signal sequence is not required for this integration. We identified three membrane-spanning segments in the C-terminal part of NS4B that are sufficient to target a cytosolic marker protein to intracellular membranes. Furthermore, we established a membrane topol. model of NS4B in which the N-terminal part of the protein is localized in the endoplasmic reticulum lumen, whereas the C-terminal part is composed of three trans-membrane domains with the C-terminal tail localized in the cytoplasm. This topol. model provides a good starting point for a detailed investigation of the function of NS4B in the DV life cycle.
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56. 56
  Li, Y.; Wong, Y. L.; Lee, M. Y.; Li, Q.; Wang, Q.-Y.; Lescar, J.; Shi, P.-Y.; Kang, C. Secondary Structure and Membrane Topology of the Full-Length Dengue Virus NS4B in Micelles. Angew. Chem., Int. Ed. 2016, 55 (39), 12068– 12072, DOI: 10.1002/anie.201606609
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  Secondary Structure and Membrane Topology of the Full-Length Dengue Virus NS4B in Micelles
  Li, Yan; Wong, Ying Lei; Lee, Michelle Yueqi; Li, Qingxin; Wang, Qing-Yin; Lescar, Julien; Shi, Pei-Yong; Kang, Cong-Bao
  Angewandte Chemie, International Edition (2016), 55 (39), 12068-12072CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Dengue virus nonstructural protein 4B (NS4B) is a membrane protein consisting of 248 residues with a crucial role in virus replication and interference with the host innate immunity. The Dengue virus serotype 3 NS4B was reconstituted into lyso-myristoyl phosphatidylglycerol (LMPG) micelles. Backbone resonance assignment of NS4B was obtained using conventional soln. NMR expts. Further studies suggested that NS4B contained 11 helixes and 6 of them form 5 potential transmembrane regions. This study provides at. level information for an important drug target to control flavivirus infections.
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  Feldmann, H.; Klenk, H.-D. Marburg and Ebola Viruses. In Advances in Virus Research; Maramorosch, K., Murphy, F. A., Shatkin, A. J., Eds.; Academic Press, 1996; Vol. 47, pp 1– 52.
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  Di Paola, N.; Sanchez-Lockhart, M.; Zeng, X.; Kuhn, J. H.; Palacios, G. Viral Genomics in Ebola Virus Research. Nat. Rev. Microbiol. 2020, 18, 1– 14, DOI: 10.1038/s41579-020-0354-7
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  Miranda, M. E. G.; Miranda, N. L. J. Reston Ebolavirus in Humans and Animals in the Philippines: A Review. J. Infect. Dis. 2011, 204, S757– S760, DOI: 10.1093/infdis/jir296
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  Barrette, R. W.; Metwally, S. A.; Rowland, J. M.; Xu, L.; Zaki, S. R.; Nichol, S. T.; Rollin, P. E.; Towner, J. S.; Shieh, W.-J.; Batten, B.; Sealy, T. K.; Carrillo, C.; Moran, K. E.; Bracht, A. J.; Mayr, G. A.; Sirios-Cruz, M.; Catbagan, D. P.; Lautner, E. A.; Ksiazek, T. G.; White, W. R.; McIntosh, M. T. Discovery of Swine as a Host for the Reston Ebolavirus. Science 2009, 325 (5937), 204– 206, DOI: 10.1126/science.1172705
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  Discovery of Swine as a Host for the Reston ebolavirus
  Barrette, Roger W.; Metwally, Samia A.; Rowland, Jessica M.; Xu, Lizhe; Zaki, Sherif R.; Nichol, Stuart T.; Rollin, Pierre E.; Towner, Jonathan S.; Shieh, Wun-Ju; Batten, Brigid; Sealy, Tara K.; Carrillo, Consuelo; Moran, Karen E.; Bracht, Alexa J.; Mayr, Gregory A.; Sirios-Cruz, Magdalena; Catbagan, Davinio P.; Lautner, Elizabeth A.; Ksiazek, Thomas G.; White, William R.; McIntosh, Michael T.
  Science (Washington, DC, United States) (2009), 325 (5937), 204-206CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  Since the discovery of the Marburg and Ebola species of filovirus, seemingly random, sporadic fatal outbreaks of disease in humans and nonhuman primates have given impetus to identification of host tropisms and potential reservoirs. Domestic swine in the Philippines, experiencing unusually severe outbreaks of porcine reproductive and respiratory disease syndrome, have now been discovered to host Reston ebolavirus (REBOV). Although REBOV is the only member of Filoviridae that has not been assocd. with disease in humans, its emergence in the human food chain is of concern. REBOV isolates were found to be more divergent from each other than from the original virus isolated in 1989, indicating polyphyletic origins and that REBOV has been circulating since, and possibly before, the initial discovery of REBOV in monkeys.
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  Brauburger, K.; Hume, A. J.; Mühlberger, E.; Olejnik, J. Forty-Five Years of Marburg Virus Research. Viruses 2012, 4 (10), 1878– 1927, DOI: 10.3390/v4101878
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  Forty-five years of Marburg virus research
  Brauburger Kristina; Hume Adam J; Muhlberger Elke; Olejnik Judith
  Viruses (2012), 4 (10), 1878-927 ISSN:.
  In 1967, the first reported filovirus hemorrhagic fever outbreak took place in Germany and the former Yugoslavia. The causative agent that was identified during this outbreak, Marburg virus, is one of the most deadly human pathogens. This article provides a comprehensive overview of our current knowledge about Marburg virus disease ranging from ecology to pathogenesis and molecular biology.
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  Messaoudi, I.; Amarasinghe, G. K.; Basler, C. F. Filovirus Pathogenesis and Immune Evasion: Insights from Ebola Virus and Marburg Virus. Nat. Rev. Microbiol. 2015, 13 (11), 663– 676, DOI: 10.1038/nrmicro3524
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  Filovirus pathogenesis and immune evasion: insights from Ebola virus and Marburg virus
  Messaoudi, Ilhem; Amarasinghe, Gaya K.; Basler, Christopher F.
  Nature Reviews Microbiology (2015), 13 (11), 663-676CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)
  A review. Ebola viruses and Marburg viruses, members of the filovirus family, are zoonotic pathogens that cause severe disease in people, as highlighted by the latest Ebola virus epidemic in West Africa. Filovirus disease is characterized by uncontrolled virus replication and the activation of host responses that contribute to pathogenesis. Underlying these phenomena is the potent suppression of host innate antiviral responses, particularly the type I interferon response, by viral proteins, which allows high levels of viral replication. In this Review, we describe the mechanisms used by filoviruses to block host innate immunity and discuss the links between immune evasion and filovirus pathogenesis.
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  Leroy, E. M.; Kumulungui, B.; Pourrut, X.; Rouquet, P.; Hassanin, A.; Yaba, P.; Délicat, A.; Paweska, J. T.; Gonzalez, J.-P.; Swanepoel, R. Fruit Bats as Reservoirs of Ebola Virus. Nature 2005, 438 (7068), 575– 576, DOI: 10.1038/438575a
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  Nature (London, United Kingdom) (2005), 438 (7068), 575-576CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
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64. 64
  Towner, J. S.; Amman, B. R.; Sealy, T. K.; Carroll, S. A. R.; Comer, J. A.; Kemp, A.; Swanepoel, R.; Paddock, C. D.; Balinandi, S.; Khristova, M. L.; Formenty, P. B. H.; Albarino, C. G.; Miller, D. M.; Reed, Z. D.; Kayiwa, J. T.; Mills, J. N.; Cannon, D. L.; Greer, P. W.; Byaruhanga, E.; Farnon, E. C.; Atimnedi, P.; Okware, S.; Katongole-Mbidde, E.; Downing, R.; Tappero, J. W.; Zaki, S. R.; Ksiazek, T. G.; Nichol, S. T.; Rollin, P. E. Isolation of Genetically Diverse Marburg Viruses from Egyptian Fruit Bats. PLoS Pathog. 2009, 5 (7), e1000536, DOI: 10.1371/journal.ppat.1000536
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65. 65
  Jahrling, P. B.; Geisbert, T. W.; Johnson, E. D.; Peters, C. J.; Dalgard, D. W.; Hall, W. C. Preliminary Report: Isolation of Ebola Virus from Monkeys Imported to USA. Lancet 1990, 335 (8688), 502– 505, DOI: 10.1016/0140-6736(90)90737-P
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  Preliminary report: isolation of Ebola virus from monkeys imported to USA
  Jahrling P B; Geisbert T W; Dalgard D W; Johnson E D; Ksiazek T G; Hall W C; Peters C J
  Lancet (London, England) (1990), 335 (8688), 502-5 ISSN:0140-6736.
  An epizootic caused by an Ebola-related filovirus and by simian haemorrhagic fever virus began among cynomolgus monkeys in a US quarantine facility after introduction of monkeys from the Philippines. This incident, the first in which a filovirus has been isolated from non-human primates without deliberate infection, raises the possibility that cynomolgus monkeys could be a reservoir of Ebola virus infection.
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66. 66
  Le Guenno, B.; Formenty, P.; Wyers, M.; Gounon, P.; Walker, F.; Boesch, C. Isolation and Partial Characterisation of a New Strain of Ebola Virus. Lancet 1995, 345 (8960), 1271– 1274, DOI: 10.1016/S0140-6736(95)90925-7
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  Isolation and partial characterisation of a new strain of Ebola virus
  Le Guenno B; Formenty P; Formentry P; Wyers M; Gounon P; Walker F; Boesch C
  Lancet (London, England) (1995), 345 (8960), 1271-4 ISSN:0140-6736.
  We have isolated a new strain of Ebola virus from a non-fatal human case infected during the autopsy of a wild chimpanzee in the Cote-d'Ivoire. The wild troop to which this animal belonged has been decimated by outbreaks of haemorrhagic syndromes. This is the first time that a human infection has been connected to naturally-infected monkeys in Africa. Data from the long-term survey of this troop of chimpanzees could answer questions about the natural reservoir of the Ebola virus.
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67. 67
  Dowell, S. F.; Mukunu, R.; Ksiazek, T. G.; Khan, A. S.; Rollin, P. E.; Peters, C. J. Transmission of Ebola Hemorrhagic Fever: A Study of Risk Factors in Family Members, Kikwit, Democratic Republic of the Congo, 1995. J. Infect. Dis. 1999, 179, S87– S91, DOI: 10.1086/514284
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68. 68
  U.S. Food and Drug Administration. FDA news release, December 19, 2019. First FDA-approved vaccine for the prevention of Ebola virus disease, marking a critical milestone in public health preparedness and response. https://www.fda.gov/news-events/press-announcements/first-fda-approved-vaccine-prevention-ebola-virus-disease-marking-critical-milestone-public-health (accessed May 21, 2020).
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69. 69
  Suschak, J. J.; Schmaljohn, C. S. Vaccines against Ebola Virus and Marburg Virus: Recent Advances and Promising Candidates. Hum. Vaccines Immunother. 2019, 15 (10), 2359– 2377, DOI: 10.1080/21645515.2019.1651140
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70. 70
  Kondratowicz, A. S.; Lennemann, N. J.; Sinn, P. L.; Davey, R. A.; Hunt, C. L.; Moller-Tank, S.; Meyerholz, D. K.; Rennert, P.; Mullins, R. F.; Brindley, M.; Sandersfeld, L. M.; Quinn, K.; Weller, M.; McCray, P. B.; Chiorini, J.; Maury, W. T-Cell Immunoglobulin and Mucin Domain 1 (TIM-1) Is a Receptor for Zaire Ebolavirus and Lake Victoria Marburgvirus. Proc. Natl. Acad. Sci. U. S. A. 2011, 108 (20), 8426– 8431, DOI: 10.1073/pnas.1019030108
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  70
  T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor for Zaire Ebolavirus and Lake Victoria Marburgvirus
  Kondratowicz, Andrew S.; Lennemann, Nicholas J.; Sinn, Patrick L.; Davey, Robert A.; Hunt, Catherine L.; Moller-Tank, Sven; Meyerholz, David K.; Rennert, Paul; Mullins, Robert F.; Brindley, Melinda; Sandersfeld, Lindsay M.; Quinn, Kathrina; Weller, Melodie; McCray, Paul B., Jr.; Chiorini, John; Maury, Wendy
  Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (20), 8426-8431, S8426/1-S8426/7CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  The glycoproteins (GP) of enveloped viruses facilitate entry into the host cell by interacting with specific cellular receptors. Despite extensive study, a cellular receptor for the deadly filoviruses Ebolavirus and Marburgvirus has yet to be identified and characterized. Here, we show that T-cell Ig and mucin domain 1 (TIM-1) binds to the receptor binding domain of the Zaire Ebola virus (EBOV) glycoprotein, and ectopic TIM-1 expression in poorly permissive cells enhances EBOV infection by 10- to 30-fold. Conversely, redn. of cell-surface expression of TIM-1 by RNAi decreased infection of highly permissive Vero cells. TIM-1 expression within the human body is broader than previously appreciated, with expression on mucosal epithelia from the trachea, cornea, and conjunctiva - tissues believed to be important during in vivo transmission of filoviruses. Recognition that TIM-1 serves as a receptor for filoviruses on these mucosal epithelial surfaces provides a mechanistic understanding of routes of entry into the human body via inhalation of aerosol particles or hand-to-eye contact. ARD5, a monoclonal antibody against the IgV domain of TIM-1, blocked EBOV binding and infection, suggesting that antibodies or small mols. directed against this cellular receptor may provide effective filovirus antivirals.
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71. 71
  Takada, A.; Watanabe, S.; Ito, H.; Okazaki, K.; Kida, H.; Kawaoka, Y. Downregulation of B1 Integrins by Ebola Virus Glycoprotein: Implication for Virus Entry. Virology 2000, 278 (1), 20– 26, DOI: 10.1006/viro.2000.0601
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  71
  Downregulation of β1 Integrins by Ebola Virus Glycoprotein: Implication for Virus Entry
  Takada, Ayato; Watanabe, Shinji; Ito, Hiroshi; Okazaki, Katsunori; Kida, Hiroshi; Kawaoka, Yoshihiro
  Virology (2000), 278 (1), 20-26CODEN: VIRLAX; ISSN:0042-6822. (Academic Press)
  Filoviruses, including Ebola virus, are cytotoxic. To investigate the role of the Ebola virus glycoprotein (GP) in this cytopathic effect, we transiently expressed the GP in human kidney 293T cells. Expression of wild-type GP, but not the secretory form of the mol. lacking a membrane anchor, induced rounding and detachment of the cells, as did a chimeric GP contg. its ectodomain and influenza virus hemagglutinin transmembrane-cytoplasmic domain. These results indicate that the GP ectodomain and its anchorage to the membrane are required for GP-induced morphol. changes in host cells. Since cell rounding and detachment could be assocd. with reduced levels of cell adhesion mols., we also studied the expression of integrins, which are major mols. for adhesion to extracellular matrixes, and found that the β1 integrin group is downregulated by the GP. This result was further extended by expts. in which anti-β1 monoclonal antibodies or purified integrins inhibited the infectivity of vesicular stomatitis virus pseudotyped with the GP. We suggest that integrins, esp. the β1 group, might interact with the GP and perhaps be involved in Ebola virus entry into cells. (c) 2000 Academic Press.
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72. 72
  Takada, A.; Fujioka, K.; Tsuiji, M.; Morikawa, A.; Higashi, N.; Ebihara, H.; Kobasa, D.; Feldmann, H.; Irimura, T.; Kawaoka, Y. Human Macrophage C-Type Lectin Specific for Galactose and N-Acetylgalactosamine Promotes Filovirus Entry. J. Virol. 2004, 78 (6), 2943– 2947, DOI: 10.1128/JVI.78.6.2943-2947.2004
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  72
  Human macrophage C-type lectin specific for galactose and N-acetylgalactosamine promotes filovirus entry
  Takada, Ayato; Fujioka, Kouki; Tsuiji, Makoto; Morikawa, Akiko; Higashi, Nobuaki; Ebihara, Hideki; Kobasa, Darwyn; Feldmann, Heinz; Irimura, Tatsuro; Kawaoka, Yoshihiro
  Journal of Virology (2004), 78 (6), 2943-2947CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
  Filoviruses cause lethal hemorrhagic disease in humans and nonhuman primates. An initial target of filovirus infection is the mononuclear phagocytic cell. Calcium-dependent (C-type) lectins such as dendritic cell- or liver/lymph node-specific ICAM-3 grabbing nonintegrin (DC-SIGN or L-SIGN, resp.), as well as the hepatic asialoglycoprotein receptor, bind to Ebola or Marburg virus glycoprotein (GP) and enhance the infectivity of these viruses in vitro. Here, we demonstrate that a recently identified human macrophage galactose- and N-acetylgalactosamine-specific C-type lectin (hMGL), whose ligand specificity differs from DC-SIGN and L-SIGN, also enhances the infectivity of filoviruses. This enhancement was substantially weaker for the Reston and Marburg viruses than for the highly pathogenic Zaire virus. We also show that the heavily glycosylated, mucin-like domain on the filovirus GP is required for efficient interaction with this lectin. Furthermore, hMGL, like DC-SIGN and L-SIGN, is present on cells known to be major targets of filoviruses (i.e., macrophages and dendritic cells), suggesting a role for these C-type lectins in viral replication in vivo. We propose that filoviruses use different C-type lectins to gain cellular entry, depending on the cell type, and promote efficient viral replication.
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73. 73
  Nanbo, A.; Imai, M.; Watanabe, S.; Noda, T.; Takahashi, K.; Neumann, G.; Halfmann, P.; Kawaoka, Y. Ebolavirus Is Internalized into Host Cells via Macropinocytosis in a Viral Glycoprotein-Dependent Manner. PLoS Pathog. 2010, 6 (9), e1001121, DOI: 10.1371/journal.ppat.1001121
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74. 74
  Carette, J. E.; Raaben, M.; Wong, A. C.; Herbert, A. S.; Obernosterer, G.; Mulherkar, N.; Kuehne, A. I.; Kranzusch, P. J.; Griffin, A. M.; Ruthel, G.; Cin, P. D.; Dye, J. M.; Whelan, S. P.; Chandran, K.; Brummelkamp, T. R. Ebola Virus Entry Requires the Cholesterol Transporter Niemann–Pick C1. Nature 2011, 477 (7364), 340– 343, DOI: 10.1038/nature10348
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  Ebola virus entry requires the cholesterol transporter Niemann-Pick C1
  Carette, Jan E.; Raaben, Matthijs; Wong, Anthony C.; Herbert, Andrew S.; Obernosterer, Gregor; Mulherkar, Nirupama; Kuehne, Ana I.; Kranzusch, Philip J.; Griffin, April M.; Ruthel, Gordon; Dal Cin, Paola; Dye, John M.; Whelan, Sean P.; Chandran, Kartik; Brummelkamp, Thijn R.
  Nature (London, United Kingdom) (2011), 477 (7364), 340-343CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  Infections by the Ebola and Marburg filoviruses cause a rapidly fatal hemorrhagic fever in humans for which no approved antivirals are available. Filovirus entry is mediated by the viral spike glycoprotein (GP), which attaches viral particles to the cell surface, delivers them to endosomes and catalyzes fusion between viral and endosomal membranes. Addnl. host factors in the endosomal compartment are probably required for viral membrane fusion; however,despite considerable efforts, these crit. host factors have defied mol. identification. Here we describe a genome-wide haploid genetic screen in human cells to identify host factors required for Ebola virus entry. Our screen uncovered 67 mutations disrupting all six members of the homotypic fusion and vacuole protein-sorting (HOPS) multisubunit tethering complex, which is involved in the fusion of endosomes to lysosomes, and 39 independent mutations that disrupt the endo/lysosomal cholesterol transporter protein Niemann-Pick C1 (NPC1). Cells defective for the HOPS complex or NPC1 function, including primary fibroblasts derived from human Niemann-Pick type C1 disease patients, are resistant to infection by Ebola virus and Marburg virus, but remain fully susceptible to a suite of unrelated viruses. We show that membrane fusion mediated by filovirus glycoproteins and viral escape from the vesicular compartment require the NPC1 protein, independent of its known function in cholesterol transport. Our findings uncover unique features of the entry pathway used by filoviruses and indicate potential antiviral strategies to combat these deadly agents.
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75. 75
  Chandran, K.; Sullivan, N. J.; Felbor, U.; Whelan, S. P.; Cunningham, J. M. Endosomal Proteolysis of the Ebola Virus Glycoprotein Is Necessary for Infection. Science 2005, 308 (5728), 1643– 1645, DOI: 10.1126/science.1110656
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  75
  Endosomal Proteolysis of the Ebola Virus Glycoprotein Is Necessary for Infection
  Chandran, Kartik; Sullivan, Nancy J.; Felbor, Ute; Whelan, Sean P.; Cunningham, James M.
  Science (Washington, DC, United States) (2005), 308 (5728), 1643-1645CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  Ebola virus (EboV) causes rapidly fatal hemorrhagic fever in humans and there is currently no effective treatment. We found that the infection of African green monkey kidney (Vero) cells by vesicular stomatitis viruses bearing the EboV glycoprotein (GP) requires the activity of endosomal cysteine proteases. Using selective protease inhibitors and protease-deficient cell lines, we identified an essential role for cathepsin B (CatB) and an accessory role for cathepsin L (CatL) in EboV GP-dependent entry. Biochem. studies demonstrate that CatB and CatL mediate entry by carrying out proteolysis of the EboV GP subunit GP1 and support a multi-step mechanism that explains the relative contributions of these enzymes to infection. CatB and CatB/CatL inhibitors diminish the multiplication of infectious EboV-Zaire in cultured cells and may merit investigation as anti-EboV drugs.
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76. 76
  Zhu, W.; Banadyga, L.; Emeterio, K.; Wong, G.; Qiu, X. The Roles of Ebola Virus Soluble Glycoprotein in Replication, Pathogenesis, and Countermeasure Development. Viruses 2019, 11 (11), 999, DOI: 10.3390/v11110999
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  The Roles of Ebola virus soluble glycoprotein in replication, pathogenesis, and countermeasure development
  Zhu, Wenjun; Banadyga, Logan; Emeterio, Karla; Wong, Gary; Qiu, Xiangguo
  Viruses (2019), 11 (11), 999CODEN: VIRUBR; ISSN:1999-4915. (MDPI AG)
  A review. Ebola virus (EBOV) is a highly lethal pathogen that has caused several outbreaks of severe hemorrhagic fever in humans since its emergence in 1976. The EBOV glycoprotein (GP1,2) is the sole viral envelope protein and a major component of immunogenicity; it is encoded by the GP gene along with two truncated versions: sol. GP (sGP) and small sol. GP (ssGP). sGP is, in fact, the primary product of the GP gene, and it is secreted in abundance during EBOV infection. Since sGP shares large portions of its sequence with GP1,2, it has been hypothesized that sGP may subvert the host immune response by inducing antibodies against sGP rather than GP1,2. Several reports have shown that sGP plays multiple roles that contribute to the complex pathogenesis of EBOV. In this review, we focus on sGP and discuss its possible roles with regards to the pathogenesis of EBOV and the development of specific antiviral drugs.
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77. 77
  Volchkov, V. E.; Feldmann, H.; Volchkova, V. A.; Klenk, H.-D. Processing of the Ebola Virus Glycoprotein by the Proprotein Convertase Furin. Proc. Natl. Acad. Sci. U. S. A. 1998, 95 (10), 5762– 5767, DOI: 10.1073/pnas.95.10.5762
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  77
  Processing of the Ebola virus glycoprotein by the proprotein convertase furin
  Volchkov, Viktor E.; Feldmann, Heinz; Volchkova, Valentina A.; Klenk, Hans-Dieter
  Proceedings of the National Academy of Sciences of the United States of America (1998), 95 (10), 5762-5767CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  The authors investigated the processing and maturation of the envelope glycoprotein (GP) of Ebola virus. When GP expressed from vaccinia virus vectors was analyzed by pulse-chase expts., the mature form and two different precursors were identified. First, the endoplasmic reticulum form preGPer, full-length GP with oligomannosidic N-glycans, was detected. PreGPer (110 kDa) was replaced by the Golgi-specific form preGP (160 kDa), full-length GP contg. mature carbohydrates. PreGP was finally converted by proteolysis into mature GP1,2, which consisted of two disulfide-linked cleavage products, the amino-terminal 140-kDa fragment GP1, and the carboxyl-terminal 26-kDa fragment GP2. GP1,2 was also identified in Ebola virions. Studies employing site-directed mutagenesis revealed that GP was cleaved at a multibasic amino acid motif located at positions 497 to 501 of the ORF. Cleavage was blocked by a peptidyl chloromethylketone contg. such a motif. GP is cleaved by the proprotein convertase furin. This was indicated by the observation that cleavage did not occur when GP was expressed in furin-defective LoVo cells but that it was restored in these cells by vector-expressed furin. The Reston subtype, which differs from all other Ebola viruses by its low human pathogenicity, has a reduced cleavability due to a mutation at the cleavage site. As a result of these observations, it should now be considered that proteolytic processing of GP may be an important determinant for the pathogenicity of Ebola virus.
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78. 78
  Mühlberger, E. Filovirus Replication and Transcription. Future Virol. 2007, 2 (2), 205– 215, DOI: 10.2217/17460794.2.2.205
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  Filovirus replication and transcription
  Muehlberger, Elke
  Future Virology (2007), 2 (2), 205-215CODEN: FVUIAM; ISSN:1746-0794. (Future Medicine Ltd.)
  A review. The highly pathogenic filoviruses, Marburg and Ebola virus, belong to the nonsegmented neg.-sense RNA viruses of the order Mononegavirales. The mode of replication and transcription is similar for these viruses. On one hand, the neg.-sense RNA genome serves as a template for replication, to generate progeny genomes, and, on the other hand, for transcription, to produce mRNAs. Despite the similarities in the replication/transcription strategy, filoviruses have evolved structural and functional properties that are unique among the nonsegmented neg.-sense RNA viruses. Moreover, there are also striking differences in the replication and transcription mechanisms of Marburg and Ebola virus. This includes nucleocapsid formation, the structure of the genomic replication promoter, the protein requirement for transcription and the use of mRNA editing. In this article, the current knowledge of the replication and transcription strategy of Marburg and Ebola virus is reviewed, with focus on the obsd. differences.
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79. 79
  Noda, T.; Sagara, H.; Suzuki, E.; Takada, A.; Kida, H.; Kawaoka, Y. Ebola Virus VP40 Drives the Formation of Virus-Like Filamentous Particles Along with GP. J. Virol. 2002, 76 (10), 4855– 4865, DOI: 10.1128/JVI.76.10.4855-4865.2002
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  79
  Ebola virus VP40 drives the formation of virus-like filamentous particles along with GP
  Noda, Takeshi; Sagara, Hiroshi; Suzuki, Emiko; Takada, Ayato; Kida, Hiroshi; Kawaoka, Yoshihiro
  Journal of Virology (2002), 76 (10), 4855-4865CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
  Using biochem. assays, it has been demonstrated that expression of Ebola virus VP40 alone in mammalian cells induced prodn. of particles with a d. similar to that of virions. To det. the morphol. properties of these particles, cells expressing VP40 and the particles released from the cells were examd. by electron microscopy. VP40 induced budding from the plasma membrane of filamentous particles, which differed in length but had uniform diams. of approx. 65 nm. When the Ebola virus glycoprotein (GP) responsible for receptor binding and membrane fusion was expressed in cells, we found pleomorphic particles budding from the plasma membrane. By contrast, when GP was coexpressed with VP40, GP was found on the filamentous particles induced by VP40. These results demonstrated the central role of VP40 in formation of the filamentous structure of Ebola virions and may suggest an interaction between VP40 and GP in morphogenesis.
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80. 80
  Coleman, C. M.; Frieman, M. B. Coronaviruses: Important Emerging Human Pathogens. J. Virol. 2014, 88 (10), 5209– 5212, DOI: 10.1128/JVI.03488-13
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  Coronaviruses: important emerging human pathogens
  Coleman, Christopher M.; Frieman, Matthew B.
  Journal of Virology (2014), 88 (10), 5209-5212, 5 pp.CODEN: JOVIAM; ISSN:1098-5514. (American Society for Microbiology)
  A review. The identification of Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 reaffirmed the importance of understanding how coronaviruses emerge, infect, and cause disease. By comparing what is known about severe acute respiratory syndrome coronavirus (SARS-CoV) to what has recently been found for MERS-CoV, researchers are discovering similarities and differences that may be important for pathogenesis. Here we discuss what is known about each virus and what gaps remain in our understanding, esp. concerning MERS-CoV.
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81. 81
  Wu, A.; Peng, Y.; Huang, B.; Ding, X.; Wang, X.; Niu, P.; Meng, J.; Zhu, Z.; Zhang, Z.; Wang, J.; Sheng, J.; Quan, L.; Xia, Z.; Tan, W.; Cheng, G.; Jiang, T. Genome Composition and Divergence of the Novel Coronavirus (2019-NCoV) Originating in China. Cell Host Microbe 2020, 27 (3), 325– 328, DOI: 10.1016/j.chom.2020.02.001
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  81
  Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China
  Wu, Aiping; Peng, Yousong; Huang, Baoying; Ding, Xiao; Wang, Xianyue; Niu, Peihua; Meng, Jing; Zhu, Zhaozhong; Zhang, Zheng; Wang, Jiangyuan; Sheng, Jie; Quan, Lijun; Xia, Zanxian; Tan, Wenjie; Cheng, Genhong; Jiang, Taijiao
  Cell Host & Microbe (2020), 27 (3), 325-328CODEN: CHMECB; ISSN:1931-3128. (Elsevier Inc.)
  An in-depth annotation of the newly discovered coronavirus (2019-nCoV) genome has revealed differences between 2019-nCoV and severe acute respiratory syndrome (SARS) or SARS-like coronaviruses. A systematic comparison identified 380 amino acid substitutions between these coronaviruses, which may have caused functional and pathogenic divergence of 2019-nCoV.
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82. 82
  Sanchez, A.; Rollin, P. E. Complete Genome Sequence of an Ebola Virus (Sudan Species) Responsible for a 2000 Outbreak of Human Disease in Uganda. Virus Res. 2005, 113 (1), 16– 25, DOI: 10.1016/j.virusres.2005.03.028
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  82
  Complete genome sequence of an Ebola virus (Sudan species) responsible for a 2000 outbreak of human disease in Uganda
  Sanchez, Anthony; Rollin, Pierre E.
  Virus Research (2005), 113 (1), 16-25CODEN: VIREDF; ISSN:0168-1702. (Elsevier B.V.)
  The entire genomic RNA of the Gulu (Uganda 2000) strain of Ebola virus was sequenced and compared to the genomes of other filoviruses. These data represents the first comprehensive genetic anal. for a representative isolate of the Sudan species of Ebola virus. The genome organization of the Sudan species is nearly identical to that of the Zaire species, but the presence of a gene overlap (between GP and VP30 genes) and a longer trailer sequence distinguish it from that of the Reston species. As has been obsd. with other filoviruses, stemloop structures were predicted to form at the 5' end of Ebola Sudan mRNA mols., and the genomic RNA termini showed a high degree of sequence complimentarity. Comparisons of the amino acid sequences of encoded gene products shows that there is a comparable level of identity or similarity between Ebola virus species, with Sudan and Zaire actually showing a slightly closer relationship to the Reston species than to one another. These comparisons also indicated that the VP24 is the most conserved Ebola virus protein (followed closely by the VP40 and L proteins), while the GP is the least conserved gene product. The most divergent regions were seen in the C-terminus of GP1 (mucin-like region) and within the C-terminal third of the nucleoprotein sequence.
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83. 83
  Feldmann, H.; Mühlberger, E.; Randolf, A.; Will, C.; Kiley, M. P.; Sanchez, A.; Klenk, H.-D. Marburg Virus, a Filovirus: Méssenger RNAs, Gene Order, and Regulatory Elements of the Replication Cycle. Virus Res. 1992, 24 (1), 1– 19, DOI: 10.1016/0168-1702(92)90027-7
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  83
  Marburg virus, a filovirus: messenger RNAs, gene order, and regulatory elements of the replication cycle
  Feldmann, Heinz; Muehlberger, Elke; Randolf, Anke; Will, Christiane; Kiley, Michael P.; Sanchez, Anthony; Klenk, Hans Dieter
  Virus Research (1992), 24 (1), 1-19CODEN: VIREDF; ISSN:0168-1702.
  The genome of Marburg virus (MBG), a filovirus, is 19.1 kb in length and thus the largest one found with neg.-strand RNA viruses. The gene order - 3' untranslated region-NP-VP35-VP40-GP-VP30-VP24-L-5' untranslated region-resembles that of other non-segmented neg.-strand (NNS) RNA viruses. Six species of polyadenylated subgenomic RNAs, isolated from MBG-infected cells, are complementary to the neg.-strand RNA genome. They can be translated in vitro into the known structural proteins NP, GP (non-glycosylated form), VP40, VP35, VP30 and VP24. At the gene boundaries conserved transcriptional start (3'-NNCUNCNUNUAAUU-5') and stop signals (3'-UAAUUCUUUUU-5') are located contg. the highly conserved pentamer 3'-UAAUU-5'. Comparison with other NNS RNA viruses shows conservation primarily in the termination signals, whereas the start signals are more variable. The intergenic regions vary in length and nucleotide compn. All genes have relatively long 3' and 5' end non-coding regions. The putative 3' and 5' leader RNA sequences of the MBG genome resemble those of other NNS RNA viruses in length, conservation at the 3' and 5' ends, and in being complementary at their extremities. The data support the concept of a common taxonomic order Mononegavirales comprising the Filoviridae, Paramyxoviridae, and Rhabdoviridae families.
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84. 84
  Hoenen, T.; Groseth, A.; Feldmann, H. Therapeutic Strategies to Target the Ebola Virus Life Cycle. Nat. Rev. Microbiol. 2019, 17 (10), 593– 606, DOI: 10.1038/s41579-019-0233-2
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  84
  Therapeutic strategies to target the Ebola virus life cycle
  Hoenen, Thomas; Groseth, Allison; Feldmann, Heinz
  Nature Reviews Microbiology (2019), 17 (10), 593-606CODEN: NRMACK; ISSN:1740-1526. (Nature Research)
  A review. Following the Ebola virus disease epidemic in west Africa, there has been increased awareness of the need for improved therapies for emerging diseases, including viral haemorrhagic fevers such as those caused by Ebola virus and other filoviruses. Our continually improving understanding of the virus life cycle coupled with the increased availability of 'omics' analyses and high-throughput screening technologies has enhanced our ability to identify potential viral and host factors and aspects involved in the infection process that might be intervention targets. In this Review we address compds. that have shown promise to various degrees in interfering with the filovirus life cycle, including monoclonal antibodies such as ZMapp, mAb114 and REGN-EB3 and inhibitors of viral RNA synthesis such as remdesivir and TKM-Ebola. Furthermore, we discuss the general potential of targeting aspects of the virus life cycle such as the entry process, viral RNA synthesis and gene expression, as well as morphogenesis and budding.
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85. 85
  García, L. L.; Padilla, L.; Castaño, J. C. Inhibitors Compounds of the Flavivirus Replication Process. Virol. J. 2017, 14 (1), 95, DOI: 10.1186/s12985-017-0761-1
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  85
  Inhibitors compounds of the flavivirus replication process
  Garcia, Leidy L.; Padilla, Leonardo; Castano, Jhon C.
  Virology Journal (2017), 14 (), 95/1-95/12CODEN: VJIOA4; ISSN:1743-422X. (BioMed Central Ltd.)
  Flaviviruses are small viruses with single-stranded RNA, which include the yellow fever virus, dengue virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, and Zika virus; and are causal agents of the most important emerging diseases that have no available treatment to date. In recent years, the strategy has focused on the development of replication inhibitors of these viruses designed to act mainly by affecting the activity of enzyme proteins, such as NS3 and NS5, which perform important functions in the viral replication process. This article describes the importance of flaviviruses and the development of mols. used as inhibitors of viral replication in this genus.
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86. 86
  Islam, M. T.; Sarkar, C.; El-Kersh, D. M.; Jamaddar, S.; Uddin, S. J.; Shilpi, J. A.; Mubarak, M. S. Natural products and their derivatives against coronavirus: A review of the non-clinical and pre-clinical data. Phytother. Res. 2020, 34, 2471– 2492, DOI: 10.1002/ptr.6700
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  86
  Natural products and their derivatives against coronavirus: A review of the non-clinical and pre-clinical data
  Islam, Muhammad T.; Sarkar, Chandan; El-Kersh, Dina M.; Jamaddar, Sarmin; Uddin, Shaikh J.; Shilpi, Jamil A.; Mubarak, Mohammad S.
  Phytotherapy Research (2020), 34 (10), 2471-2492CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)
  A review. Several corona viral infections have created serious threats in the last couple of decades claiming the death of thousands of human beings. Recently, corona viral epidemic raised the issue of developing effective antiviral agents at the earliest to prevent further losses. Natural products have always played a crucial role in drug development process against various diseases, which resulted in screening of such agents to combat emergent mutants of corona virus. This review focuses on those natural compds. that showed promising results against corona viruses. Although inhibition of viral replication is often considered as a general mechanism for antiviral activity of most of the natural products, studies have shown that some natural products can interact with key viral proteins that are assocd. with virulence. In this context, some of the natural products have antiviral activity in the nanomolar concn. (e.g., lycorine, homoharringtonine, silvestrol, ouabain, tylophorine, and 7-methoxycryptopleurine) and could be leads for further drug development on their own or as a template for drug design. In addn., a good no. of natural products with anti-corona virus activity are the major constituents of some common dietary supplements, which can be exploited to improve the immunity of the general population in certain epidemics.
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87. 87
  Ehrhardt, S. A.; Zehner, M.; Krähling, V.; Cohen-Dvashi, H.; Kreer, C.; Elad, N.; Gruell, H.; Ercanoglu, M. S.; Schommers, P.; Gieselmann, L.; Eggeling, R.; Dahlke, C.; Wolf, T.; Pfeifer, N.; Addo, M. M.; Diskin, R.; Becker, S.; Klein, F. Polyclonal and Convergent Antibody Response to Ebola Virus Vaccine RVSV-ZEBOV. Nat. Med. 2019, 25 (10), 1589– 1600, DOI: 10.1038/s41591-019-0602-4
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  87
  Polyclonal and convergent antibody response to Ebola virus vaccine rVSV-ZEBOV
  Ehrhardt, Stefanie A.; Zehner, Matthias; Kraehling, Verena; Cohen-Dvashi, Hadas; Kreer, Christoph; Elad, Nadav; Gruell, Henning; Ercanoglu, Meryem S.; Schommers, Philipp; Gieselmann, Lutz; Eggeling, Ralf; Dahlke, Christine; Wolf, Timo; Pfeifer, Nico; Addo, Marylyn M.; Diskin, Ron; Becker, Stephan; Klein, Florian
  Nature Medicine (New York, NY, United States) (2019), 25 (10), 1589-1600CODEN: NAMEFI; ISSN:1078-8956. (Nature Research)
  Recombinant vesicular stomatitis virus-Zaire Ebola virus (rVSV-ZEBOV) is the most advanced Ebola virus vaccine candidate and is currently being used to combat the outbreak of Ebola virus disease (EVD) in the Democratic Republic of the Congo (DRC). Here we examine the humoral immune response in a subset of human volunteers enrolled in a phase 1 rVSV-ZEBOV vaccination trial by performing comprehensive single B cell and electron microscopy structure analyses. Four studied vaccinees show polyclonal, yet reproducible and convergent B cell responses with shared sequence characteristics. EBOV-targeting antibodies cross-react with other Ebolavirus species, and detailed epitope mapping revealed overlapping target epitopes with antibodies isolated from EVD survivors. Moreover, in all vaccinees, we detected highly potent EBOV-neutralizing antibodies with activities comparable or superior to the monoclonal antibodies currently used in clin. trials. These include antibodies combining the IGHV3-15/IGLV1-40 Ig gene segments that were identified in all investigated individuals. Our findings will help to evaluate and d.c. and future vaccination strategies and offer opportunities for novel EVD therapies.
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88. 88
  Bosch, B. J.; Martina, B. E. E.; van der Zee, R.; Lepault, J.; Haijema, B. J.; Versluis, C.; Heck, A. J. R.; de Groot, R.; Osterhaus, A. D. M. E.; Rottier, P. J. M. Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection Inhibition Using Spike Protein Heptad Repeat-Derived Peptides. Proc. Natl. Acad. Sci. U. S. A. 2004, 101 (22), 8455– 8460, DOI: 10.1073/pnas.0400576101
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  88
  Severe acute respiratory syndrome coronavirus (SARS-CoV) infection inhibition using spike protein heptad repeat-derived peptides
  Bosch, Berend Jan; Martina, Byron E. E.; Van Der Zee, Ruurd; Lepault, Jean; Haijema, Bert Jan; Versluis, Cees; Heck, Albert J. R.; De Groot, Raoul; Osterhaus, Albert D. M. E.; Rottier, Peter J. M.
  Proceedings of the National Academy of Sciences of the United States of America (2004), 101 (22), 8455-8460CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  The coronavirus SARS-CoV is the primary cause of the life-threatening severe acute respiratory syndrome (SARS). With the aim of developing therapeutic agents, we have tested peptides derived from the membrane-proximal (HR2) and membrane-distal (HR1) heptad repeat region of the spike protein as inhibitors of SARS-CoV infection of Vero cells. It appeared that HR2 peptides, but not HR1 peptides, were inhibitory. Their efficacy was, however, significantly lower than that of corresponding HR2 peptides of the murine coronavirus mouse hepatitis virus (MHV) in inhibiting MHV infection. Biochem. and electron microscopical analyses showed that, when mixed, SARS-CoV HR1 and HR2 peptides assemble into a six-helix bundle consisting of HR1 as a central triple-stranded coiled coil in assocn. with three HR2 α-helixes oriented in an antiparallel manner. The stability of this complex, as measured by its resistance to heat dissocn., appeared to be much lower than that of the corresponding MHV complex, which may explain the different inhibitory potencies of the HR2 peptides. Analogous to other class I viral fusion proteins, the six-helix complex supposedly represents a postfusion conformation that is formed after insertion of the fusion peptide, proposed here for coronaviruses to be located immediately upstream of HR1, into the target membrane. The resulting close apposition of fusion peptide and spike transmembrane domain facilitates membrane fusion. The inhibitory potency of the SARS-CoV HR2-peptides provides an attractive basis for the development of a therapeutic drug for SARS.
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89. 89
  Sainz, B.; Mossel, E. C.; Gallaher, W. R.; Wimley, W. C.; Peters, C. J.; Wilson, R. B.; Garry, R. F. Inhibition of Severe Acute Respiratory Syndrome-Associated Coronavirus (SARS-CoV) Infectivity by Peptides Analogous to the Viral Spike Protein. Virus Res. 2006, 120 (1), 146– 155, DOI: 10.1016/j.virusres.2006.03.001
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  89
  Inhibition of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infectivity by peptides analogous to the viral spike protein
  Sainz, Bruno; Mossel, Eric C.; Gallaher, William R.; Wimley, William C.; Peters, C. J.; Wilson, Russell B.; Garry, Robert F.
  Virus Research (2006), 120 (1-2), 146-155CODEN: VIREDF; ISSN:0168-1702. (Elsevier B.V.)
  Severe acute respiratory syndrome-assocd. coronavirus (SARS-Co-V) is the cause of an atypical pneumonia that affected Asia, North America and Europe in 2002-2003. The viral spike (S) glycoprotein is responsible for mediating receptor binding and membrane fusion. Recent studies have proposed that the carboxyl terminal portion (S2 subunit) of the S protein is a class I viral fusion protein. The Wimley and White interfacial hydrophobicity scale was used to identify regions within the Co-V S2 subunit that may preferentially assoc. with lipid membranes with the premise that peptides analogous to these regions may function as inhibitors of viral infectivity. Five regions of high interfacial hydrophobicity spanning the length of the S2 subunit of SARS-Co-V and murine hepatitis virus (MHV) were identified. Peptides analogous to regions of the N-terminus or the pretransmembrane domain of the S2 subunit inhibited SARS-Co-V plaque formation by 40-70% at concns. of 15-30 μM. Interestingly, peptides analogous to the SARS-Co-V or MHV loop region inhibited viral plaque formation by >80% at similar concns. The obsd. effects were dose-dependent (IC50 values of 2-4 μM) and not a result of peptide-mediated cell cytotoxicity. The antiviral activity of the Co-V peptides tested provides an attractive basis for the development of new fusion peptide inhibitors corresponding to regions outside the fusion protein heptad repeat regions.
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90. 90
  Xia, S.; Liu, M.; Wang, C.; Xu, W.; Lan, Q.; Feng, S.; Qi, F.; Bao, L.; Du, L.; Liu, S.; Qin, C.; Sun, F.; Shi, Z.; Zhu, Y.; Jiang, S.; Lu, L. Inhibition of SARS-CoV-2 (Previously 2019-NCoV) Infection by a Highly Potent Pan-Coronavirus Fusion Inhibitor Targeting Its Spike Protein That Harbors a High Capacity to Mediate Membrane Fusion. Cell Res. 2020, 30 (4), 343– 355, DOI: 10.1038/s41422-020-0305-x
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  90
  Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
  Xia, Shuai; Liu, Meiqin; Wang, Chao; Xu, Wei; Lan, Qiaoshuai; Feng, Siliang; Qi, Feifei; Bao, Linlin; Du, Lanying; Liu, Shuwen; Qin, Chuan; Sun, Fei; Shi, Zhengli; Zhu, Yun; Jiang, Shibo; Lu, Lu
  Cell Research (2020), 30 (4), 343-355CODEN: CREEB6; ISSN:1001-0602. (Nature Research)
  The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the mol. mechanism that underlies viral infection must first be defined. Therefore, we herein established a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that SARS-CoV-2 showed a superior plasma membrane fusion capacity compared to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in the SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be assocd. with enhanced interactions with the HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted the HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. Here we generated a series of lipopeptides derived from EK1 and found that EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than the original EK1 peptide, resp. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, and potently inhibited the replication of 5 live human coronaviruses examd., including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by the currently circulating SARS-CoV-2 and other emerging SARSr-CoVs.
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91. 91
  Ho, T.-Y.; Wu, S.-L.; Chen, J.-C.; Li, C.-C.; Hsiang, C.-Y. Emodin Blocks the SARS Coronavirus Spike Protein and Angiotensin-Converting Enzyme 2 Interaction. Antiviral Res. 2007, 74 (2), 92– 101, DOI: 10.1016/j.antiviral.2006.04.014
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  91
  Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction
  Ho, Tin-Yun; Wu, Shih-Lu; Chen, Jaw-Chyun; Li, Chia-Cheng; Hsiang, Chien-Yun
  Antiviral Research (2007), 74 (2), 92-101CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
  Severe acute respiratory syndrome (SARS) is an emerging infectious disease caused by a novel coronavirus (SARS-CoV). SARS-CoV spike (S) protein, a type I membrane-bound protein, is essential for the viral attachment to the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening 312 controlled Chinese medicinal herbs supervised by Committee on Chinese Medicine and Pharmacy at Taiwan, we identified that three widely used Chinese medicinal herbs of the family Polygonaceae inhibited the interaction of SARS-CoV S protein and ACE2. The IC50 values for Radix et Rhizoma Rhei (the root tubers of Rheum officinale Baill.), Radix Polygoni multiflori (the root tubers of Polygonum multiflorum Thunb.), and Caulis Polygoni multiflori (the vines of P. multiflorum Thunb.) ranged from 1 to 10 μg/mL. Emodin, an anthraquinone compd. derived from genus Rheum and Polygonum, significantly blocked the S protein and ACE2 interaction in a dose-dependent manner. It also inhibited the infectivity of S protein-pseudotyped retrovirus to Vero E6 cells. These findings suggested that emodin may be considered as a potential lead therapeutic agent in the treatment of SARS.
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92. 92
  O’Keefe, B. R.; Giomarelli, B.; Barnard, D. L.; Shenoy, S. R.; Chan, P. K. S.; McMahon, J. B.; Palmer, K. E.; Barnett, B. W.; Meyerholz, D. K.; Wohlford-Lenane, C. L.; McCray, P. B. Broad-Spectrum In Vitro Activity and In Vivo Efficacy of the Antiviral Protein Griffithsin against Emerging Viruses of the Family Coronaviridae. J. Virol. 2010, 84 (5), 2511– 2521, DOI: 10.1128/JVI.02322-09
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  92
  Broad-spectrum in vitro activity and in vivo efficacy of the antiviral protein griffithsin against emerging viruses of the family Coronaviridae
  O'Keefe Barry R; Giomarelli Barbara; Barnard Dale L; Shenoy Shilpa R; Chan Paul K S; McMahon James B; Palmer Kenneth E; Barnett Brian W; Meyerholz David K; Wohlford-Lenane Christine L; McCray Paul B Jr
  Journal of virology (2010), 84 (5), 2511-21 ISSN:.
  Viruses of the family Coronaviridae have recently emerged through zoonotic transmission to become serious human pathogens. The pathogenic agent responsible for severe acute respiratory syndrome (SARS), the SARS coronavirus (SARS-CoV), is a member of this large family of positive-strand RNA viruses that cause a spectrum of disease in humans, other mammals, and birds. Since the publicized outbreaks of SARS in China and Canada in 2002-2003, significant efforts successfully identified the causative agent, host cell receptor(s), and many of the pathogenic mechanisms underlying SARS. With this greater understanding of SARS-CoV biology, many researchers have sought to identify agents for the treatment of SARS. Here we report the utility of the potent antiviral protein griffithsin (GRFT) in the prevention of SARS-CoV infection both in vitro and in vivo. We also show that GRFT specifically binds to the SARS-CoV spike glycoprotein and inhibits viral entry. In addition, we report the activity of GRFT against a variety of additional coronaviruses that infect humans, other mammals, and birds. Finally, we show that GRFT treatment has a positive effect on morbidity and mortality in a lethal infection model using a mouse-adapted SARS-CoV and also specifically inhibits deleterious aspects of the host immunological response to SARS infection in mammals.
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93. 93
  Lee, C. Griffithsin, a Highly Potent Broad-Spectrum Antiviral Lectin from Red Algae: From Discovery to Clinical Application. Mar. Drugs 2019, 17 (10), 567, DOI: 10.3390/md17100567
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  93
  Griffithsin, a highly potent broad-spectrum antiviral lectin from red algae: from discovery to clinical application
  Lee, Choongho
  Marine Drugs (2019), 17 (10), 567CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)
  Virus entry into a susceptible host cell is the first step in the formation of all viral diseases. Controlling viral infections by disrupting viral entry is advantageous for antibody-mediated neutralization by the host's immune system and as a preventive and therapeutic antiviral strategy. Recently, several plant-derived carbohydrate-binding proteins (lectins) have emerged as a new class of antiviral biologics by taking advantage of a unique glycosylation pattern only found on the surface of viruses. In particular, a red algae-derived griffithsin (GRFT) protein has demonstrated superior in vitro and in vivo antiviral activity with min. host toxicity against a variety of clin. relevant, enveloped viruses. Its in vitro antiviral profiles against human immunodeficiency virus (HIV) are also discussed followed by a description of the results from a combination study using anti-HIV drugs. The results of several studies regarding its novel antiviral mechanism of action are provided in conjunction with an explanation of viral resistance profiles to GRFT. In addn., its in vitro and in vivo host toxicity profiles are summarized with its pharmacokinetic behavior using in vivo efficacy study results. Also, a large-scale prodn. and formulation strategy, as well as a drug delivery strategy, for GRFT as a new class of broad-spectrum microbicides is discussed. Finally, results from two ongoing clin. studies examg. GRFT's effects on viruses are presented.
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94. 94
  Soto-Acosta, R.; Bautista-Carbajal, P.; Syed, G. H.; Siddiqui, A.; Del Angel, R. M. Nordihydroguaiaretic Acid (NDGA) Inhibits Replication and Viral Morphogenesis of Dengue Virus. Antiviral Res. 2014, 109, 132– 140, DOI: 10.1016/j.antiviral.2014.07.002
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  94
  Nordihydroguaiaretic acid (NDGA) inhibits replication and viral morphogenesis of dengue virus
  Soto-Acosta, Ruben; Bautista-Carbajal, Patricia; Syed, Gulam H.; Siddiqui, Aleem; Del Angel, Rosa M.
  Antiviral Research (2014), 109 (), 132-140CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
  Dengue is the most common mosquito borne viral disease in humans. The infection with any of the 4 dengue virus serotypes (DENV) can either be asymptomatic or manifest in two clin. forms, the mild dengue fever or the more severe dengue hemorrhagic fever that may progress into dengue shock syndrome. A DENV replicative cycle relies on host lipid metab.; specifically, DENV infection modulates cholesterol and fatty acid synthesis, generating a lipid-enriched cellular environment necessary for viral replication. Thus, the aim of this work was to evaluate the anti-DENV effect of the Nordihydroguaiaretic acid (NDGA), a hypolipidemic agent with antioxidant and anti-inflammatory properties. A dose-dependent inhibition in viral yield and NS1 secretion was obsd. in supernatants of infected cells treated for 24 and 48 h with different concns. of NDGA. To evaluate the effect of NDGA in DENV replication, a DENV4 replicon transfected Vero cells were treated with different concns. of NDGA. NDGA treatment significantly reduced DENV replication, reiterating the importance of lipids in viral replication. NDGA treatment also led to redn. in no. of lipid droplets (LDs), the neutral lipid storage organelles involved in DENV morphogenesis that are known to increase in no. during DENV infection. Furthermore, NDGA treatment resulted in dissocn. of the C protein from LDs. Overall our results suggest that NDGA inhibits DENV infection by targeting genome replication and viral assembly.
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95. 95
  Braun, E.; Sauter, D. Furin-mediated Protein Processing in Infectious Diseases and Cancer. Clin. Transl. Immunol. 2019, 8 (8), DOI: 10.1002/cti2.1073 .
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96. 96
  Modhiran, N.; Gandhi, N. S.; Wimmer, N.; Cheung, S.; Stacey, K.; Young, P. R.; Ferro, V.; Watterson, D. Dual Targeting of Dengue Virus Virions and NS1 Protein with the Heparan Sulfate Mimic PG545. Antiviral Res. 2019, 168, 121– 127, DOI: 10.1016/j.antiviral.2019.05.004
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  96
  Dual targeting of dengue virus virions and NS1 protein with the heparan sulfate mimic PG545
  Modhiran, Naphak; Gandhi, Neha S.; Wimmer, Norbert; Cheung, Stacey; Stacey, Katryn; Young, Paul R.; Ferro, Vito; Watterson, Daniel
  Antiviral Research (2019), 168 (), 121-127CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
  Dengue virus (DENV) is the most prevalent mosquito-borne flavivirus that infects humans. At present, there are no specific antiviral drugs to treat DENV infection and vaccine development has met with challenges. DENV encodes two glycosaminoglycan (GAG) binding proteins; Envelope (E) and non-structural protein 1 (NS1). While previous work has validated the use of GAG analogs as inhibitors of E mediated virus-cell attachment, their potential for antiviral intervention in NS1 protein toxicity has not yet been explored. Here, we investigate the potential of the heparan sulfate mimetic PG545 as a dual purpose compd. to target both DENV virion infectivity and NS1 function. In comparison to a non-sulfated analog, we show that PG545 potently inhibits DENV infectivity with no cytotoxic effect. Against NS1, PG545 completely blocks the induction of cellular activation and abolishes NS1-mediated disruption of endothelial monolayer integrity. Furthermore, PG545 treatment moderately improves survival from lethal DENV challenge in a murine model. At peak disease, PG545-treated mice have lower viremia, circulating NS1 and serum TNF-a. Consistent with anti-NS1 activity, PG545 treatment also reduces systemic vascular leakage caused by DENV infection in vivo. Taken together, these findings demonstrate that the dual targeting of DENV virions and NS1 using GAG analogs offers a new avenue for DENV drug development.
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97. 97
  Cui, Q.; Du, R.; Anantpadma, M.; Schafer, A.; Hou, L.; Tian, J.; Davey, R. A.; Cheng, H.; Rong, L. Identification of Ellagic Acid from Plant Rhodiola Rosea L. as an Anti-Ebola Virus Entry Inhibitor. Viruses 2018, 10 (4), 152, DOI: 10.3390/v10040152
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  97
  Identification of ellagic acid from plant Rhodiola rosea L. as an anti-Ebola virus entry inhibitor
  Cui, Qinghua; Du, Ruikun; Anantpadma, Manu; Schafer, Adam; Hou, Lin; Tian, Jingzhen; Davey, Robert A.; Cheng, Han; Rong, Lijun
  Viruses (2018), 10 (4), 152/1-152/12CODEN: VIRUBR; ISSN:1999-4915. (MDPI AG)
  The recent 2014-2016 West African Ebola virus epidemic underscores the need for the development of novel anti-Ebola therapeutics, due to the high mortality rates of Ebola virus infections and the lack of FDA-approved vaccine or therapy that is available for the prevention and treatment. Traditional Chinese medicines (TCMs) represent a huge reservoir of bioactive chems. and many TCMs have been shown to have antiviral activities. 373 exts. from 128 TCMs were evaluated using a high throughput assay to screen for inhibitors of Ebola virus cell entry. Ext. of Rhodiola rosea displayed specific and potent inhibition against cell entry of both Ebola virus and Marburg virus. In addn., twenty com. compds. that were isolated from Rhodiola rosea were evaluated using the pseudotyped Ebola virus entry assay, and it was found that ellagic acid and gallic acid, which are two structurally related compds., are the most effective ones. The activity of the ext. and the two pure compds. were validated using infectious Ebola virus. The time-of-addn. expts. suggest that, mechanistically, the Rhodiola rosea ext. and the effective compds. act at an early step in the infection cycle following initial cell attachment, but prior to viral/cell membrane fusion. Our findings provide evidence that Rhodiola rosea has potent anti-filovirus properties that may be developed as a novel anti-Ebola treatment.
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98. 98
  Cheng, H.; Lear-Rooney, C. M.; Johansen, L.; Varhegyi, E.; Chen, Z. W.; Olinger, G. G.; Rong, L. Inhibition of Ebola and Marburg Virus Entry by G Protein-Coupled Receptor Antagonists. J. Virol. 2015, 89 (19), 9932– 9938, DOI: 10.1128/JVI.01337-15
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  98
  Inhibition of Ebola and Marburg virus entry by G protein-coupled receptor antagonists
  Cheng, Han; Lear-Rooney, Calli M.; Johansen, Lisa; Varhegyi, Elizabeth; Chen, Zheng W.; Olinger, Gene G.; Rong, Lijun
  Journal of Virology (2015), 89 (19), 9932-9938CODEN: JOVIAM; ISSN:1098-5514. (American Society for Microbiology)
  Filoviruses, consisting of Ebola virus (EBOV) and Marburg virus (MARV), are among the most lethal infectious threats to mankind. Infections by these viruses can cause severe hemorrhagic fevers in humans and nonhuman primates with high mortality rates. Since there is currently no vaccine or antiviral therapy approved for humans, there is an urgent need to develop prophylactic and therapeutic options for use during filoviral outbreaks and bioterrorist attacks. One of the ideal targets against filoviral infection and diseases is at the entry step, which is mediated by the filoviral glycoprotein (GP). In this report, we screened a chem. library of small mols. and identified numerous inhibitors, which are known G protein-coupled receptor (GPCR) antagonists targeting different GPCRs, including histamine receptors, 5-HT (serotonin) receptors, muscarinic acetylcholine receptor, and adrenergic receptor. These inhibitors can effectively block replication of both infectious EBOV and MARV, indicating a broad antiviral activity of the GPCR antagonists. The time-of-addn. expt. and microscopic studies suggest that GPCR antagonists block filoviral entry at a step following the initial attachment but prior to viral/cell membrane fusion. These results strongly suggest that GPCRs play a crit. role in filoviral entry and GPCR antagonists can be developed as an effective anti-EBOV/MARV therapy.
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99. 99
  Si, L.; Meng, K.; Tian, Z.; Sun, J.; Li, H.; Zhang, Z.; Soloveva, V.; Li, H.; Fu, G.; Xia, Q.; Xiao, S.; Zhang, L.; Zhou, D. Triterpenoids Manipulate a Broad Range of Virus-Host Fusion via Wrapping the HR2 Domain Prevalent in Viral Envelopes. Sci. Adv. 2018, 4 (11), eaau8408, DOI: 10.1126/sciadv.aau8408
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  There is no corresponding record for this reference.
100. 100
  Kononova, A. A.; Sokolova, A. S.; Cheresiz, S. V.; Yarovaya, O. I.; Nikitina, R. A.; Chepurnov, A. A.; Pokrovsky, A. G.; Salakhutdinov, N. F. N-Heterocyclic Borneol Derivatives as Inhibitors of Marburg Virus Glycoprotein-Mediated VSIV Pseudotype Entry. MedChemComm 2017, 8 (12), 2233– 2237, DOI: 10.1039/C7MD00424A
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  100
  N-Heterocyclic borneol derivatives as inhibitors of Marburg virus glycoprotein-mediated VSIV pseudotype entry
  Kononova, A. A.; Sokolova, A. S.; Cheresiz, S. V.; Yarovaya, O. I.; Nikitina, R. A.; Chepurnov, A. A.; Pokrovsky, A. G.; Salakhutdinov, N. F.
  MedChemComm (2017), 8 (12), 2233-2237CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
  There is currently no approved antiviral therapy for treatment of Marburg virus disease (MVD). Although filovirus infection outbreaks are quite rare, the high mortality rates in such outbreaks make the development of anti-filoviral drugs an important goal of medical chem. and virol. Here, we performed screening of a large library of natural derivs. for their virus entry inhibition activity using pseudotype systems. The bornyl ester derivs. contg. satd. N-heterocycles exhibited the highest antiviral activity. It is supposed that compds. with specific inhibitory activity toward MarV-GP-dependent virus entry will inhibit the rVSIV-ΔG-MarV-GP pseudotype much more efficiently than the control rVSIV-ΔG-G pseudotype. At the same time, the compds. similarly inhibiting both pseudotypes will likely affect rVSIV capsid replication or the cellular mechanisms common to the entry of both viruses. Borneol itself is not active against both pseudotypes and is nontoxic, whereas its derivs. have varying toxicity and antiviral activity. Among low-toxic borneol derivs., six compds. turned out to be relatively specific inhibitors of MarV-GP-mediated infection (SC > 10). Of them, compd. 6 contg. a methylpiperidine moiety exhibited the highest virus-specific activity. Notably, the virus-specific activity of this compd. is twice as high as that of the ref.
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101. 101
  Boyd, M. R. Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating protein that binds viral surface envelope glycoprotein gp120: potential applications to microbicide development. Antimicrob. Agents Chemother. 1997, 41, 1521– 1530, DOI: 10.1128/AAC.41.7.1521
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  101
  Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating protein that binds viral surface envelope glycoprotein gp120: potential applications to microbicide development
  Boyd, Michael R.; Gustafson, Kirk R.; Mcmahon, James B.; Shoemaker, Robert H.; O'Keefe, Barry R.; Mori, Toshiyuki; Gulakowski, Robert J.; Wu, Lin; Rivera, Maria I.; Laurencot, Carolyn M.; Currens, Michael J.; Cardellina, John H., II; Buckheit, Robert W., Jr.; Nara, Peter L.; Pannell, Lewis K.; Sowder, Raymond C., II; Henderson, Louis E.
  Antimicrobial Agents and Chemotherapy (1997), 41 (7), 1521-1530CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  We have isolated and sequenced a novel 11-kDa virucidal protein, named cyanovirin-N (CV-N), from cultures of the cyanobacterium (blue-green alga) Nostoc ellipsosporum. We also have produced CV-N recombinantly by expression of a corresponding DNA sequence in Escherichia coli. Low nanomolar concns. of either natural or recombinant CV-N irreversibly inactivate diverse lab. strains and primary isolates of human immunodeficiency virus (HIV) type 1 as well as strains of HIV type 2 and simian immunodeficiency virus. In addn., CV-N aborts cell-to-cell fusion and transmission of HIV-1 infection. Continuous, 2-day exposures of uninfected CEM-SS cells or peripheral blood lymphocytes to high concns. (e.g., 9000 nM) of CV-N were not lethal to these representative host cell types. The antiviral activity of CV-N is due, at least in part, to unique, high-affinity interactions of CV-N with the viral surface envelope glycoprotein gp120. The biol. activity of CV-N is highly resistant to physicochem. denaturation, further enhancing its potential as an anti-HIV microbicide.
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102. 102
  Barrientos, L. G. Cyanovirin-N binds to the viral surface glycoprotein, GP1,2 and inhibits infectivity of Ebola virus. Antiviral Res. 2003, 58, 47– 56, DOI: 10.1016/S0166-3542(02)00183-3
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  102
  Cyanovirin-N binds to the viral surface glycoprotein, GP1,2 and inhibits infectivity of Ebola virus
  Barrientos, Laura G.; O'Keefe, Barry R.; Bray, Mike; Sanchez, Anthony; Gronenborn, Angela M.; Boyd, Michael R.
  Antiviral Research (2003), 58 (1), 47-56CODEN: ARSRDR; ISSN:0166-3542. (Elsevier Science B.V.)
  Ebola virus (Ebo) causes severe hemorrhagic fever and high mortality in humans. There are currently no effective therapies. Here, the authors have explored potential anti-Ebo activity of the human immunodeficiency virus (HIV)-inactivating protein cyanovirin-N (CV-N). CV-N is known to potently inhibit the infectivity of a broad spectrum of HIV strains at the level of viral entry. This involves CV-N binding to N-linked high-mannose oligossacharides on the viral glycoprotein gp120. The Ebola envelope contains somewhat similar oligosaccharide constituents, suggesting possible susceptibility to inhibition by CV-N. Our initial results revealed that CV-N had both in vitro and in vivo antiviral activity against the Zaire strain of the Ebola virus (Ebo-Z). Addn. of CV-N to the cell culture medium at the time of Ebo-Z infection inhibited the development of viral cytopathic effects (CPEs). CV-N also delayed the death of Ebo-Z-infected mice, both when given as a series of daily s.c. injections and when the virus was incubated ex vivo together with CV-N before inoculation into the mice. Furthermore, similar to earlier results with HIV gp120, CV-N bound with considerable affinity to the Ebola surface envelope glycoprotein, GP1,2. Competition expts. with free oligosaccharides were consistent with the view that carbohydrate-mediated CV-N/GP1,2 interactions involve oligosaccharides residing on the Ebola viral envelope. Overall, these studies broaden the range of viruses known to be inhibited by CV-N, and further implicate carbohydrate moieties on viral surface proteins as common viral mol. targets for this novel protein.
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103. 103
  Báez-Santos, Y. M.; St. John, S. E.; Mesecar, A. D. The SARS-Coronavirus Papain-like Protease: Structure, Function and Inhibition by Designed Antiviral Compounds. Antiviral Res. 2015, 115, 21– 38, DOI: 10.1016/j.antiviral.2014.12.015
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  103
  The SARS-coronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds
  Baez-Santos, Yahira M.; St. John, Sarah E.; Mesecar, Andrew D.
  Antiviral Research (2015), 115 (), 21-38CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
  A review. Over 10 years have passed since the deadly human coronavirus that causes severe acute respiratory syndrome (SARS-CoV) emerged from the Guangdong Province of China. Despite the fact that the SARS-CoV pandemic infected over 8500 individuals, claimed over 800 lives and cost billions of dollars in economic loss worldwide, there still are no clin. approved antiviral drugs, vaccines or monoclonal antibody therapies to treat SARS-CoV infections. The recent emergence of the deadly human coronavirus that causes Middle East respiratory syndrome (MERS-CoV) is a sobering reminder that new and deadly coronaviruses can emerge at any time with the potential to become pandemics. Therefore, the continued development of therapeutic and prophylactic countermeasures to potentially deadly coronaviruses is warranted. The coronaviral proteases, papain-like protease (PLpro) and 3C-like protease (3CLpro), are attractive antiviral drug targets because they are essential for coronaviral replication. Although the primary function of PLpro and 3CLpro are to process the viral polyprotein in a coordinated manner, PLpro has the addnl. function of stripping ubiquitin and ISG15 from host-cell proteins to aid coronaviruses in their evasion of the host innate immune responses. Therefore, targeting PLpro with antiviral drugs may have an advantage in not only inhibiting viral replication but also inhibiting the dysregulation of signaling cascades in infected cells that may lead to cell death in surrounding, uninfected cells. This review provides an up-to-date discussion on the SARS-CoV papain-like protease including a brief overview of the SARS-CoV genome and replication followed by a more in-depth discussion on the structure and catalytic mechanism of SARS-CoV PLpro, the multiple cellular functions of SARS-CoV PLpro, the inhibition of SARS-CoV PLpro by small mol. inhibitors, and the prospect of inhibiting papain-like protease from other coronaviruses. This paper forms part of a series of invited articles in Antiviral Research on "From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses.".
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104. 104
  Jo, S.; Kim, S.; Shin, D. H.; Kim, M.-S. Inhibition of SARS-CoV 3CL Protease by Flavonoids. J. Enzyme Inhib. Med. Chem. 2020, 35 (1), 145– 151, DOI: 10.1080/14756366.2019.1690480
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  104
  Inhibition of SARS-CoV 3CL protease by flavonoids
  Jo, Seri; Kim, Suwon; Shin, Dong Hae; Kim, Mi-Sun
  Journal of Enzyme Inhibition and Medicinal Chemistry (2020), 35 (1), 145-151CODEN: JEIMAZ; ISSN:1475-6366. (Taylor & Francis Ltd.)
  There were severe panics caused by severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) and Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV). Therefore, researches targeting these viruses have been required. Coronaviruses (CoVs) have been rising targets of some flavonoids. The antiviral activity of some flavonoids against CoVs is presumed directly caused by inhibiting 3C-like protease (3CLpro). Here, the authors applied a flavonoid library to systematically probe inhibitory compds. against SARS-CoV 3CLpro. Herbacetin, rhoifolin and pectolinarin were found to efficiently block the enzymic activity of SARS-CoV 3CLpro. The interaction of the three flavonoids was confirmed using a tryptophan-based fluorescence method, too. An induced-fit docking anal. indicated that S1, S2 and S3' sites are involved in binding with flavonoids. The comparison with previous studies showed that Triton X-100 played a crit. role in objecting false pos. or overestimated inhibitory activity of flavonoids. With the systematic anal., the three flavonoids are suggested to be templates to design functionally improved inhibitors.
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105. 105
  Wu, C.-Y.; Jan, J.-T.; Ma, S.-H.; Kuo, C.-J.; Juan, H.-F.; Cheng, Y.-S. E.; Hsu, H.-H.; Huang, H.-C.; Wu, D.; Brik, A.; Liang, F.-S.; Liu, R.-S.; Fang, J.-M.; Chen, S.-T.; Liang, P.-H.; Wong, C.-H. Small Molecules Targeting Severe Acute Respiratory Syndrome Human Coronavirus. Proc. Natl. Acad. Sci. U. S. A. 2004, 101 (27), 10012– 10017, DOI: 10.1073/pnas.0403596101
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  105
  Small molecules targeting severe acute respiratory syndrome human coronavirus
  Wu, Chung-Yi; Jan, Jia-Tsrong; Ma, Shiou-Hwa; Kuo, Chih-Jung; Juan, Hsueh-Fen; Cheng, Yih-Shyun E.; Hsu, Hsien-Hua; Huang, Hsuan-Cheng; Wu, Douglass; Brik, Ashraf; Liang, Fu-Sen; Liu, Rai-Shung; Fang, Jim-Min; Chen, Shui-Tein; Liang, Po-Huang; Wong, Chi-Huey
  Proceedings of the National Academy of Sciences of the United States of America (2004), 101 (27), 10012-10017CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  Severe acute respiratory syndrome (SARS) is an infectious disease caused by a novel human coronavirus. Currently, no effective antiviral agents exist against this type of virus. A cell-based assay, with SARS virus and Vero E6 cells, was developed to screen existing drugs, natural products, and synthetic compds. to identify effective anti-SARS agents. Of > 10,000 agents tested, ≈50 compds. were found active at 10 μM; among these compds., two are existing drugs (Reserpine and Aescin) and several are in clin. development. These 50 active compds. were tested again, and compds. 2-6, 10, and 13 showed active at 3 μM. The 50% inhibitory concns. for the inhibition of viral replication (EC50) and host growth (CC50) were then measured and the selectivity index (SI = CC50/EC50) was detd. The EC50, based on ELISA, and SI for Reserpine, Aescin, and Valinomycin are 3.4 μM (SI = 7.3), 6.0 μM (SI = 2.5), and 0.85 μM (SI = 80), resp. Addnl. studies were carried out to further understand the mode of action of some active compds., including ELISA, Western blot anal., immunofluorescence and flow cytometry assays, and inhibition against the 3CL protease and viral entry. Of particular interest are the two anti-HIV agents, one as an entry blocker and the other as a 3CL protease inhibitor (Ki = 0.6 μM).
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106. 106
  Cho, J. K.; Curtis-Long, M. J.; Lee, K. H.; Kim, D. W.; Ryu, H. W.; Yuk, H. J.; Park, K. H. Geranylated Flavonoids Displaying SARS-CoV Papain-like Protease Inhibition from the Fruits of Paulownia Tomentosa. Bioorg. Med. Chem. 2013, 21 (11), 3051– 3057, DOI: 10.1016/j.bmc.2013.03.027
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  106
  Geranylated flavonoids displaying SARS-CoV papain-like protease inhibition from the fruits of Paulownia tomentosa
  Cho, Jung Keun; Curtis-Long, Marcus J.; Lee, Kon Ho; Kim, Dae Wook; Ryu, Hyung Won; Yuk, Heung Joo; Park, Ki Hun
  Bioorganic & Medicinal Chemistry (2013), 21 (11), 3051-3057CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
  SARS-CoV papain-like protease (PLpro) is an important antiviral target due to its key roles in SARS virus replication. The MeOH exts. of the fruits of the Paulownia tree yielded many small mols. capable of targeting PLpro. Five of these compds. were new geranylated flavonoids, tomentin A, tomentin B, tomentin C, tomentin D, tomentin E (1-5). Structure anal. of new compds. (1-5) by NMR showed that they all contain a 3,4-dihydro-2H-pyran moiety. This chemotype is very rare and is derived from cyclization of a geranyl group with a phenol functionality. Most compds. (1-12) inhibited PLpro in a dose dependent manner with IC50's raging between 5.0 and 14.4 μM. All new compds. having the dihydro-2H-pyran group showed better inhibition than their parent compds. (1 vs 11, 2 vs 9, 4 vs 12, 5 vs 6). In kinetic studies, 1-12 emerged to be reversible, mixed inhibitors.
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107. 107
  Park, J.-Y.; Jeong, H. J.; Kim, J. H.; Kim, Y. M.; Park, S.-J.; Kim, D.; Park, K. H.; Lee, W. S.; Ryu, Y. B. Diarylheptanoids from Alnus Japonica Inhibit Papain-Like Protease of Severe Acute Respiratory Syndrome Coronavirus. Biol. Pharm. Bull. 2012, 35, advpub, DOI: 10.1248/bpb.b12-00623
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  There is no corresponding record for this reference.
108. 108
  Park, J.-Y.; Kim, J. H.; Kim, Y. M.; Jeong, H. J.; Kim, D. W.; Park, K. H.; Kwon, H.-J.; Park, S.-J.; Lee, W. S.; Ryu, Y. B. Tanshinones as Selective and Slow-Binding Inhibitors for SARS-CoV Cysteine Proteases. Bioorg. Med. Chem. 2012, 20 (19), 5928– 5935, DOI: 10.1016/j.bmc.2012.07.038
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  108
  Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases
  Park, Ji-Young; Kim, Jang Hoon; Kim, Young Min; Jeong, Hyung Jae; Kim, Dae Wook; Park, Ki Hun; Kwon, Hyung-Jun; Park, Su-Jin; Lee, Woo Song; Ryu, Young Bae
  Bioorganic & Medicinal Chemistry (2012), 20 (19), 5928-5935CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
  In the search for anti-SARS-CoV, tanshinones derived from Salvia miltiorrhiza were found to be specific and selective inhibitors for the SARS-CoV 3CLpro and PLpro, viral cysteine proteases. A literature search for studies involving the seven isolated tanshinone hits showed that at present, none have been identified as coronaviral protease inhibitors. We have identified that all of the isolated tanshinones are good inhibitors of both cysteine proteases. However, their activity was slightly affected by subtle changes in structure and targeting enzymes. All isolated compds. (1-7) act as time dependent inhibitors of PLpro, but no improved inhibition was obsd. following preincubation with the 3CLpro. In a detail kinetic mechanism study, all of the tanshinones except rosmariquinone (7) were identified as noncompetitive enzyme isomerization inhibitors. However, rosmariquinone (7) showed a different kinetic mechanism through mixed-type simple reversible slow-binding inhibition. Furthermore, tanshinone I (5) exhibited the most potent nanomolar level inhibitory activity toward deubiquitinating (IC50 = 0.7 μM). Addnl., the inhibition is selective because these compds. do not exert significant inhibitory effects against other proteases including chymotrysin, papain, and HIV protease. These findings provide potential inhibitors for SARS-CoV viral infection and replication.
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109. 109
  Kim, D. W.; Seo, K. H.; Curtis-Long, M. J.; Oh, K. Y.; Oh, J.-W.; Cho, J. K.; Lee, K. H.; Park, K. H. Phenolic Phytochemical Displaying SARS-CoV Papain-like Protease Inhibition from the Seeds of Psoralea Corylifolia. J. Enzyme Inhib. Med. Chem. 2014, 29 (1), 59– 63, DOI: 10.3109/14756366.2012.753591
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  109
  Phenolic phytochemical displaying SARS-CoV papain-like protease inhibition from the seeds of Psoralea corylifolia
  Kim, Dae Wook; Seo, Kyung Hye; Curtis-Long, Marcus J.; Oh, Kyeong Yeol; Oh, Jong-Won; Cho, Jung Keun; Lee, Kon Ho; Park, Ki Hun
  Journal of Enzyme Inhibition and Medicinal Chemistry (2014), 29 (1), 59-63CODEN: JEIMAZ; ISSN:1475-6366. (Informa Healthcare)
  Severe acute respiratory syndrome coronavirus (SARS-CoV) papain-like protease (PLpro) is a key enzyme that plays an important role in SARS virus replication. The ethanol ext. of the seeds of Psoralea corylifolia showed high activity against the SARS-CoV PLpro with an IC50 of value of 15 μg/mL. Due to its potency, subsequent bioactivity-guided fractionation of the ethanol ext. led to six arom. compds. (1-6), which were identified as bavachinin (1), neobavaisoflavone (2), isobavachalcone (3), 4'-O-methylbavachalcone (4), psoralidin (5) and corylifol A (6). All isolated flavonoids (1-6) inhibited PLpro in a dose-dependent manner with IC50 ranging between 4.2 and 38.4 μM. Lineweaver-Burk and Dixon plots and their secondary replots indicated that inhibitors (1-6) were mixed inhibitors of PLpro. The anal. of KI and KIS values proved that the two most promising compds. (3 and 5) had reversible mixed type I mechanisms.
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110. 110
  Sayed, A. M.; Khattab, A. R.; AboulMagd, A. M.; Hassan, H. M.; Rateb, M. E.; Zaid, H.; Abdelmohsen, U. R. Nature as a Treasure Trove of Potential Anti-SARS-CoV Drug Leads: A Structural/Mechanistic Rationale. RSC Adv. 2020, 10 (34), 19790– 19802, DOI: 10.1039/D0RA04199H
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  110
  Nature as a treasure trove of potential anti-SARS-CoV drug leads: a structural/mechanistic rationale
  Sayed, Ahmed M.; Khattab, Amira R.; AboulMagd, Asmaa M.; Hassan, Hossam M.; Rateb, Mostafa E.; Zaid, Hala; Abdelmohsen, Usama Ramadan
  RSC Advances (2020), 10 (34), 19790-19802CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
  A review. The novel Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is a potential factor for fatal illness and a tremendous concern for global public health. The COVID-19 pandemic has entered a dangerous new phase. In the context of drug discovery, the structurally-unique and chem.-diverse natural products have been valuable sources for drug leads. In this review, we report for potential candidates derived from natural sources with well-reported in vitro efficacy against SARS-CoV during the last decade. Addnl., a library of 496 phenolic metabolites was subjected to a computer-aided virtual screening against the active site of the recently reported SARS-CoV Main protease (Mpro). Anal. of physicochem. properties of these natural products has been carried out and presented for all the tested phenolic metabolites. Only three of the top candidates, viz. acetylglucopetunidin (31), isoxanthohumol (32) and ellagic acid (33), which are widely available in many edible fruits, obey both Lipinski's and Veber's rules of drug-likeness and thus possess high degrees of predicted bioavailability. These natural products are suggested as potential drug candidates for the development of anti-SARS-CoV-2 therapeutics in the near future.
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111. 111
  Luo, D.; Vasudevan, S. G.; Lescar, J. The Flavivirus NS2B–NS3 Protease–Helicase as a Target for Antiviral Drug Development. Antiviral Res. 2015, 118, 148– 158, DOI: 10.1016/j.antiviral.2015.03.014
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  111
  The flavivirus NS2B-NS3 protease-helicase as a target for antiviral drug development
  Luo, Dahai; Vasudevan, Subhash G.; Lescar, Julien
  Antiviral Research (2015), 118 (), 148-158CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
  The flavivirus NS3 protein is assocd. with the endoplasmic reticulum membrane via its close interaction with the central hydrophilic region of the NS2B integral membrane protein. The multiple roles played by the NS2B-NS3 protein in the virus life cycle makes it an attractive target for antiviral drug discovery. The N-terminal region of NS3 and its cofactor NS2B constitute the protease that cleaves the viral polyprotein. The NS3 C-terminal domain possesses RNA helicase, nucleoside and RNA triphosphatase activities and is involved both in viral RNA replication and virus particle formation. In addn., NS2B-NS3 serves as a hub for the assembly of the flavivirus replication complex and also modulates viral pathogenesis and the host immune response. Here, we review biochem. and structural advances on the NS2B-NS3 protein, including the network of interactions it forms with NS5 and NS4B and highlight recent drug development efforts targeting this protein. This article forms part of a symposium in Antiviral Research on flavivirus drug discovery.
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112. 112
  Bharadwaj, S.; Lee, K. E.; Dwivedi, V. D.; Yadava, U.; Panwar, A.; Lucas, S. J.; Pandey, A.; Kang, S. G. Discovery of Ganoderma Lucidum Triterpenoids as Potential Inhibitors against Dengue Virus NS2B-NS3 Protease. Sci. Rep. 2019, 9 (1), 19059, DOI: 10.1038/s41598-019-55723-5
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  112
  Discovery of Ganoderma lucidum triterpenoids as potential inhibitors against Dengue virus NS2B-NS3 protease
  Bharadwaj, Shiv; Lee, Kyung Eun; Dwivedi, Vivek Dhar; Yadava, Umesh; Panwar, Aleksha; Lucas, Stuart. J.; Pandey, Amit; Kang, Sang Gu
  Scientific Reports (2019), 9 (1), 19059CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
  Dengue virus (DENV) infection causes serious health problems in humans for which no drug is currently available. Recently, DENV NS2B-NS3 protease has been proposed as a primary target for anti-dengue drug discovery due to its important role in new virus particle formation by conducting DENV polyprotein cleavage. Triterpenoids from the medicinal fungus Ganoderma lucidum have been suggested as pharmacol. bioactive compds. and tested as anti-viral agents against various viral pathogens including human immunodeficiency virus. However, no reports are available concerning the anti-viral activity of triterpenoids from Ganoderma lucidum against DENV. Therefore, we employed a virtual screening approach to predict the functional triterpenoids from Ganoderma lucidum as potential inhibitors of DENV NS2B-NS3 protease, followed by an in-vitro assay. From in-silico anal. of twenty-two triterpenoids of Ganoderma lucidum, four triterpenoids, viz.Ganodermanontriol (-6.291 kcal/mol), Lucidumol A (-5.993 kcal/mol), Ganoderic acid C2 (-5.948 kcal/mol) and Ganosporeric acid A (-5.983 kcal/mol) were predicted to be viral protease inhibitors by comparison to ref. inhibitor 1,8-Dihydroxy-4,5-dinitroanthraquinone (-5.377 kcal/mol). These results were further studied for binding affinity and stability using the mol. mechanics/generalized Born surface area method and Mol. Dynamics simulations, resp. Also, in-vitro viral infection inhibition suggested that Ganodermanontriol is a potent bioactive triterpenoid.
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113. 113
  Sheahan, T. P.; Sims, A. C.; Zhou, S.; Graham, R. L.; Pruijssers, A. J.; Agostini, M. L.; Leist, S. R.; Schäfer, A.; Dinnon, K. H.; Stevens, L. J.; Chappell, J. D.; Lu, X.; Hughes, T. M.; George, A. S.; Hill, C. S.; Montgomery, S. A.; Brown, A. J.; Bluemling, G. R.; Natchus, M. G.; Saindane, M.; Kolykhalov, A. A.; Painter, G.; Harcourt, J.; Tamin, A.; Thornburg, N. J.; Swanstrom, R.; Denison, M. R.; Baric, R. S. An Orally Bioavailable Broad-Spectrum Antiviral Inhibits SARS-CoV-2 in Human Airway Epithelial Cell Cultures and Multiple Coronaviruses in Mice. Sci. Transl. Med. 2020, 12, eabb5883, DOI: 10.1126/scitranslmed.abb5883
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114. 114
  Yu, M.-S.; Lee, J.; Lee, J. M.; Kim, Y.; Chin, Y.-W.; Jee, J.-G.; Keum, Y.-S.; Jeong, Y.-J. Identification of Myricetin and Scutellarein as Novel Chemical Inhibitors of the SARS Coronavirus Helicase, NsP13. Bioorg. Med. Chem. Lett. 2012, 22 (12), 4049– 4054, DOI: 10.1016/j.bmcl.2012.04.081
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  114
  Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13
  Yu, Mi-Sun; Lee, June; Lee, Jin Moo; Kim, Younggyu; Chin, Young-Won; Jee, Jun-Goo; Keum, Young-Sam; Jeong, Yong-Joo
  Bioorganic & Medicinal Chemistry Letters (2012), 22 (12), 4049-4054CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  Severe acute respiratory syndrome (SARS) is an infectious disease with a strong potential for transmission upon close personal contact and is caused by the SARS-coronavirus (CoV). However, there are no natural or synthetic compds. currently available that can inhibit SARS-CoV. We examd. the inhibitory effects of 64 purified natural compds. against the activity of SARS helicase, nsP13, and the hepatitis C virus (HCV) helicase, NS3h, by conducting fluorescence resonance energy transfer (FRET)-based double-strand (ds) DNA unwinding assay or by using a colorimetry-based ATP hydrolysis assay. While none of the compds., examd. in our study inhibited the DNA unwinding activity or ATPase activity of human HCV helicase protein, we found that myricetin and scutellarein potently inhibit the SARS-CoV helicase protein in vitro by affecting the ATPase activity, but not the unwinding activity, nsP13. In addn., we obsd. that myricetin and scutellarein did not exhibit cytotoxicity against normal breast epithelial MCF10A cells. Our study demonstrates for the first time that selected naturally-occurring flavonoids, including myricetin and scultellarein might serve as SARS-CoV chem. inhibitors.
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115. 115
  Botta, L.; Rivara, M.; Zuliani, V.; Radi, M. Drug Repurposing Approaches to Fight Dengue Virus Infection and Related Diseases. Front. Biosci., Landmark Ed. 2018, 23, 997– 1019, DOI: 10.2741/4630
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  115
  Drug repurposing approaches to fight Dengue virus infection and related diseases
  Botta, Lorenzo; Rivara, Mirko; Zuliani, Valentina; Radi, Marco
  Frontiers in Bioscience, Landmark Edition (2018), 23 (6), 997-1019CODEN: FRBIF6; ISSN:1093-4715. (Frontiers in Bioscience)
  Dengue is a mosquito-borne viral disease caused by four antigenically distinct serotypes of Dengue Virus (DENV), namely DENV1-4 and is currently considered the most important arthropodborn viral disease in the world. An effective antiviral therapy to treat Dengue Virus infection is still missing and a no. of replicative cycle inhibitors are currently under study. Considering the rapid spreading of DENV and the common timeframe required for bringing a new drug on the market, the repurposing of approved drugs used for different diseases to identify novel inhibitors of this pathogen represents an attractive approach for a rapid therapeutic intervention. Herein, we will describe the most recent drug repurposing approaches to fight DENV infection and their implications in antiviral drug-discovery.
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116. 116
  Shimizu, H.; Saito, A.; Mikuni, J.; Nakayama, E. E.; Koyama, H.; Honma, T.; Shirouzu, M.; Sekine, S.; Shioda, T. Discovery of a Small Molecule Inhibitor Targeting Dengue Virus NS5 RNA-Dependent RNA Polymerase. PLoS Neglected Trop. Dis. 2019, 13 (11), e0007894, DOI: 10.1371/journal.pntd.0007894
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  116
  Discovery of a small molecule inhibitor targeting dengue virus NS5 RNA-dependent RNA polymerase
  Shimizu, Heaki; Saito, Akatsuki; Mikuni, Junko; Nakayama, Emi E.; Koyama, Hiroo; Honma, Teruki; Shirouzu, Mikako; Sekine, Shun-ichi; Shioda, Tatsuo
  PLoS Neglected Tropical Diseases (2019), 13 (11), e0007894/1-e0007894/21CODEN: PNTDAM; ISSN:1935-2735. (Public Library of Science)
  Dengue is a mosquito-borne viral infection that has spread globally in recent years. Around half of the world's population, esp. in the tropics and subtropics, is at risk of infection. Every year, 50-100 million clin. cases are reported, and more than 500,000 patients develop the symptoms of severe dengue infection: dengue haemorrhagic fever and dengue shock syndrome, which threaten life in Asia and Latin America. No antiviral drug for dengue is available. The dengue virus (DENV) non-structural protein 5 (NS5), which possesses the RNA-dependent RNA polymerase (RdRp) activity and is responsible for viral replication and transcription, is an attractive target for anti-dengue drug development. In the present study, 16,240 small-mol. compds. in a fragment library were screened for their capabilities to inhibit the DENV type 2 (DENV2) RdRp activities in vitro. Based on in cellulo antiviral and cytotoxity assays, we selected the compd. RK-0404678 with the EC50 value of 6.0 μM for DENV2. Crystallog. analyses revealed two unique binding sites for RK-0404678 within the RdRp, which are conserved in flavivirus NS5 proteins. No resistant viruses emerged after nine rounds of serial passage of DENV2 in the presence of RK-0404678, suggesting the high genetic barrier of this compd. to the emergence of a resistant virus. Collectively, RK-0404678 and its binding sites provide a new framework for antiviral drug development.
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117. 117
  Hamill, R. L.; Hoehn, M. M. A9145, A new adenine-containing antifungal antibiotic I. Discovery and isolation. J. Antibiot. 1973, 26 (8), 463– 465, DOI: 10.7164/antibiotics.26.463
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  117
  A 9145, a new adenine-containing antifungal antibiotic. I. Discovery and isolation
  Hamill, Robert L.; Hoehn, Marvin M.
  Journal of Antibiotics (1973), 26 (8), 463-5CODEN: JANTAJ; ISSN:0021-8820.
  A9145 (I) is a new, water-sol. antifungal antibiotic produced by a strain of Streptomyces griseolus (NRRL 3739). This basic antibiotic has an apparent mol. wt. of about 510, contains adenine and a possible sugar moiety, and forms cryst. org. and inorg. salts. I is active against Candida species, Saccharomyces pastorianus, plant disease fungi and Trypanosoma species. I has an LD50 (s.c.) of 185 mg/kg in mice.
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118. 118
  Krafcikova, P.; Silhan, J.; Nencka, R.; Boura, E. Structural Analysis of the SARS-CoV-2 Methyltransferase Complex Involved in RNA Cap Creation Bound to Sinefungin. Nat. Commun. 2020, 11 (1), 3717, DOI: 10.1038/s41467-020-17495-9
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  118
  Structural analysis of the SARS-CoV-2 methyltransferase complex involved in RNA cap creation bound to sinefungin
  Krafcikova, Petra; Silhan, Jan; Nencka, Radim; Boura, Evzen
  Nature Communications (2020), 11 (1), 3717CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
  Abstr.: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. 2'-O-RNA methyltransferase (MTase) is one of the enzymes of this virus that is a potential target for antiviral therapy as it is crucial for RNA cap formation; an essential process for viral RNA stability. This MTase function is assocd. with the nsp16 protein, which requires a cofactor, nsp10, for its proper activity. Here we show the crystal structure of the nsp10-nsp16 complex bound to the pan-MTase inhibitor sinefungin in the active site. Our structural comparisons reveal low conservation of the MTase catalytic site between Zika and SARS-CoV-2 viruses, but high conservation of the MTase active site between SARS-CoV-2 and SARS-CoV viruses; these data suggest that the prepn. of MTase inhibitors targeting several coronaviruses - but not flaviviruses - should be feasible. Together, our data add to important information for structure-based drug discovery.
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119. 119
  Hercik, K.; Brynda, J.; Nencka, R.; Boura, E. Structural Basis of Zika Virus Methyltransferase Inhibition by Sinefungin. Arch. Virol. 2017, 162 (7), 2091– 2096, DOI: 10.1007/s00705-017-3345-x
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  119
  Structural basis of Zika virus methyltransferase inhibition by sinefungin
  Hercik, Kamil; Brynda, Jiri; Nencka, Radim; Boura, Evzen
  Archives of Virology (2017), 162 (7), 2091-2096CODEN: ARVIDF; ISSN:0304-8608. (Springer-Verlag GmbH)
  Zika virus is considered a major global threat to human kind. Here, we present a crystal structure of one of its essential enzymes, the methyltransferase, with the inhibitor sinefungin. This structure, together with previously solved structures with bound substrates, will provide the information needed for rational inhibitor design. Based on the structural data we suggest the modification of the adenine moiety of sinefungin to increase selectivity and to covalently link it to a GTP analog, to increase the affinity of the synthesized compds.
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120. 120
  Noble, C. G.; Li, S.-H.; Dong, H.; Chew, S. H.; Shi, P.-Y. Crystal Structure of Dengue Virus Methyltransferase without S-Adenosyl-L-Methionine. Antiviral Res. 2014, 111, 78– 81, DOI: 10.1016/j.antiviral.2014.09.003
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  120
  Crystal structure of dengue virus methyltransferase without S-adenosyl-L-methionine
  Noble, Christian G.; Li, Shi-Hua; Dong, Hongping; Chew, Sock Hui; Shi, Pei-Yong
  Antiviral Research (2014), 111 (), 78-81CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
  Flavivirus methyltransferase is a genetically-validated antiviral target. Crystal structures of almost all available flavivirus methyltransferases contain S-adenosyl-L-methionine (SAM), the Me donor mol. that co-purifies with the enzymes. This raises a possibility that SAM is an integral structural component required for the folding of dengue virus (DENV) methyltransferase. Here we exclude this possibility by solving the crystal structure of DENV methyltransferase without SAM. The SAM ligand was removed from the enzyme through a urea-mediated denaturation-and-renaturation protocol. The crystal structure of the SAM-depleted enzyme exhibits a vacant SAM-binding pocket, with a conformation identical to that of the SAM-enzyme co-crystal structure. Functionally, equiv. enzymic activities (N-7 methylation, 2'-O methylation, and GMP-enzyme complex formation) were detected for the SAM-depleted and SAM-contg. recombinant proteins. These results clearly indicate that the SAM mol. is not an essential component for the correct folding of DENV methyltransferase. Furthermore, the results imply a potential antiviral approach to search for inhibitors that can bind to the SAM-binding pocket and compete against SAM binding. To demonstrate this potential, we have soaked crystals of DENV methyltransferase without a bound SAM with the natural product Sinefungin and show that preformed crystals are capable of binding ligands in this pocket.
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121. 121
  De Clercq, E. Ebola Virus (EBOV) Infection: Therapeutic Strategies. Biochem. Pharmacol. 2015, 93 (1), 1– 10, DOI: 10.1016/j.bcp.2014.11.008
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  121
  Ebola virus (EBOV) infection: Therapeutic strategies
  De Clercq, Erik
  Biochemical Pharmacology (Amsterdam, Netherlands) (2015), 93 (1), 1-10CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)
  A review. Within less than a year after its epidemic started (in Dec. 2013) in Guinea, Ebola virus (EBOV), a member of the filoviridae, has spread over a no. of West-African countries (Guinea, Sierra Leone and Liberia) and gained allures that have been unprecedented except by human immunodeficiency virus (HIV). Although EBOV is highly contagious and transmitted by direct contact with body fluids, it could be counteracted by the adequate chemoprophylactic and -therapeutic interventions: vaccines, antibodies, siRNAs (small interfering RNAs), interferons and chem. substances, i.e. neplanocin A derivs. (i.e. 3-deazaneplanocin A), BCX4430, favipiravir (T-705), endoplasmic reticulum (ER) α-glucosidase inhibitors and a variety of compds. that have been found to inhibit EBOV infection blocking viral entry or by a mode of action that still has to be resolved. Much has to be learned from the mechanism of action of the compds. active against VSV (vesicular stomatitis virus), a virus belonging to the rhabdoviridae, that in its mode of replication could be exemplary for the replication of filoviridae. BCX44303-Deazaneplanocin AFavipiravirFiloviridae.
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122. 122
  Oestereich, L.; Lüdtke, A.; Wurr, S.; Rieger, T.; Muñoz-Fontela, C.; Günther, S. Successful Treatment of Advanced Ebola Virus Infection with T-705 (Favipiravir) in a Small Animal Model. Antiviral Res. 2014, 105, 17– 21, DOI: 10.1016/j.antiviral.2014.02.014
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  122
  Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model
  Oestereich, Lisa; Ludtke, Anja; Wurr, Stephanie; Rieger, Toni; Munoz-Fontela, Cesar; Gunther, Stephan
  Antiviral Research (2014), 105 (), 17-21CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
  Outbreaks of Ebola hemorrhagic fever in sub-Saharan Africa are assocd. with case fatality rates of up to 90%. Currently, neither a vaccine nor an effective antiviral treatment is available for use in humans. Here, we evaluated the efficacy of the pyrazinecarboxamide deriv. T-705 (favipiravir) against Zaire Ebola virus (EBOV) in vitro and in vivo. T-705 suppressed replication of Zaire EBOV in cell culture by 4 log units with an IC90 of 110 μM. Mice lacking the type I interferon receptor (IFNAR-/-) were used as in vivo model for Zaire EBOV-induced disease. Initiation of T-705 administration at day 6 post infection induced rapid virus clearance, reduced biochem. parameters of disease severity, and prevented a lethal outcome in 100% of the animals. The findings suggest that T-705 is a candidate for treatment of Ebola hemorrhagic fever.
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123. 123
  Warren, T. K.; Jordan, R.; Lo, M. K.; Ray, A. S.; Mackman, R. L.; Soloveva, V.; Siegel, D.; Perron, M.; Bannister, R.; Hui, H. C.; Larson, N.; Strickley, R.; Wells, J.; Stuthman, K. S.; Van Tongeren, S. A.; Garza, N. L.; Donnelly, G.; Shurtleff, A. C.; Retterer, C. J.; Gharaibeh, D.; Zamani, R.; Kenny, T.; Eaton, B. P.; Grimes, E.; Welch, L. S.; Gomba, L.; Wilhelmsen, C. L.; Nichols, D. K.; Nuss, J. E.; Nagle, E. R.; Kugelman, J. R.; Palacios, G.; Doerffler, E.; Neville, S.; Carra, E.; Clarke, M. O.; Zhang, L.; Lew, W.; Ross, B.; Wang, Q.; Chun, K.; Wolfe, L.; Babusis, D.; Park, Y.; Stray, K. M.; Trancheva, I.; Feng, J. Y.; Barauskas, O.; Xu, Y.; Wong, P.; Braun, M. R.; Flint, M.; McMullan, L. K.; Chen, S.-S.; Fearns, R.; Swaminathan, S.; Mayers, D. L.; Spiropoulou, C. F.; Lee, W. A.; Nichol, S. T.; Cihlar, T.; Bavari, S. Therapeutic Efficacy of the Small Molecule GS-5734 against Ebola Virus in Rhesus Monkeys. Nature 2016, 531 (7594), 381– 385, DOI: 10.1038/nature17180
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  123
  Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys
  Warren, Travis K.; Jordan, Robert; Lo, Michael K.; Ray, Adrian S.; Mackman, Richard L.; Soloveva, Veronica; Siegel, Dustin; Perron, Michel; Bannister, Roy; Hui, Hon C.; Larson, Nate; Strickley, Robert; Wells, Jay; Stuthman, Kelly S.; Van Tongeren, Sean A.; Garza, Nicole L.; Donnelly, Ginger; Shurtleff, Amy C.; Retterer, Cary J.; Gharaibeh, Dima; Zamani, Rouzbeh; Kenny, Tara; Eaton, Brett P.; Grimes, Elizabeth; Welch, Lisa S.; Gomba, Laura; Wilhelmsen, Catherine L.; Nichols, Donald K.; Nuss, Jonathan E.; Nagle, Elyse R.; Kugelman, Jeffrey R.; Palacios, Gustavo; Doerffler, Edward; Neville, Sean; Carra, Ernest; Clarke, Michael O.; Zhang, Lijun; Lew, Willard; Ross, Bruce; Wang, Queenie; Chun, Kwon; Wolfe, Lydia; Babusis, Darius; Park, Yeojin; Stray, Kirsten M.; Trancheva, Iva; Feng, Joy Y.; Barauskas, Ona; Xu, Yili; Wong, Pamela; Braun, Molly R.; Flint, Mike; McMullan, Laura K.; Chen, Shan-Shan; Fearns, Rachel; Swaminathan, Swami; Mayers, Douglas L.; Spiropoulou, Christina F.; Lee, William A.; Nichol, Stuart T.; Cihlar, Tomas; Bavari, Sina
  Nature (London, United Kingdom) (2016), 531 (7594), 381-385CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  The most recent Ebola virus outbreak in West Africa, which was unprecedented in the no. of cases and fatalities, geog. distribution, and no. of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clin. efficacy. Here we report the discovery of a novel small mol. GS-5734, a monophosphoramidate prodrug of an adenosine analog, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacol. active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. I.v. administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily i.v. administration of 10 mg kg-1 GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clin. disease signs and pathophysiol. markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-mol. antiviral compd. against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufg., and clin. studies investigating the drug safety and pharmacokinetics are ongoing.
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124. 124
  Warren, T. K.; Wells, J.; Panchal, R. G.; Stuthman, K. S.; Garza, N. L.; Van Tongeren, S. A.; Dong, L.; Retterer, C. J.; Eaton, B. P.; Pegoraro, G.; Honnold, S.; Bantia, S.; Kotian, P.; Chen, X.; Taubenheim, B. R.; Welch, L. S.; Minning, D. M.; Babu, Y. S.; Sheridan, W. P.; Bavari, S. Protection against Filovirus Diseases by a Novel Broad-Spectrum Nucleoside Analogue BCX4430. Nature 2014, 508 (7496), 402– 405, DOI: 10.1038/nature13027
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  124
  Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430
  Warren, Travis K.; Wells, Jay; Panchal, Rekha G.; Stuthman, Kelly S.; Garza, Nicole L.; Van Tongeren, Sean A.; Dong, Lian; Retterer, Cary J.; Eaton, Brett P.; Pegoraro, Gianluca; Honnold, Shelley; Bantia, Shanta; Kotian, Pravin; Chen, Xilin; Taubenheim, Brian R.; Welch, Lisa S.; Minning, Dena M.; Babu, Yarlagadda S.; Sheridan, William P.; Bavari, Sina
  Nature (London, United Kingdom) (2014), 508 (7496), 402-405CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  Filoviruses are emerging pathogens and causative agents of viral haemorrhagic fever. Case fatality rates of filovirus disease outbreaks are among the highest reported for any human pathogen, exceeding 90% (ref. 1). Licensed therapeutic or vaccine products are not available to treat filovirus diseases. Candidate therapeutics previously shown to be efficacious in non-human primate disease models are based on virus-specific designs and have limited broad-spectrum antiviral potential. Here we show that BCX4430, a novel synthetic adenosine analog, inhibits infection of distinct filoviruses in human cells. Biochem., reporter-based and primer-extension assays indicate that BCX4430 inhibits viral RNA polymerase function, acting as a non-obligate RNA chain terminator. Post-exposure i.m. administration of BCX4430 protects against Ebola virus and Marburg virus disease in rodent models. Most importantly, BCX4430 completely protects cynomolgus macaques from Marburg virus infection when administered as late as 48 h after infection. In addn., BCX4430 exhibits broad-spectrum antiviral activity against numerous viruses, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses and flaviviruses. This is the first report, to our knowledge, of non-human primate protection from filovirus disease by a synthetic drug-like small mol. We provide addnl. pharmacol. characterizations supporting the potential development of BCX4430 as a countermeasure against human filovirus diseases and other viral diseases representing major public health threats.
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125. 125
  Daino, G. L.; Frau, A.; Sanna, C.; Rigano, D.; Distinto, S.; Madau, V.; Esposito, F.; Fanunza, E.; Bianco, G.; Taglialatela-Scafati, O.; Zinzula, L.; Maccioni, E.; Corona, A.; Tramontano, E. Identification of Myricetin as an Ebola Virus VP35–Double-Stranded RNA Interaction Inhibitor through a Novel Fluorescence-Based Assay. Biochemistry 2018, 57 (44), 6367– 6378, DOI: 10.1021/acs.biochem.8b00892
  [ACS Full Text ], [CAS], Google Scholar
  125
  Identification of myricetin as an Ebola virus VP35-double-stranded RNA interaction inhibitor through a novel fluorescence-based assay
  Daino, Gian Luca; Frau, Aldo; Sanna, Cinzia; Rigano, Daniela; Distinto, Simona; Madau, Veronica; Esposito, Francesca; Fanunza, Elisa; Bianco, Giulia; Taglialatela-Scafati, Orazio; Zinzula, Luca; Maccioni, Elias; Corona, Angela; Tramontano, Enzo
  Biochemistry (2018), 57 (44), 6367-6378CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
  Ebola virus (EBOV) is a filovirus that causes a severe and rapidly progressing hemorrhagic syndrome; a recent epidemic illustrated the urgent need for novel therapeutic agents because no drugs have been approved for treatment of Ebola virus. A key contribution to the high lethality obsd. during EBOV outbreaks comes from viral evasion of the host antiviral innate immune response in which viral protein VP35 plays a crucial role, blocking interferon type I prodn., first by masking the viral double-stranded RNA (dsRNA) and preventing its detection by the pattern recognition receptor RIG-I. Aiming to identify inhibitors of the interaction of VP35 with the viral dsRNA, counteracting the VP35 viral innate immune evasion, we established a new methodol. for high-yield recombinant VP35 (rVP35) expression and purifn. and a novel and robust fluorescence-based rVP35-RNA interaction assay (Z' factor of 0.69). Taking advantage of such newly established methods, we screened a small library of Sardinian natural exts., identifying Limonium morisianum as the most potent inhibitor ext. A bioguided fractionation led to the identification of myricetin as the component that can inhibit rVP35-dsRNA interaction with an IC50 value of 2.7 μM. Mol. docking studies showed that myricetin interacts with the highly conserved region of the VP35 RNA binding domain, laying the basis for further structural optimization of potent inhibitors of VP35-dsRNA interaction.
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126. 126
  Kamitani, W.; Narayanan, K.; Huang, C.; Lokugamage, K.; Ikegami, T.; Ito, N.; Kubo, H.; Makino, S. Severe Acute Respiratory Syndrome Coronavirus Nsp1 Protein Suppresses Host Gene Expression by Promoting Host MRNA Degradation. Proc. Natl. Acad. Sci. U. S. A. 2006, 103 (34), 12885– 12890, DOI: 10.1073/pnas.0603144103
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  126
  Severe acute respiratory syndrome coronavirus nsp1 protein suppresses host gene expression by promoting host mRNA degradation
  Kamitani, Wataru; Narayanan, Krishna; Huang, Cheng; Lokugamage, Kumari; Ikegami, Tetsuro; Ito, Naoto; Kubo, Hideyuki; Makino, Shinji
  Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (34), 12885-12890CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  Severe acute respiratory syndrome (SARS) coronavirus (SCoV) causes a recently emerged human disease assocd. with pneumonia. The 5' end two-thirds of the single-stranded pos.-sense viral genomic RNA, gene 1, encodes 16 mature proteins. Expression of nsp1, the most N-terminal gene 1 protein, prevented Sendai virus-induced endogenous IFN-β mRNA accumulation without inhibiting dimerization of IFN regulatory factor 3, a protein that is essential for activation of the IFN-β promoter. Furthermore, nsp1 expression promoted degrdn. of expressed RNA transcripts and host endogenous mRNAs, leading to a strong host protein synthesis inhibition. SCoV replication also promoted degrdn. of expressed RNA transcripts and host mRNAs, suggesting that nsp1 exerted its mRNA destabilization function in infected cells. In contrast to nsp1-induced mRNA destabilization, no degrdn. of the 28S and 18S rRNAs occurred in either nsp1-expressing cells or SCoV-infected cells. These data suggested that, in infected cells, nsp1 promotes host mRNA degrdn. and thereby suppresses host gene expression, including proteins involved in host innate immune functions. SCoV nsp1-mediated promotion of host mRNA degrdn. may play an important role in SCoV pathogenesis.
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127. 127
  Shi, C.-S.; Nabar, N. R.; Huang, N.-N.; Kehrl, J. H. SARS-Coronavirus Open Reading Frame-8b Triggers Intracellular Stress Pathways and Activates NLRP3 Inflammasomes. Cell Death Discovery 2019, 5 (1), 1– 12, DOI: 10.1038/s41420-019-0230-2
  [Crossref], [CAS], Google Scholar
  127
  Hyperglycemia exacerbates acetaminophen-induced acute liver injury by promoting liver-resident macrophage proinflammatory response via AMPK/PI3K/AKT-mediated oxidative stress
  Wang, Qi; Wei, Song; Zhou, Haoming; Shen, Gefenqiang; Gan, Xiaojie; Zhou, Shun; Qiu, Jiannan; Shi, Chenyu; Lu, Ling
  Cell Death Discovery (2019), 5 (1), 1-12CODEN: CDDEB5; ISSN:2058-7716. (Nature Research)
  Although diabetes mellitus/hyperglycemia is a risk factor for acute liver injury, the underlying mechanism remains largely unknown. Liver-resident macrophages (Kupffer cells, KCs) and oxidative stress play crit. roles in the pathogenesis of toxin-induced liver injury. Here, we evaluated the role of oxidative stress in regulating KC polarization against acetaminophen (APAP)-mediated acute liver injury in a streptozotocin-induced hyperglycemic murine model. Compared to the controls, hyperglycemic mice exhibited a significant increase in liver injury and intrahepatic inflammation. KCs obtained from hyperglycemic mice secreted higher levels of the proinflammatory factors, such as TNF-α and IL-6, lower levels of the anti-inflammatory factor IL-10. Furthermore, enhanced oxidative stress was revealed by increased levels of reactive oxygen species (ROS) in KCs from hyperglycemic mice post APAP treatment. In addn., ROS inhibitor NAC resulted in a significant decrease of ROS prodn. in hyperglycemic KCs from mice posttreated with APAP. We also analyzed the role of hyperglycemia in macrophage M1/M2 polarization. Interestingly, we found that hyperglycemia promoted M1 polarization, but inhibited M2 polarization of KCs obtained from APAP-exposed livers, as evidenced by increased MCP-1 and inducible NO synthase (iNOS) gene induction but decreased Arg-1 and CD206 gene induction accompanied by increased STAT1 activation and decreased STAT6 activation. NAC restored Arg-1, CD206 gene induction, and STAT6 activation. To explore the mechanism how hyperglycemia regulates KCs polarization against APAP-induced acute liver injury, we examd. the AMPK/PI3K/AKT signaling pathway and found decreased AMPK activation and increased AKT activation in liver and KCs from hyperglycemic mice post APAP treatment. AMPK activation by its agonist AICAR or PI3K inhibition by its antagonist LY294002 inhibited ROS prodn. in KCs from hyperglycemic mice post APAP treatment and significantly attenuated APAP-induced liver injury in the hyperglycemic mice, compared to the control mice. Our results demonstrated that hyperglycemia exacerbated APAP-induced acute liver injury by promoting liver-resident macrophage proinflammatory response via AMPK/PI3K/AKT-mediated oxidative stress.
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128. 128
  McBride, R.; Fielding, B. C. The Role of Severe Acute Respiratory Syndrome (SARS)-Coronavirus Accessory Proteins in Virus Pathogenesis. Viruses 2012, 4 (11), 2902– 2923, DOI: 10.3390/v4112902
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  128
  The role of severe acute respiratory syndrome (SARS)-coronavirus accessory proteins in virus pathogenesis
  McBride, Ruth; Fielding, Burtram C.
  Viruses (2012), 4 (), 2902-2923CODEN: VIRUBR; ISSN:1999-4915. (MDPI AG)
  A review. A respiratory disease caused by a novel coronavirus, termed the severe acute respiratory syndrome coronavirus (SARS-CoV), was first reported in China in late 2002. The subsequent efficient human-to-human transmission of this virus eventually affected more than 30 countries worldwide, resulting in a mortality rate of ∼10% of infected individuals. The spread of the virus was ultimately controlled by isolation of infected individuals and there has been no infections reported since Apr. 2004. However, the natural reservoir of the virus was never identified and it is not known if this virus will re-emerge and, therefore, research on this virus continues. The SARS-CoV genome is about 30 kb in length and is predicted to contain 14 functional open reading frames (ORFs). The genome encodes for proteins that are homologous to known coronavirus proteins, such as the replicase proteins (ORFs 1a and 1b) and the four major structural proteins: nucleocapsid (N), spike (S), membrane (M) and envelope (E). SARS-CoV also encodes for eight unique proteins, called accessory proteins, with no known homologues. This review will summarize the current knowledge on SARS-CoV accessory proteins and will include: (i) expression and processing; (ii) the effects on cellular processes; and (iii) functional studies.
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129. 129
  Whitby, K.; Pierson, T. C.; Geiss, B.; Lane, K.; Engle, M.; Zhou, Y.; Doms, R. W.; Diamond, M. S. Castanospermine, a Potent Inhibitor of Dengue Virus Infection In Vitro and In Vivo. J. Virol. 2005, 79 (14), 8698– 8706, DOI: 10.1128/JVI.79.14.8698-8706.2005
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  129
  Castanospermine, a potent inhibitor of dengue virus infection in vitro and in vivo
  Whitby, Kevin; Pierson, Theodore C.; Geiss, Brian; Lane, Kelly; Engle, Michael; Zhou, Yi; Doms, Robert W.; Diamond, Michael S.
  Journal of Virology (2005), 79 (14), 8698-8706CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
  Previous studies have suggested that α-glucosidase inhibitors such as castanospermine and deoxynojirimycin inhibit dengue virus type 1 infection by disrupting the folding of the structural proteins prM and E, a step crucial to viral secretion. We extend these studies by evaluating the inhibitory activity of castanospermine against a panel of clin. important flaviviruses including all four serotypes of dengue virus, yellow fever virus, and West Nile virus. Using in vitro assays we demonstrated that infections by all serotypes of dengue virus were inhibited by castanospermine. In contrast, yellow fever virus and West Nile virus were partially and almost completely resistant to the effects of the drug, resp. Castanospermine inhibited dengue virus infection at the level of secretion and infectivity of viral particles. Importantly, castanospermine prevented mortality in a mouse model of dengue virus infection, with doses of 10, 50, and 250 mg/kg of body wt. per day being highly effective at promoting survival (P ≤ 0.0001). Correspondingly, castanospermine had no adverse or protective effect on West Nile virus mortality in an analogous mouse model. Overall, our data suggest that castanospermine has a strong antiviral effect on dengue virus infection and warrants further development as a possible treatment in humans.
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130. 130
  Watanabe, S.; Rathore, A. P. S.; Sung, C.; Lu, F.; Khoo, Y. M.; Connolly, J.; Low, J.; Ooi, E. E.; Lee, H. S.; Vasudevan, S. G. Dose- and Schedule-Dependent Protective Efficacy of Celgosivir in a Lethal Mouse Model for Dengue Virus Infection Informs Dosing Regimen for a Proof of Concept Clinical Trial. Antiviral Res. 2012, 96 (1), 32– 35, DOI: 10.1016/j.antiviral.2012.07.008
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  130
  Dose- and schedule-dependent protective efficacy of celgosivir in a lethal mouse model for dengue virus infection informs dosing regimen for a proof of concept clinical trial
  Watanabe, Satoru; Rathore, Abhay P. S.; Sung, Cynthia; Lu, Fan; Khoo, Yok Moi; Connolly, John; Low, Jenny; Ooi, Eng Eong; Lee, How Sung; Vasudevan, Subhash G.
  Antiviral Research (2012), 96 (1), 32-35CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
  Celgosivir (6-O-butanoyl castanospermine), a pro-drug of the naturally occurring castanospermine, is an inhibitor of α-glucosidase I and II that is found to be a potent inhibitor of several enveloped viruses including all four serotypes of dengue virus. We showed previously that the compd. fully protected AG129 mice from lethal infection with a mouse adapted dengue virus at a dose of 50 mg/kg twice daily (BID) for 5 days and was effective even after 48 h delayed treatment. Here we show that the protection by celgosivir is dose- and schedule-dependent and that a twice-a-day regimen of 50, 25 or 10 mg/kg is more protective than a single daily dose of 100 mg/kg. Treatment with 50 mg/kg BID castanospermine had comparable efficacy as 25 mg/kg BID celgosivir, suggesting that celgosivir is approx. twice as potent as castanospermine with respect to in vivo antiviral efficacy. Pharmacokinetics (PK) studies of celgosivir in mice showed that it rapidly metabolized to castanospermine. Simulation of the PK data with the survival data for the various doses of celgosivir tested suggests that the steady-state min. concn. is a crit. parameter to note in choosing dose and schedule. These results influenced the selection of the dose regimen for a proof-of-concept clin. trial of celgosivir as a treatment against dengue fever.
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131. 131
  Shen, L. W.; Mao, H. J.; Wu, Y. L.; Tanaka, Y.; Zhang, W. TMPRSS2: A Potential Target for Treatment of Influenza Virus and Coronavirus Infections. Biochimie 2017, 142, 1– 10, DOI: 10.1016/j.biochi.2017.07.016
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  131
  TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections
  Shen, Li Wen; Mao, Hui Juan; Wu, Yan Ling; Tanaka, Yoshimasa; Zhang, Wen
  Biochimie (2017), 142 (), 1-10CODEN: BICMBE; ISSN:0300-9084. (Elsevier Masson SAS)
  Influenza virus and coronavirus epidemics or pandemics have occurred in succession worldwide throughout the early 21st century. These epidemics or pandemics pose a major threat to human health. Here, we outline a crit. role of the host cell protease TMPRSS2 in influenza virus and coronavirus infections and highlight an antiviral therapeutic strategy targeting TMPRSS2.
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132. 132
  Dana, D.; Pathak, S. K. A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L. Molecules 2020, 25 (3), 698, DOI: 10.3390/molecules25030698
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  132
  A review of small molecule inhibitors and functional probes of human cathepsin L
  Dana, Dibyendu; Pathak, Sanjai K.
  Molecules (2020), 25 (3), 698CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
  A review. Human cathepsin L belongs to the cathepsin family of proteolytic enzymes with primarily an endopeptidase activity. Although its primary functions were originally thought to be only of a housekeeping enzyme that degraded intracellular and endocytosed proteins in lysosome, numerous recent studies suggest that it plays many crit. and specific roles in diverse cellular settings. Not surprisingly, the dysregulated function of cathepsin L has manifested itself in several human diseases, making it an attractive target for drug development. Unfortunately, several redundant and isoform-specific functions have recently emerged, adding complexities to the drug discovery process. To address this, a series of chem. biol. tools have been developed that helped define cathepsin L biol. with exquisite precision in specific cellular contexts. This review elaborates on the recently developed small mol. inhibitors and probes of human cathepsin L, outlining their mechanisms of action, and describing their potential utilities in dissecting unknown function.
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133. 133
  Vidal-Albalat, A.; González, F. V. In Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier, 2016; Vol. 50, Chapter 6, pp 179– 213.
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134. 134
  Mori, Y.; Yamashita, T.; Tanaka, Y.; Tsuda, Y.; Abe, T.; Moriishi, K.; Matsuura, Y. Processing of Capsid Protein by Cathepsin L Plays a Crucial Role in Replication of Japanese Encephalitis Virus in Neural and Macrophage Cells. J. Virol. 2007, 81 (16), 8477– 8487, DOI: 10.1128/JVI.00477-07
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  134
  Processing of capsid protein by cathepsin L plays a crucial role in replication of Japanese encephalitis virus in neural and macrophage cells
  Mori, Yoshio; Yamashita, Tetsuo; Tanaka, Yoshinori; Tsuda, Yoshimi; Abe, Takayuki; Moriishi, Kohji; Matsuura, Yoshiharu
  Journal of Virology (2007), 81 (16), 8477-8487CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
  The flavivirus capsid protein not only is a component of nucleocapsids but also plays a role in viral replication. In this study, the authors found a small capsid protein in cells infected with Japanese encephalitis virus (JEV) but not in the viral particles. The small capsid protein was shown to be generated by processing with host cysteine protease cathepsin L. An in vitro cleavage assay revealed that cathepsin L cleaves the capsid protein between amino acid residues Lys18 and Arg19, which are well conserved among the mosquito-borne flaviviruses. A mutant JEV resistant to the cleavage of the capsid protein by cathepsin L was generated from an infectious cDNA clone of JEV by introducing a substitution in the cleavage site. The mutant JEV exhibited growth kinetics similar to those of the wild-type JEV in monkey (Vero), mosquito (C6/36), and porcine (PK15) cell lines, whereas replication of the mutant JEV in mouse macrophage (RAW264.7) and neuroblastoma (N18) cells was impaired. Furthermore, the neurovirulence and neuroinvasiveness of the mutant JEV to mice were lower than those of the wild-type JEV. These results suggest that the processing of the JEV capsid protein by cathepsin L plays a crucial role in the replication of JEV in neural and macrophage cells, which leads to the pathogenesis of JEV infection.
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135. 135
  Puerta-Guardo, H.; Glasner, D. R.; Harris, E. Dengue Virus NS1 Disrupts the Endothelial Glycocalyx, Leading to Hyperpermeability. PLoS Pathog. 2016, 12 (7), e1005738, DOI: 10.1371/journal.ppat.1005738
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  135
  Dengue virus NS1 disrupts the endothelial glycocalyx, leading to hyperpermeability
  Puerta-Guardo, Henry; Glasner, Dustin R.; Harris, Eva
  PLoS Pathogens (2016), 12 (7), e1005738/1-e1005738/29CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
  Dengue is the most prevalent arboviral disease in humans and a major public health problem worldwide. Systemic plasma leakage, leading to hypovolemic shock and potentially fatal complications, is a crit. determinant of dengue severity. Recently, we and others described a novel pathogenic effect of secreted dengue virus (DENV) non-structural protein 1 (NS1) in triggering hyperpermeability of human endothelial cells in vitro and systemic vascular leakage in vivo. NS1 was shown to activate toll-like receptor 4 signaling in primary human myeloid cells, leading to secretion of pro-inflammatory cytokines and vascular leakage. However, distinct endothelial cell-intrinsic mechanisms of NS1-induced hyperpermeability remained to be defined. The endothelial glycocalyx layer (EGL) is a network of membrane-bound proteoglycans and glycoproteins lining the vascular endothelium that plays a key role in regulating endothelial barrier function. Here, we demonstrate that DENV NS1 disrupts the EGL on human pulmonary microvascular endothelial cells, inducing degrdn. of sialic acid and shedding of heparan sulfate proteoglycans. This effect is mediated by NS1-induced expression of sialidases and heparanase, resp. NS1 also activates cathepsin L, a lysosomal cysteine proteinase, in endothelial cells, which activates heparanase via enzymic cleavage. Specific inhibitors of sialidases, heparanase, and cathepsin L prevent DENV NS1-induced EGL disruption and endothelial hyperpermeability. All of these effects are specific to NS1 from DENV1-4 and are not induced by NS1 from West Nile virus, a related flavivirus. Together, our data suggest an important role for EGL disruption in DENV NS1-mediated endothelial dysfunction during severe dengue disease.
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136. 136
  Miller, B.; Friedman, A. J.; Choi, H.; Hogan, J.; McCammon, J. A.; Hook, V.; Gerwick, W. H. The Marine Cyanobacterial Metabolite Gallinamide A Is a Potent and Selective Inhibitor of Human Cathepsin L. J. Nat. Prod. 2014, 77 (1), 92– 99, DOI: 10.1021/np400727r
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  136
  The marine cyanobacterial metabolite gallinamide A is a potent and selective inhibitor of human cathepsin L
  Miller, Bailey; Friedman, Aaron J.; Choi, Hyukjae; Hogan, James; McCammon, J. Andrew; Hook, Vivian; Gerwick, William H.
  Journal of Natural Products (2014), 77 (1), 92-99CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
  Marine natural products can be potent inhibitors of proteases, an important drug target class in human diseases. Marine cyanobacterial exts. were assessed for inhibitory activity to human cathepsin L. The active component gallinamide A potently and selectively inhibited the human cysteine protease cathepsin L in vitro. With 30-min preincubation, gallinamide A had IC50 = 5.0 nM and the kinetic anal. showed inhibition const. ki = 9000±260 M-1 s-1. Preincubation-diln. and activity-probe expts. revealed an irreversible mode of inhibition. Comparison of IC50 values showed 28- to 320-fold greater selectivity toward cathepsin L than closely related human cysteine proteases cathepsin V or B. Mol. docking and mol. dynamics simulations were used to det. the positioning of gallinamide A in the active site of cathepsin L. These data resulted in the identification of a pose characterized by high stability, consistent hydrogen bond network, and the reactive Michael acceptor enamide of gallinamide A positioned near the active site cysteine of the protease, leading to the proposed mechanism of covalent inhibition. These data reveal and characterize the novel activity of gallinamide A as a potent inhibitor of human cathepsin L.
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137. 137
  Brosius, A. D.; Overman, L. E. Aloperine: Stereocontrolled Synthesis of Two Stereoisomers and Determination of Absolute Configuration. J. Org. Chem. 1997, 62 (3), 440– 441, DOI: 10.1021/jo9621231
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  137
  Aloperine: Stereocontrolled Synthesis of Two Stereoisomers and Determination of Absolute Configuration
  Brosius, Arthur D.; Overman, Larry E.
  Journal of Organic Chemistry (1997), 62 (3), 440-441CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Racemic diastereoisomers of aloperine I (R = α-H, β-H) were prepd starting from 1-(3-cyclohexenylmethyl)-3,4-dihydro-(1H)-pyridin-2-one (II) via the use of iodine to control the stereoselectivity of N-acyliminium ion-alkene cyclization. Pyridinone II was stereoselectively cyclized with Bu4NI to form III, which could be converted to isomers I. The abs. configuration of the natural enantiomer of aloperine was reported to be 6R,7R,9R,11S.
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138. 138
  Fusetani, N.; Fujita, M.; Nakao, Y.; Matsunaga, S.; van Soest, R. W. M. Tokaramide A,a New Cathepsin B Inhibitor from the Marine Sponge Theonella Aff. Mirabilis. Bioorg. Med. Chem. Lett. 1999, 9 (24), 3397– 3402, DOI: 10.1016/S0960-894X(99)00618-6
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  138
  Tokaramide A, a new cathepsin B inhibitor from the marine sponge Theonella aff. mirabilis
  Fusetani, Nobuhiro; Fujita, Masaki; Nakao, Yoichi; Matsunaga, Shigeki; Van Soest, Rob W. M.
  Bioorganic & Medicinal Chemistry Letters (1999), 9 (24), 3397-3402CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)
  A new cathepsin B inhibitor, tokaramide A (I) has been isolated from the marine sponge Theonella aff. mirabilis. Its structure was detd. by spectroscopic and chem. methods. Tokaramide A inhibits cathepsin B with an IC50 value of 29.0 ng/mL.
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139. 139
  Nakao, Y.; Fujita, M.; Warabi, K.; Matsunaga, S.; Fusetani, N. Miraziridine A, a Novel Cysteine Protease Inhibitor from the Marine Sponge Theonella Aff. Mirabilis1. J. Am. Chem. Soc. 2000, 122 (42), 10462– 10463, DOI: 10.1021/ja001859j
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  139
  Miraziridine A, a novel cysteine protease inhibitor from the marine sponge Theonella aff. mirabilis
  Nakao, Yoichi; Fujita, Masaki; Warabi, Kaoru; Matsunaga, Shigeki; Fusetani, Nobuhiro
  Journal of the American Chemical Society (2000), 122 (42), 10462-10463CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  This work describes the isolation and structure elucidation of miraziridine A from T. mirabilis and its cathepsin B inhibitory activity.
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140. 140
  Zhang, X.; Liu, Q.; Zhang, N.; Li, Q.; Liu, Z.; Li, Y.; Gao, L.; Wang, Y.; Deng, H.; Song, D. Discovery and Evolution of Aloperine Derivatives as Novel Anti-Filovirus Agents through Targeting Entry Stage. Eur. J. Med. Chem. 2018, 149, 45– 55, DOI: 10.1016/j.ejmech.2018.02.061
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  140
  Discovery and evolution of aloperine derivatives as novel anti-filo virus agents through targeting entry stage
  Zhang, Xin; Liu, Qiang; Zhang, Na; Li, Qian-Qian; Liu, Zhan-Dong; Li, Ying-Hong; Gao, Li-Mei; Wang, You-Chun; Deng, Hong-Bin; Song, Dan-Qing
  European Journal of Medicinal Chemistry (2018), 149 (), 45-55CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
  Preventing filoviruses in the entry stage is an attractive antiviral strategy. Taking aloperine, a Chinese natural herb with an endocyclic skeleton, as the lead, 23 new aloperine derivs. were synthesized and evaluated for their anti-filovirus activities including ebola virus (EBOV) and marburg virus (MARV) using pseudotyped virus model. Structure-activity relationship (SAR) anal. indicated that the introduction of a 12N-dichlorobenzyl group was beneficial for the potency. Compd. 2e (12N-3',4'-dichlorobenzylaloperine dihydrochloride) exhibited the most potent anti-EBOV and anti-MARV effects both in vitro and in vivo. It also displayed a good pharmacokinetic and safety profile in vivo, indicating an ideal druglike feature. The primary mechanism study showed that 2e could block a late stage of viral entry, mainly through inhibiting cysteine cathepsin B activity of host components. The authors consider compd. 2e to be a promising broad-spectrum anti-filovirus agent with the advantages of a unique chem. scaffold and a specific biol. mechanism.
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141. 141
  Hanada, K.; Tamai, M.; Yamagishi, M.; Ohmura, S.; Sawada, J.; Tanaka, I. Isolation and Characterization of E–64, a New Thiol Protease Inhibitor. Agric. Biol. Chem. 1978, 42 (3), 523– 528, DOI: 10.1271/bbb1961.42.523
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  141
  Studies on thiol protease inhibitors. Part I. Isolation and characterization of E-64, a new thiol protease inhibitor
  Hanada, Kazunori; Tamai, Masaharu; Yamagishi, Michio; Ohmura, Sadafumi; Sawada, Jiro; Tanaka, Ichiro
  Agricultural and Biological Chemistry (1978), 42 (3), 523-8CODEN: ABCHA6; ISSN:0002-1369.
  A new thiol protease inhibitor, named E-64, was isolated from the ext. of a solid culture of Aspergillus japonicus TPR-64 freshly isolated from soil. E-64 was obtained as white needles and the empirical formula was estd. to be C15N5H27O5. This was neutral in its electrophoretic behavior and proved to be a specific and strong inhibitor toward thiol proteases such as papain and cathepsin B. They combine equimolecularly and irreversibly.
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142. 142
  Tamai, M.; Matsumoto, K.; Omura, S.; Koyama, I.; Ozawa, Y.; Hanada, K. In Vitro and in Vivo Inhibition of Cysteine Proteinases by Est, a New Analog of E-64. J. Pharmacobio-Dyn. 1986, 9 (8), 672– 677, DOI: 10.1248/bpb1978.9.672
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  142
  In vitro and in vivo inhibition of cysteine proteinases by EST, a new analog of E-64
  Tamai, Masaharu; Matsumoto, Kazuko; Omura, Sadafumi; Koyama, Ikuo; Ozawa, Yasuo; Hanada, Kazunori
  Journal of Pharmacobio-Dynamics (1986), 9 (8), 672-7CODEN: JOPHDQ; ISSN:0386-846X.
  The in vitro and in vivo inhibitory activities of EST (I; R = Et) and E-64c (I; R = H), both analogs of E-64, against cysteine proteinases such as cathepsin B, cathepsin H, and papain were studied. Following their synthesis, both EST and E-64c demonstrated a specificity for these cysteine proteinases, however, E-64c was 100-1000 times stronger than EST in the in vitro inhibition of these enzymes. However when they were administered orally to hamsters, the inhibitory activity of EST against cathepsins in skeletal muscle, heart, and liver was much greater than that obsd. with E-64c. E-64c, but no unchanged EST, was found in the plasma of treated hamsters, indicating a conversion of EST to E-64c. EST, in contrast to E-64c, was readily absorbed through the intestinal membrane due to its greater lipophilicity. Thus, EST is a useful oral prodrug for E-64c. The therapeutic use of oral EST as a specific inhibitor of cysteine proteinases for the treatment of muscular dystrophy is discussed.
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143. 143
  Murata, M.; Miyashita, S.; Yokoo, C.; Tamai, M.; Hanada, K.; Hatayama, K.; Towatari, T.; Nikawa, T.; Katunuma, N. Novel Epoxysuccinyl Peptides Selective Inhibitors of Cathepsin B, in Vitro. FEBS Lett. 1991, 280 (2), 307– 310, DOI: 10.1016/0014-5793(91)80318-W
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  143
  Novel epoxysuccinyl peptides. Selective inhibitors of cathepsin B, in vitro
  Murata, Mitsuo; Miyashita, Satsuki; Yokoo, Chihiro; Tamai, Masaharu; Hanada, Kazunori; Hatayama, Katsuo; Towatari, Takae; Nikawa, Takeshi; Katunuma, Nobuhiko
  FEBS Letters (1991), 280 (2), 307-10CODEN: FEBLAL; ISSN:0014-5793.
  A series of new epoxysuccinyl peptides were designed and synthesized to develop a specific inhibitor of cathepsin B. Of these compds., N-(L-3-trans-ethoxycarbonyloxirane-2-carbonyl)-L-isoleucyl-L-proline (compd. CA-030) and N-(L-3-trans-propylcarbamoyloxirane-2-carbonyl)-L-isoleucyl-L-proline (compd. CA-074) were the most potent and specific inhibitors of cathepsin B in vitro. The carboxyl group of proline and the Et ester group or n-propylamide group in the oxirane ring were necessary, the Et ester group or the n-propylamide group being particularly effective for distinguishing cathepsin B from other cysteine proteinases such as cathepsins L and H, and calpains.
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144. 144
  Smith, S. A.; Nivarthi, U. K.; de Alwis, R.; Kose, N.; Sapparapu, G.; Bombardi, R.; Kahle, K. M.; Pfaff, J. M.; Lieberman, S.; Doranz, B. J.; de Silva, A. M.; Crowe, J. E. Dengue Virus PrM-Specific Human Monoclonal Antibodies with Virus Replication-Enhancing Properties Recognize a Single Immunodominant Antigenic Site. J. Virol. 2016, 90 (2), 780– 789, DOI: 10.1128/JVI.01805-15
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  144
  Dengue virus prM-specific human monoclonal antibodies with virus replication-enhancing properties recognize a single immunodominant antigenic site
  Smith, Scott A.; Nivarthi, Usha K.; de Alwis, Ruklanthi; Kose, Nurgun; Sapparapu, Gopal; Bombardi, Robin; Kahle, Kristen M.; Pfaff, Jennifer M.; Lieberman, Sherri; Doranz, Benjamin J.; de Silva, Aravinda M.; Crowe, James E., Jr.
  Journal of Virology (2016), 90 (2), 780-789CODEN: JOVIAM; ISSN:1098-5514. (American Society for Microbiology)
  The proposed antibody-dependent enhancement (ADE) mechanism for severe dengue virus (DENV) disease suggests that nonneutralizing serotype cross-reactive antibodies generated during a primary infection facilitate entry into Fc receptor bearing cells during secondary infection, resulting in enhanced viral replication and severe disease. One group of cross-reactive antibodies that contributes considerably to this serum profile target the premembrane (prM) protein. We report here the isolation of a large panel of naturally occurring human monoclonal antibodies (MAbs) obtained from subjects following primary DENV serotype 1, 2, or 3 or secondary natural DENV infections or following primary DENV serotype 1 live attenuated virus vaccination to det. the antigenic landscape on the prM protein that is recognized by human antibodies. We isolated 25 prM-reactive human MAbs, encoded by diverse antibody-variable genes. Competition-binding studies revealed that all of the antibodies bound to a single major antigenic site on prM. Alanine scanning-based shotgun mutagenesis epitope mapping studies revealed diverse patterns of fine specificity of various clones, suggesting that different antibodies use varied binding poses to recognize several overlapping epitopes within the immunodominant site. Several of the antibodies interacted with epitopes on both prM and E protein residues. Despite the diverse genetic origins of the antibodies and differences in the fine specificity of their epitopes, each of these prM-reactive antibodies was capable of enhancing the DENV infection of Fc receptor-bearing cells.
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145. 145
  Dalbey, R. E.; von Heijne, G. Signal Peptidases in Prokaryotes and Eukaryotes - a New Protease Family. Trends Biochem. Sci. 1992, 17 (11), 474– 478, DOI: 10.1016/0968-0004(92)90492-R
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  145
  Signal peptidases in prokaryotes and eukaryotes - a new protease family
  Dalbey, Ross E.; Von Heijne, Gunnar
  Trends in Biochemical Sciences (1992), 17 (11), 474-8CODEN: TBSCDB; ISSN:0968-0004.
  A review, with 30 refs., on signal peptidases, the family of proteinases involved in removing targeting peptides from preproteins. These peptidases play central roles in the secretory pathway, as well as in the delivery of proteins to the mitochondrial intermembrane space and to the lumen to thylakoids. The catalytic mechanism of preprotein cleavage has long been an enigma, but recent data from site-directed mutagenesis and sequence studies suggest that signal peptidases may constitute a new type of serine protease, mechanistically related to the β-lactamases. Emphasis is given to membrane topol., substrate specificity, sequence homol. and mechanism of catalysis of signal peptidases.
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146. 146
  Estoppey, D.; Lee, C. M.; Janoschke, M.; Lee, B. H.; Wan, K. F.; Dong, H.; Mathys, P.; Filipuzzi, I.; Schuhmann, T.; Riedl, R.; Aust, T.; Galuba, O.; McAllister, G.; Russ, C.; Spiess, M.; Bouwmeester, T.; Bonamy, G. M. C.; Hoepfner, D. The Natural Product Cavinafungin Selectively Interferes with Zika and Dengue Virus Replication by Inhibition of the Host Signal Peptidase. Cell Rep. 2017, 19 (3), 451– 460, DOI: 10.1016/j.celrep.2017.03.071
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  146
  The Natural Product Cavinafungin Selectively Interferes with Zika and Dengue Virus Replication by Inhibition of the Host Signal Peptidase
  Estoppey, David; Lee, Chia Min; Janoschke, Marco; Lee, Boon Heng; Wan, Kah Fei; Dong, Hongping; Mathys, Philippe; Filipuzzi, Ireos; Schuhmann, Tim; Riedl, Ralph; Aust, Thomas; Galuba, Olaf; McAllister, Gregory; Russ, Carsten; Spiess, Martin; Bouwmeester, Tewis; Bonamy, Ghislain M. C.; Hoepfner, Dominic
  Cell Reports (2017), 19 (3), 451-460CODEN: CREED8; ISSN:2211-1247. (Cell Press)
  Flavivirus infections by Zika and dengue virus impose a significant global healthcare threat with no US Food and Drug Administration (FDA)-approved vaccination or specific antiviral treatment available. Here, we present the discovery of an anti-flaviviral natural product named cavinafungin. Cavinafungin is a potent and selectively active compd. against Zika and all four dengue virus serotypes. Unbiased, genome-wide genomic profiling in human cells using a novel CRISPR/Cas9 protocol identified the endoplasmic-reticulum-localized signal peptidase as the efficacy target of cavinafungin. Orthogonal profiling in S. cerevisiae followed by the selection of resistant mutants pinpointed the catalytic subunit of the signal peptidase SEC11 as the evolutionary conserved target. Biochem. anal. confirmed a rapid block of signal sequence cleavage of both host and viral proteins by cavinafungin. This study provides an effective compd. against the eukaryotic signal peptidase and independent confirmation of the recently identified crit. role of the signal peptidase in the replicative cycle of flaviviruses.
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147. 147
  Wu, S.-F.; Lee, C.-J.; Liao, C.-L.; Dwek, R. A.; Zitzmann, N.; Lin, Y.-L. Antiviral Effects of an Iminosugar Derivative on Flavivirus Infections. J. Virol. 2002, 76 (8), 3596– 3604, DOI: 10.1128/JVI.76.8.3596-3604.2002
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  147
  Antiviral effects of an iminosugar derivative on flavivirus infections
  Wu, Shu-Fen; Lee, Chyan-Jang; Liao, Ching-Len; Dwek, Raymond A.; Zitzmann, Nicole; Lin, Yi-Ling
  Journal of Virology (2002), 76 (8), 3596-3604CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
  Endoplasmic reticulum (ER) α-glucosidase inhibitors, which block the trimming step of N-linked glycosylation, have been shown to eliminate the prodn. of several ER-budding viruses. Here we investigated the effects of one such inhibitor, N-nonyl-deoxynojirimycin (NN-DNJ), a 9-carbon alkyl iminosugar deriv., on infection by Japanese encephalitis virus (JEV) and dengue virus serotype 2 (DEN-2). In the presence of NN-DNJ, JEV and DEN-2 infections were suppressed in a dose-dependent manner. This inhibitory effect appeared to influence DEN-2 infection more than JEV infection, since lower concns. of NN-DNJ substantially blocked DEN-2 replication. Secretion of the flaviviral glycoproteins E and NS1 was greatly reduced, and levels of DEN-2 viral RNA replication measured by fluorogenic reverse transcription-PCR were also decreased, by NN-DNJ. Notably, the viral glycoproteins, prM, E, and NS1 were found to assoc. transiently with the ER chaperone calnexin, and this interaction was affected by NN-DNJ, suggesting a potential role of calnexin in the folding of flaviviral glycoproteins. Addnl., in a mouse model of lethal challenge by JEV infection, oral delivery of NN-DNJ reduced the mortality rate. These findings show that NN-DNJ has an antiviral effect on flavivirus infection, likely through interference with virus replication at the posttranslational modification level, occurring mainly in the ER.
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148. 148
  Yagi, M.; Kouno, T.; Aoyagi, Y.; Murai, H. The Structure of Moranoline, a Piperidine Alkaloid from Morus Species. Nippon Nogei Kagaku Kaishi 1976, 50 (11), 571– 572, DOI: 10.1271/nogeikagaku1924.50.11_571
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  148
  The structure of moranoline, a piperidine alkaloid from Morus species
  Yagi, Masahiro; Kouno, Tatsuhiko; Aoyagi, Yoshiaki; Murai, Hiromu
  Nippon Nogei Kagaku Kaishi (1976), 50 (11), 571-2CODEN: NNKKAA; ISSN:0002-1407.
  A new piperidine alkaloid, moranoline (I), m.p. 204-5°, C6H13NO4, was isolated from Morus. The structure of moranoline was detd. as (2R,3R,4R,5S)-2-hydroxymethyl-3,4,5-trihydroxypiperidine by spectral anal.
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149. 149
  Yu, W.; Gill, T.; Wang, L.; Du, Y.; Ye, H.; Qu, X.; Guo, J.-T.; Cuconati, A.; Zhao, K.; Block, T. M.; Xu, X.; Chang, J. Design, Synthesis, and Biological Evaluation of N-Alkylated Deoxynojirimycin (DNJ) Derivatives for the Treatment of Dengue Virus Infection. J. Med. Chem. 2012, 55 (13), 6061– 6075, DOI: 10.1021/jm300171v
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  149
  Design, Synthesis, and Biological Evaluation of N-Alkylated Deoxynojirimycin (DNJ) Derivatives for the Treatment of Dengue Virus Infection
  Yu, Wenquan; Gill, Tina; Wang, Lijuan; Du, Yanming; Ye, Hong; Qu, Xiaowang; Guo, Ju-Tao; Cuconati, Andrea; Zhao, Kang; Block, Timothy M.; Xu, Xiaodong; Chang, Jinhong
  Journal of Medicinal Chemistry (2012), 55 (13), 6061-6075CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  We recently described the discovery of oxygenated N-alkyl deoxynojirimycin (DNJ) deriv. I [R = C(OH)Et2] with antiviral activity against dengue virus (DENV) infection both in vitro and in vivo. This imino sugar was promising but had an EC50 against DENV in BHK cells of 6.5 μM, which limited its use in in vivo. I [R = C(OH)Et2] presented structural opportunities for activity relationship anal., which we exploited and report here. These structure-activity relationship studies led to analogs, e.g. I (R = OC6H4-2,5-difluoro) with nano-molar antiviral activity (EC50 = 0.3-0.5 μM) against DENV infection, while maintaining low cytotoxicity (CC50 > 500 μM, SI > 1000). In male Sprague-Dawley rats, compd. I (R = OC6H4-2,5-difluoro) was well tolerated at a dose up to 200 mg/kg and displayed desirable PK profiles, with significantly improved bioavailability (F = 92 ± 4%).
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150. 150
  Wang, H.; Shen, Y.; Zhao, L.; Ye, Y. 1-Deoxynojirimycin and its Derivatives: A Mini Review of the Literature. Curr. Med. Chem. 2020, 27, 1– 15, DOI: 10.2174/0929867327666200114112728
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151. 151
  Chang, J.; Warren, T. K.; Zhao, X.; Gill, T.; Guo, F.; Wang, L.; Comunale, M. A.; Du, Y.; Alonzi, D. S.; Yu, W.; Ye, H.; Liu, F.; Guo, J.-T.; Mehta, A.; Cuconati, A.; Butters, T. D.; Bavari, S.; Xu, X.; Block, T. M. Small Molecule Inhibitors of ER α-Glucosidases Are Active against Multiple Hemorrhagic Fever Viruses. Antiviral Res. 2013, 98 (3), 432– 440, DOI: 10.1016/j.antiviral.2013.03.023
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  151
  Small molecule inhibitors of ER α-glucosidases are active against multiple hemorrhagic fever viruses
  Chang, Jinhong; Warren, Travis K.; Zhao, Xuesen; Gill, Tina; Guo, Fang; Wang, Lijuan; Comunale, Mary Ann; Du, Yanming; Alonzi, Dominic S.; Yu, Wenquan; Ye, Hong; Liu, Fei; Guo, Ju-Tao; Mehta, Anand; Cuconati, Andrea; Butters, Terry D.; Bavari, Sina; Xu, Xiaodong; Block, Timothy M.
  Antiviral Research (2013), 98 (3), 432-440CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
  Host cellular endoplasmic reticulum α-glucosidases I and II are essential for the maturation of viral glycosylated envelope proteins that use the calnexin mediated folding pathway. Inhibition of these glycan processing enzymes leads to the misfolding and degrdn. of these viral glycoproteins and subsequent redn. in virion secretion. We previously reported that, CM-10-18, an imino sugar α-glucosidase inhibitor, efficiently protected the lethality of dengue virus infection of mice. In the current study, through an extensive structure-activity relationship study, we have identified three CM-10-18 derivs. that demonstrated superior in vitro antiviral activity against representative viruses from four viral families causing hemorrhagic fever. Moreover, the three novel imino sugars significantly reduced the mortality of two of the most pathogenic hemorrhagic fever viruses, Marburg virus and Ebola virus, in mice. Our study thus proves the concept that imino sugars are promising drug candidates for the management of viral hemorrhagic fever caused by variety of viruses.
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152. 152
  Zhang, X. G.; Mason, P. W.; Dubovi, E. J.; Xu, X.; Bourne, N.; Renshaw, R. W.; Block, T. M.; Birk, A. V. Antiviral Activity of Geneticin against Dengue Virus. Antiviral Res. 2009, 83 (1), 21– 27, DOI: 10.1016/j.antiviral.2009.02.204
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  152
  Antiviral activity of geneticin against dengue virus
  Zhang, Xianchao G.; Mason, Peter W.; Dubovi, Edward J.; Xu, Xiaodong; Bourne, Nigel; Renshaw, Randall W.; Block, Timothy M.; Birk, Alexander V.
  Antiviral Research (2009), 83 (1), 21-27CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
  The aminoglycoside, geneticin (G418), was recently shown to have antiviral activity against bovine viral diarrhea virus (BVDV). Since BVDV, dengue virus (DENV) and yellow fever virus (YFV) all belong to the Flaviviridae family, it seemed possible that a common step in their life cycle might be affected by this aminoglycoside. Here it is shown that geneticin prevented the cytopathic effect (CPE) resulting from DENV-2 infection of BHK cells, in a dose-dependent manner with an 50% effective concn. (EC50) value of 3 ± 0.4 μg/mL. Geneticin had no detectable effect on CPE caused by YFV in BHK cells. Geneticin also inhibited DENV-2 viral yield with an EC50 value of 2 ± 0.1 μg/mL and an EC90 value of 20 ± 2 μg/mL. With a CC50 value of 165 ± 5 μg/mL, the selectivity index of anti-DENV activity of geneticin in BHK cells was established to be 66. Furthermore, 25 μg/mL of geneticin nearly completely blocked plaque formation induced by DENV-2, but not YFV. In addn., geneticin, inhibited DENV-2 viral RNA replication and viral translation. Gentamicin, kanamycin, and the guanidinylated geneticin showed no anti-DENV activity. Neomycin and paromomycin demonstrated weak antiviral activity at high concns. Finally, aminoglycoside-3'-phosphotransferase activity of neomycin-resistant gene abolished antiviral activity of geneticin.
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153. 153
  Hwang, B. Y.; Su, B.-N.; Chai, H.; Mi, Q.; Kardono, L. B. S.; Afriastini, J. J.; Riswan, S.; Santarsiero, B. D.; Mesecar, A. D.; Wild, R.; Fairchild, C. R.; Vite, G. D.; Rose, W. C.; Farnsworth, N. R.; Cordell, G. A.; Pezzuto, J. M.; Swanson, S. M.; Kinghorn, A. D. Silvestrol and Episilvestrol, Potential Anticancer Rocaglate Derivatives from Aglaia Silvestris. J. Org. Chem. 2004, 69 (10), 3350– 3358, DOI: 10.1021/jo040120f
  [ACS Full Text ], [CAS], Google Scholar
  153
  Silvestrol and episilvestrol, potential anticancer rocaglate derivatives from Aglaia silvestris
  Hwang, Bang Yeon; Su, Bao-Ning; Chai, Heebyung; Mi, Qiuwen; Kardono, Leonardus B. S.; Afriastini, Johar J.; Riswan, Soedarsono; Santarsiero, Bernard D.; Mesecar, Andrew D.; Wild, Robert; Fairchild, Craig R.; Vite, Gregory D.; Rose, William C.; Farnsworth, Norman R.; Cordell, Geoffrey A.; Pezzuto, John M.; Swanson, Steven M.; Kinghorn, A. Douglas
  Journal of Organic Chemistry (2004), 69 (10), 3350-3358CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Two cytotoxic rocaglate derivs. possessing an unusual dioxanyloxy unit, silvestrol (I) and episilvestrol (II), were isolated from the fruits and twigs of Aglaia silvestris by bioassay-guided fractionation monitored with a human oral epidermoid carcinoma (KB) cell line. Addnl., two new baccharane-type triterpenoids, 17,24-epoxy-25-hydroxybaccharan-3-one (III) and 17,24-epoxy-25-hydroxy-3-oxobaccharan-21-oic acid (IV), as well as eleven known compds., 1β,6α-dihydroxy-4(15)-eudesmene (5), ferulic acid (6), grasshopper ketone (7), apigenin, cabraleone, chrysoeriol, 1β,4β-dihydroxy-6α,15α-epoxyeudesmane, 4-hydroxy-3-methoxyacetophenone, 4-hydroxyphenethyl alc., ocotillone, and β-sitosterol 3-O-β-D-glucopyranoside, were also isolated and characterized. The structures of compds. (I-IV) were elucidated by spectroscopic studies and by chem. transformation. The abs. stereochem. of silvestrol was established by a X-ray diffraction study of its di-p-bromobenzoate deriv., and the structure of 3 was also confirmed by single-crystal X-ray diffraction. The isolates and chem. transformation products were evaluated for cytotoxicity against several human cancer cell lines, and silvestrol and episilvestrol exhibited potent in vitro cytotoxic activity. Silvestrol was further evaluated in vivo in the hollow fiber test and in the murine P-388 leukemia model.
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154. 154
  Biedenkopf, N.; Lange-Grünweller, K.; Schulte, F. W.; Weißer, A.; Müller, C.; Becker, D.; Becker, S.; Hartmann, R. K.; Grünweller, A. The Natural Compound Silvestrol Is a Potent Inhibitor of Ebola Virus Replication. Antiviral Res. 2017, 137, 76– 81, DOI: 10.1016/j.antiviral.2016.11.011
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  154
  The natural compound silvestrol is a potent inhibitor of Ebola virus replication
  Biedenkopf, Nadine; Lange-Gruenweller, Kerstin; Schulte, Falk W.; Weisser, Aileen; Mueller, Christin; Becker, Dirk; Becker, Stephan; Hartmann, Roland K.; Gruenweller, Arnold
  Antiviral Research (2017), 137 (), 76-81CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
  The DEAD-box RNA helicase eIF4A, which is part of the heterotrimeric translation initiation complex in eukaryotes, is an important novel drug target in cancer research because its helicase activity is required to unwind extended and highly structured 5'-UTRs of several proto-oncogenes. Silvestrol, a natural compd. isolated from the plant Aglaia foveolata, is a highly efficient, non-toxic and specific inhibitor of eIF4A. Importantly, 5'-capped viral mRNAs often contain structured 5'-UTRs as well, which may suggest a dependence on eIF4A for their translation by the host protein synthesis machinery. In view of the recent Ebola virus (EBOV) outbreak in West Africa, the identification of potent antiviral compds. is urgently required. Since Ebola mRNAs are 5'-capped and harbor RNA secondary structures in their extended 5'-UTRs, we initiated a BSL4 study to analyze silvestrol in EBOV-infected Huh-7 cells and in primary human macrophages for its antiviral activity. We obsd. that silvestrol inhibits EBOV infection at low nanomolar concns., as inferred from large redns. of viral titers. This correlated with an almost complete disappearance of EBOV proteins, comparable in effect to the translational shutdown of expression of the proto-oncoprotein PIM1, a cellular kinase known to be affected by silvestrol. Effective silvestrol concns. were non-toxic in the tested cell systems. Thus, silvestrol appears to be a promising first-line drug for the treatment of acute EBOV and possibly other viral infections.
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155. 155
  Werner, G.; Hagenmaier, H.; Albert, K.; Kohlshorn, H. The Structure of the Bafilomycins, a New Group of Macrolide Antibiotics. Tetrahedron Lett. 1983, 24 (47), 5193– 5196, DOI: 10.1016/S0040-4039(00)88394-X
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  The structure of the bafilomycins, a new group of macrolide antibiotics
  Werner, Gerhard; Hagenmaier, Hanspaul; Albert, Klaus; Kohlshorn, Heinz; Drautz, Hannelore
  Tetrahedron Letters (1983), 24 (47), 5193-6CODEN: TELEAY; ISSN:0040-4039.
  Bafilomycins A1 (I), A2, B2, C1, and C2 were isolated from EtOAc ext. of the culture medium of Streptomyces griseus subspecies sulfurus by column chromatog. on silica gel with CHCl3-MeOH (9:1). Each component was further purified by multiple column chromatog. on silica gel. Structures of these 16-membered lactone macrolide antibiotics were detd. mainly by spectroscopic studies; physicochem. properties of these antibiotics are given.
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156. 156
  Yonezawa, A.; Cavrois, M.; Greene, W. C. Studies of Ebola Virus Glycoprotein-Mediated Entry and Fusion by Using Pseudotyped Human Immunodeficiency Virus Type 1 Virions: Involvement of Cytoskeletal Proteins and Enhancement by Tumor Necrosis Factor Alpha. J. Virol. 2005, 79 (2), 918– 926, DOI: 10.1128/JVI.79.2.918-926.2005
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  156
  Studies of Ebola virus glycoprotein-mediated entry and fusion by using pseudotyped human immunodeficiency virus type 1 virions: Involvement of cytoskeletal proteins and enhancement by tumor necrosis factor alpha
  Yonezawa, Akihito; Cavrois, Marielle; Greene, Warner C.
  Journal of Virology (2005), 79 (2), 918-926CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
  The Ebola filoviruses are aggressive pathogens that cause severe and often lethal hemorrhagic fever syndromes in humans and nonhuman primates. To date, no effective therapies have been identified. To analyze the entry and fusion properties of Ebola virus, the authors adapted a human immunodeficiency virus type 1 (HIV-1) virion-based fusion assay by substituting Ebola virus glycoprotein (GP) for the HIV-1 envelope. Fusion was detected by cleavage of the fluorogenic substrate CCF2 by β-lactamase-Vpr incorporated into virions and released as a result of virion fusion. Entry and fusion induced by the Ebola virus GP occurred with much slower kinetics than with vesicular stomatitis virus G protein (VSV-G) and were blocked by depletion of membrane cholesterol and by inhibition of vesicular acidification with bafilomycin A1. These properties confirmed earlier studies and validated the assay for exploring other properties of Ebola virus GP-mediated entry and fusion. Entry and fusion of Ebola virus GP pseudotypes, but not VSV-G or HIV-1 Env pseudotypes, were impaired in the presence of the microtubule-disrupting agent nocodazole but were enhanced in the presence of the microtubule-stabilizing agent paclitaxel (Taxol). Agents that impaired microfilament function, including cytochalasin B, cytochalasin D, latrunculin A, and jasplakinolide, also inhibited Ebola virus GP-mediated entry and fusion. Together, these findings suggest that both microtubules and microfilaments may play a role in the effective trafficking of vesicles contg. Ebola virions from the cell surface to the appropriate acidified vesicular compartment where fusion occurs. In terms of Ebola virus GP-mediated entry and fusion to various target cells, primary macrophages proved highly sensitive, while monocytes from the same donors displayed greatly reduced levels of entry and fusion. The authors further obsd. that tumor necrosis factor alpha, which is released by Ebola virus-infected monocytes/macrophages, enhanced Ebola virus GP-mediated entry and fusion to human umbilical vein endothelial cells. Thus, Ebola virus infection of one target cell may induce biol. changes that facilitate infection of secondary target cells that play a key role in filovirus pathogenesis. Finally, these studies indicate that pseudotyping in the HIV-1 virion-based fusion assay may be a valuable approach to the study of entry and fusion properties mediated through the envelopes of other viral pathogens.
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157. 157
  Aldridge, D. C.; Armstrong, J. J.; Speake, R. N.; Turner, W. B. The Cytochalasins, a New Class of Biologically Active Mould Metabolites. Chem. Commun. 1967, 26– 27, DOI: 10.1039/c19670000026
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  Cytochalasins, a new class of biologically active mold metabolites
  Aldridge, D. C.; Armstrong, J. J.; Speake, Roy N.; Turner, William Brian
  Chemical Communications (London) (1967), (1), 26-7CODEN: CCOMA8; ISSN:0009-241X.
  A new class of mold products was isolated for which the name cytochalasins (cyto = cell, chalasis = relaxation) was proposed. Four cytochalasins (A and B from Helminthosporium dematioideum and C and D from Metarrhizium amisopliae) were isolated. Structures (Ia) and (IIb) have been suggested for cytochalasin A (C29H35NO5) and cytochalasin B (C29H37NO5), resp. The relation between cytochalasins A and B was established by oxidn. of the latter to the former with MnO2. Cytochalasins C and D are isomers, C30H37NO6, whose relation to each other has not been established.
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158. 158
  Kashman, Y.; Groweiss, A.; Shmueli, U. Latrunculin, a New 2-Thiazolidinone Macrolide from the Marine Sponge Latrunculia Magnifica. Tetrahedron Lett. 1980, 21 (37), 3629– 3632, DOI: 10.1016/0040-4039(80)80255-3
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  Latrunculin, a new 2-thiazolidinone macrolide from the marine sponge Latrunculia magnifica
  Kashman, Y.; Groweiss, A.; Shmueli, U.
  Tetrahedron Letters (1980), 21 (37), 3629-32CODEN: TELEAY; ISSN:0040-4039.
  L. magnifica, Yielded 3 new thiazolidinone macrolide toxins, named latrunculin-A (I), -B (II), and -C (a stereoisomer of I); structures were detd. by chem. and spectral anal. with special ref. to x-ray diffraction data of a cryst. deriv. of I. The biogenesis of the latrunculins, a new class of 14- and 16-membered macrolides to which the 2-thiazolidinone moiety is attached, is proposed.
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159. 159
  Crews, P.; Manes, L. V.; Boehler, M. Jasplakinolide, a Cyclodepsipeptide from the Marine Sponge, Jaspis SP. Tetrahedron Lett. 1986, 27 (25), 2797– 2800, DOI: 10.1016/S0040-4039(00)84645-6
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  159
  Jasplakinolide, a cyclodepsipeptide from the marine sponge, Jaspis sp
  Crews, Phillip; Manes, Lawrence V.; Boehler, Mark
  Tetrahedron Letters (1986), 27 (25), 2797-800CODEN: TELEAY; ISSN:0040-4039.
  Jasplakinolide (I), which has antifungal and anthelminthic bioactivity, was isolated from the soft sponge Jaspis and its structure was detd. as a cyclodepsipeptide comprised of 3 amino acids and an oxy-trimethyl-nonanoyl group by using NMR and mass spectrometry.
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160. 160
  Beck, S.; Henß, L.; Weidner, T.; Herrmann, J.; Müller, R.; Chao, Y.-K.; Grimm, C.; Weber, C.; Sliva, K.; Schnierle, B. S. Identification of Entry Inhibitors of Ebola Virus Pseudotyped Vectors from a Myxobacterial Compound Library. Antiviral Res. 2016, 132, 85– 91, DOI: 10.1016/j.antiviral.2016.05.017
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  160
  Identification of entry inhibitors of Ebola virus pseudotyped vectors from a myxobacterial compound library
  Beck, Simon; Henss, Lisa; Weidner, Tatjana; Herrmann, Jennifer; Mueller, Rolf; Chao, Yu-Kai; Grimm, Christian; Weber, Christopher; Sliva, Katja; Schnierle, Barbara S.
  Antiviral Research (2016), 132 (), 85-91CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
  Myxobacteria produce secondary metabolites many of which were described to have various biol. effects including anti-fungal, anti-bacterial and anti-viral activity. The majority of these metabolites are novel scaffolds with unique modes-of-action and hence might be potential leads for drug discovery. Here, we tested a myxobacterial natural product library for compds. with inhibitory activity against Ebola virus (EBOV). The assay was performed with a surrogate system using Ebola envelope glycoprotein (GP) pseudotyped lentiviral vectors. EBOV specificity was proven by counter-screening with vesicular stomatitis virus G protein pseudotyped vectors. Two compds. were identified that preferentially inhibited EBOV GP mediated cell entry: Chondramides that act on the actin skeleton but might be too toxic and noricumazole A, a potassium channel inhibitor, which might constitute a novel pathway to inhibit Ebola virus cell entry.
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161. 161
  Kunze, B.; Jansen, R.; Sasse, F.; Höfle, G.; Reichenbach, H. Chondramides A-D, New Antifungal and Cytostatic Depsipeptides from Chondromyces Crocatus (Myxobacteria). J. Antibiot. 1995, 48 (11), 1262– 1266, DOI: 10.7164/antibiotics.48.1262
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  161
  Antibiotics from gliding bacteria. 71. Chondramides A-D, new antifungal and cytostatic depsipeptides from Chondromyces crocatus (Myxobacteria): production, physico-chemical and biological properties
  Kunze, Brigitte; Jansen, Rolf; Sasse, Florenz; Hoefle, Gerhard; Reichenbach, Hans
  Journal of Antibiotics (1995), 48 (11), 1262-6CODEN: JANTAJ; ISSN:0021-8820. (Japan Antibiotics Research Association)
  Novel depsipeptides, named chondramides were produced at levels up to 4.3 mg/L by several myxobacteria of the genus Chondromyces. The compds. are structurally closely related to jaspamide/jasplakinolide from marine sponges of the genus Jaspis. Initially the chondramides were detected in acetone exts. of the biomass of Chondromyces crocatus, strain Cm c2. So far, four structural variants could be characterized, the chondramides A-D. They inhibited the growth of a few yeasts and showed high cytostatic activity against cultivated human and animal cells.
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162. 162
  Herrmann, J.; Hüttel, S.; Müller, R. Discovery and Biological Activity of New Chondramides from Chondromyces Sp. ChemBioChem 2013, 14 (13), 1573– 1580, DOI: 10.1002/cbic.201300140
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  162
  Discovery and Biological Activity of New Chondramides from Chondromyces sp.
  Herrmann, Jennifer; Huettel, Stephan; Mueller, Rolf
  ChemBioChem (2013), 14 (13), 1573-1580CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Myxobacteria have proven to be highly valuable sources of natural products, as they produce a variety of secondary metabolites with unique structures and often new modes of action. In this study, high-content screening is demonstrated to be a convenient tool for bioactivity-guided isolation of natural products from crude bacterial exts. By the application of focused, image-based screens we were able to identify over 30 novel chondramide derivs. from Chondromyces sp. MSr9030, some of which were present in only minute amts. These cyclic depsipeptides were shown to target actin filaments with a similar binding mode to that of the mushroom toxin phalloidin. Fermns. of the myxobacterial strain were carried out under improved cultivation conditions, and supplementation of the culture broth with potassium bromide afforded the prodn. of brominated analogs that are superior (in terms of biol. activity) to all chondramides described to date. Initial biol. profiling of 11 new derivs. in comparison to the ref. compds. (chondramides A-C) showed that bromo-chondramide C3 and propionyl-bromo-chondramide C3 are the most active in cell-based studies, with GI50 values on human cancer cell lines in the low nanomolar range. Given that these brominated C3 analogs were also less potent on noncancerous human cells (by a factor of 2 to 4 in comparison to cancer cell lines), our results can aid further structure-activity relationship-guided development of chondramides, either as mol. probes or pharmaceutical agents.
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163. 163
  Fan, H.-H.; Wang, L.-Q.; Liu, W.-L.; An, X.-P.; Liu, Z.-D.; He, X.-Q.; Song, L.-H.; Tong, Y.-G. Repurposing of Clinically Approved Drugs for Treatment of Coronavirus Disease 2019 in a 2019-Novel Coronavirus-Related Coronavirus Model. Chin. Med. J. (Engl.) 2020, 133 (9), 1051– 1056, DOI: 10.1097/CM9.0000000000000797
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  163
  Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus-related coronavirus model
  Fan Hua-Hao; Wang Li-Qin; Liu Wen-Li; An Xiao-Ping; Liu Zhen-Dong; He Xiao-Qi; Song Li-Hua; Tong Yi-Gang
  Chinese medical journal (2020), 133 (9), 1051-1056 ISSN:.
  BACKGROUND: Medicines for the treatment of 2019-novel coronavirus (2019-nCoV) infections are urgently needed. However, drug screening using live 2019-nCoV requires high-level biosafety facilities, which imposes an obstacle for those institutions without such facilities or 2019-nCoV. This study aims to repurpose the clinically approved drugs for the treatment of coronavirus disease 2019 (COVID-19) in a 2019-nCoV-related coronavirus model. METHODS: A 2019-nCoV-related pangolin coronavirus GX_P2V/pangolin/2017/Guangxi was described. Whether GX_P2V uses angiotensin-converting enzyme 2 (ACE2) as the cell receptor was investigated by using small interfering RNA (siRNA)-mediated silencing of ACE2. The pangolin coronavirus model was used to identify drug candidates for treating 2019-nCoV infection. Two libraries of 2406 clinically approved drugs were screened for their ability to inhibit cytopathic effects on Vero E6 cells by GX_P2V infection. The anti-viral activities and anti-viral mechanisms of potential drugs were further investigated. Viral yields of RNAs and infectious particles were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and plaque assay, respectively. RESULTS: The spike protein of coronavirus GX_P2V shares 92.2% amino acid identity with that of 2019-nCoV isolate Wuhan-hu-1, and uses ACE2 as the receptor for infection just like 2019-nCoV. Three drugs, including cepharanthine (CEP), selamectin, and mefloquine hydrochloride, exhibited complete inhibition of cytopathic effects in cell culture at 10 μmol/L. CEP demonstrated the most potent inhibition of GX_P2V infection, with a concentration for 50% of maximal effect [EC50] of 0.98 μmol/L. The viral RNA yield in cells treated with 10 μmol/L CEP was 15,393-fold lower than in cells without CEP treatment ([6.48 ± 0.02] × 10vs. 1.00 ± 0.12, t = 150.38, P < 0.001) at 72 h post-infection (p.i.). Plaque assays found no production of live viruses in media containing 10 μmol/L CEP at 48 h p.i. Furthermore, we found CEP had potent anti-viral activities against both viral entry (0.46 ± 0.12, vs.1.00 ± 0.37, t = 2.42, P < 0.05) and viral replication ([6.18 ± 0.95] × 10vs. 1.00 ± 0.43, t = 3.98, P < 0.05). CONCLUSIONS: Our pangolin coronavirus GX_P2V is a workable model for 2019-nCoV research. CEP, selamectin, and mefloquine hydrochloride are potential drugs for treating 2019-nCoV infection. Our results strongly suggest that CEP is a wide-spectrum inhibitor of pan-betacoronavirus, and further study of CEP for treatment of 2019-nCoV infection is warranted.
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164. 164
  Li, S.; Chen, C.; Zhang, H.; Guo, H.; Wang, H.; Wang, L.; Zhang, X.; Hua, S.; Yu, J.; Xiao, P. Identification of Natural Compounds with Antiviral Activities against SARS-Associated Coronavirus. Antiviral Res. 2005, 67 (1), 18– 23, DOI: 10.1016/j.antiviral.2005.02.007
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  164
  Identification of natural compounds with antiviral activities against SARS-associated coronavirus
  Li, Shi-you; Chen, Cong; Zhang, Hai-qing; Guo, Hai-yan; Wang, Hui; Wang, Lin; Zhang, Xiang; Hua, Shi-neng; Yu, Jun; Xiao, Pei-gen; Li, Rong-song; Tan, Xuehai
  Antiviral Research (2005), 67 (1), 18-23CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
  More than 200 Chinese medicinal herb exts. were screened for antiviral activities against Severe Acute Respiratory Syndrome-assocd. coronavirus (SARS-CoV) using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay for virus-induced cytopathic effect (CPE). Four of these exts. showed moderate to potent antiviral activities against SARS-CoV with 50% effective concn. (EC50) ranging from 2.4±0.2 to 88.2±7.7 μg/mL. Out of the four, Lycoris radiata was most potent. To identify the active component, L. radiata ext. was subjected to further fractionation, purifn., and CPE/MTS assays. This process led to the identification of a single substance lycorine as an anti-SARS-CoV component with an EC50 value of 15.7±1.2 nM. This compd. has a CC50 value of 14980.0±912.0 nM in cytotoxicity assay and a selective index (SI) greater than 900. The results suggested that four herbal exts. and the compd. lycorine are candidates for the development of new anti-SARS-CoV drugs in the treatment of SARS.
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165. 165
  Lane, T.; Anantpadma, M.; Freundlich, J. S.; Davey, R. A.; Madrid, P. B.; Ekins, S. The Natural Product Eugenol Is an Inhibitor of the Ebola Virus In Vitro. Pharm. Res. 2019, 36 (7), 104, DOI: 10.1007/s11095-019-2629-0
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  165
  The Natural Product Eugenol Is an Inhibitor of the Ebola Virus In Vitro
  Lane Thomas; Ekins Sean; Anantpadma Manu; Davey Robert A; Anantpadma Manu; Davey Robert A; Freundlich Joel S; Madrid Peter B
  Pharmaceutical research (2019), 36 (7), 104 ISSN:.
  PURPOSE: Since the 2014 Ebola virus (EBOV) outbreak in West Africa there has been considerable effort towards developing drugs to treat Ebola virus disease and yet to date there is no FDA approved treatment. This is important as at the time of writing this manuscript there is an ongoing outbreak in the Democratic Republic of the Congo which has killed over 1000. METHODS: We have evaluated a small number of natural products, some of which had shown antiviral activity against other pathogens. This is exemplified with eugenol, which is found in high concentrations in multiple essential oils, and has shown antiviral activity against feline calicivirus, tomato yellow leaf curl virus, Influenza A virus, Herpes Simplex virus type 1 and 2, and four airborne phages. RESULTS: Four compounds possessed EC50 values less than or equal to 11 μM. Of these, eugenol, had an EC50 of 1.3 μM against EBOV and is present in several plants including clove, cinnamon, basil and bay. Eugenol is much smaller and structurally unlike any compound that has been previously identified as an inhibitor of EBOV, therefore it may provide new mechanistic insights. CONCLUSION: This compound is readily accessible in bulk quantities, is inexpensive, and has a long history of human consumption, which endorses the idea for further assessment as an antiviral therapeutic. This work also suggests that a more exhaustive assessment of natural product libraries against EBOV and other viruses is warranted to improve our ability to identify compounds that are so distinct from FDA approved drugs.
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166. 166
  Caly, L.; Druce, J. D.; Catton, M. G.; Jans, D. A.; Wagstaff, K. M. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in Vitro. Antiviral Res. 2020, 178, 104787, DOI: 10.1016/j.antiviral.2020.104787
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  The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro
  Caly, Leon; Druce, Julian D.; Catton, Mike G.; Jans, David A.; Wagstaff, Kylie M.
  Antiviral Research (2020), 178 (), 104787CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
  Although several clin. trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addn. to Vero-hSLAM cells 2 h post infection with SARS-CoV-2 able to effect ∼5000-fold redn. in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.
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167. 167
  Chaccour, C.; Hammann, F.; Ramon-Garcia, S.; Rabinovich, N. R. Ivermectin and COVID-19: Keeping Rigor in Times of Urgency. Am. J. Trop. Med. Hyg. 2020, 102, 1156– 1157, DOI: 10.4269/ajtmh.20-0271
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  Ivermectin and COVID-19: Keeping Rigor in Times of Urgency
  Chaccour Carlos; Rabinovich N Regina; Chaccour Carlos; Chaccour Carlos; Hammann Felix; Ramon-Garcia Santiago; Ramon-Garcia Santiago; Rabinovich N Regina
  The American journal of tropical medicine and hygiene (2020), 102 (6), 1156-1157 ISSN:.
  There is no expanded citation for this reference.
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168. 168
  Maga, E. R. Latin America’s Embrace of an Unproven COVID Treatment is Hindering Drug Trials. Nature 2020, 586, 481– 482, DOI: 10.1038/d41586-020-02958-2
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Natural Products with Potential to Treat RNA Virus Pathogens Including SARS-CoV-2

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Abstract

Note

Introduction

Viral Life Cycles

Coronaviridae

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Flaviviridae

Filoviridae

Genome Structures

Protein Targets and Drug Development

A. Viral Proteins

Structural Proteins

Proteases

Replicase/Transcriptase Complex Proteins

Figure 8

Accessory Proteins

Figure 9

B. Host Proteins

Proteases

Figure 10

Others

Figure 11

C. Unknown Targets

Figure 12

Summary and Outlook

Author Information

Acknowledgments

References

Cited By

Abstract

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Figure 12

References

STEP 1:

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