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COVID-19: Living through Another Pandemic
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  • Essam Eldin A. Osman
    Essam Eldin A. Osman
    Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
    Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
    More by Essam Eldin A. Osman
  • Peter L. Toogood
    Peter L. Toogood
    Department of Medicinal Chemistry, College of Pharmacy  and  Michigan Drug Discovery, Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States
    More by Peter L. Toogood
  • Nouri Neamati*
    Nouri Neamati
    Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
    *Email: [email protected]
    More by Nouri Neamati
    Orcidhttp://orcid.org/0000-0003-3291-7131
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ACS Infectious Diseases

Cite this: ACS Infect. Dis. 2020, 6, 7, 1548–1552
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https://doi.org/10.1021/acsinfecdis.0c00224
Published May 10, 2020
Copyright © 2020 American Chemical Society
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Abstract

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Novel beta-coronavirus SARS-CoV-2 is the pathogenic agent responsible for coronavirus disease-2019 (COVID-19), a globally pandemic infectious disease. Due to its high virulence and the absence of immunity among the general population, SARS-CoV-2 has quickly spread to all countries. This pandemic highlights the urgent unmet need to expand and focus our research tools on what are considered “neglected infectious diseases” and to prepare for future inevitable pandemics. This global emergency has generated unprecedented momentum and scientific efforts around the globe unifying scientists from academia, government and the pharmaceutical industry to accelerate the discovery of vaccines and treatments. Herein, we shed light on the virus structure and life cycle and the potential therapeutic targets in SARS-CoV-2 and briefly refer to both active and passive immunization modalities, drug repurposing focused on speed to market, and novel agents against specific viral targets as therapeutic interventions for COVID-19.

Copyright © 2020 American Chemical Society

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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.

As first reported in December 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused an outbreak of atypical pneumonia in Wuhan, China, that has since spread globally. (1) The disease caused by this new virus has been named coronavirus disease-2019 (COVID-19) and on March 11, 2020 was declared a global pandemic by the World Health Organization (WHO). (1) Currently, there are seven known human coronaviruses classified into two broad genera of alpha- and beta-coronaviruses. The alpha-coronaviruses comprise HCoV-NL63 and HCoV-229E, while the beta-coronaviruses comprise HCoV-OC43, HCoV-HKU1, SARS, Middle East Respiratory Syndrome virus (MERS), and SARS-CoV-2. (2) The alpha-coronaviruses and HCoV-OC43 and HCoV-HKU1 are among the causes of the common cold and have been circulating in human and animal populations for many years. (2) All these viruses originate from a common ancestor and enter the human population through zoonotic transfer or species jumping. (3) Although the first four known human coronaviruses originated from birds, SARS, MERS, and SARS-CoV-2 appear, on the basis of gene sequence analysis, to have originated from bats. (4) However, in each case, these more recent viruses appear to have been transmitted through an intermediate host such as a civet, a small nocturnal mammal native to tropical Asia and Africa (SARS), a camel (MERS), or a pangolin (SARS-CoV-2) after acquiring additional mutations. (2) Bats harbor more strains of coronavirus than other mammals, estimated to range from 5000 to 10,000 distinct subtypes. (5) Therefore, additional epidemics are highly likely to occur in the future due to the abundant number of coronaviruses present in the bat population.
As of May 6th, 2020, more than 3.7 million cases of SARS-CoV-2 positive patients have been reported worldwide with over 260,000 deaths, reflecting a ∼6.8% case fatality rate. While the infection fatality rate is currently unknown, and likely to be lower than the current case fatality rate, estimates suggest it is close to 1%, or approximately 10 times the infection fatality rate of seasonal influenza (flu), which is fatal in only ∼0.1% of infected patients. (6) In contrast to previous coronavirus epidemics (Table S1), COVID-19 is indiscriminately wreaking havoc globally with no apparent end in sight due to its high virulence and the absence of resistance among the general population.
In general, all pandemics pass through three phases until they become endemic. The first phase of “seeding” or slow spread is often not noticed early enough, leading to dissemination of the disease before effective countermeasures can be initiated. During the second phase, there is a rapid increase in cases until a peak occurs in the number of infected individuals; parallel efforts to control and contain the virus can mitigate this phase. In the third phase, the infection rate curve will start to decrease until the disease becomes extinct or endemic. The kinetics of increase and decrease in the rate of infections can vary significantly between populations depending on the use of preventive measures and the availability of effective treatments. Previous coronavirus outbreaks and the current pandemic highlight the urgent unmet medical need to expand and focus our research tools on these long neglected infectious diseases and to prepare for future inevitable pandemics. Herein, we briefly recap the current and potential future therapeutic interventions for SARS-CoV-2 and highlight the recently published crystal structures of the SARS-CoV-2 main protease and its inhibitors as novel agents against SARS-CoV-2.

Virus Structure and Life Cycle

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SARS-CoV-2 is an enveloped, nonsegmented single stranded, positive sense RNA virus. It has one of the largest genomes among all RNA viruses, comprising approximately 30 kilobases (kb) (NC_045512.2). SARS-CoV and SARS-CoV-2 belong to the same Coronaviridae family that also includes the highly fatal Middle East Respiratory Syndrome virus (MERS) that appeared in 2012. (7) SARS-CoV-2 enters cells through the interaction of its surface Spike protein with the host receptor, angiotensin-converting enzyme 2 (ACE2). (8) Subsequent proteolytic cleavage by the host serine protease TMPRSS2 or perhaps other proteases allows subsequent cell entry by endocytosis. (8) Upon membrane fusion and endocytosis, the viral nucleocapsid with its genome payload is released into the cytoplasm of the infected cell. Following its release into the host cell, the virus usurps portions of the endoplasmic reticulum to form numerous double membrane vesicles. (9) These vesicles are perfect sanctuaries to protect the viral genome and allow an efficient replication process to occur through a macromolecule complex called the replication–transcription complex (RTC). (10) The viral genome is subsequently translated into viral polyproteins using the host cell protein translation machinery, which are then cleaved into structural and nonstructural viral proteins by two viral proteases, Mpro and PLpro. (11) This step is followed by the assembly of viral particles (virions) in the endoplasmic reticulum/golgi compartment. (12) The packaged virions are then transported to the cell surface, are released from the cells through exocytosis, and proceed to infect other cells.

Clinical Course and Outcomes of COVID-19

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SARS-CoV-2 likely binds to epithelial cells in the nasal cavity during the asymptomatic state of the disease (initial 1–2 days of infection) where there might be some local propagation of the virus but with a limited innate immune response. Within the next few days the infection starts in the upper airway and during this stage the infection can be detected by nasal swabs or sputum as well as early markers of the innate immune response. About 80% of infected patients show mild symptoms that are mostly restricted to the upper and conducting airways. (13) However, about 20% of infected patients will progress to develop a lower respiratory tract infection leading to hypoxia, and lung damage. These patients are liable to succumb to acute respiratory distress syndrome (ARDS), which is frequently fatal. Patients with comorbidities such as cardiovascular disease, diabetes mellitus, hypertension, chronic lung disease, cancer, chronic kidney disease, and obesity (body mass index ≥30) and ARDS are at increased risk of death. (14) The available data indicate that the viral infection can produce an excessive immune reaction known as cytokine release syndrome (CRS) or “cytokine storm” associated with elevated levels of interleukin-6 (IL-6). (15) Laboratory findings associated with worse clinical outcomes include lymphopenia, and elevations in liver enzymes, lactate dehydrogenase (LDH), inflammatory markers (e.g., C-reactive protein [CRP], ferritin), d-dimer, prothrombin time (PT), troponin and creatine phosphokinase (CPK), and acute kidney injury. (15) Chest CT scans in patients with COVID-19 commonly show ground-glass opacification, consistent with viral pneumonia with abnormalities more likely to be bilateral with a peripheral distribution involving the lower lobes. (16) While SARS-CoV-2 entry is dependent on ACE2 in lung cells, (8) ACE2 expression is not exclusive to the lungs, and higher relative ACE2 expression is observed in heart, kidney, GIT, and testes (Gene ID: 59272). The organ- and cell-specific expression of ACE2 suggests that it may play a role in the regulation of cardiovascular and renal function as well as fertility. Surprisingly, the 2003 SARS-CoV infection was shown to downregulate the expression of ACE2 in lung tissue reducing transmissibility but increasing virulence. (17) ACE2, a component of the renin-angiotensin system (RAS), catalyzes the cleavage of angiotensin I into angiotensin 1–9 and angiotensin II into the vasodilator angiotensin 1–7. (18) The balance between angiotensin II and angiotensin (1–7) is critical since angiotensin II elicits vasoconstriction via the angiotensin AT1 receptor, whereas angiotensin (1–7) exerts a vasodilatory effect mediated by AT2 with multiple beneficial effects on the cardiovascular and respiratory system. (18) While ACE2 appears to be involved in the hypertension and respiratory manifestations of severely ill patients, the benefits and merits of ACE inhibitors (ACEI) or angiotensin receptor 1 blockers (ARBs) in the SARS-CoV-2 patient is still controversial. (18) The priming of the S viral protein by TMPRSS2 is crucial for viral entry where TMPRSS2 expression is very high in the lungs, kidneys, and prostate tissue (Gene ID: 7113). (8) TMPRSS2 is predominantly expressed in the luminal cells of the prostate epithelium, where its expression is regulated positively by androgens and negatively regulated by estrogens. The hormonal regulation of TMPRSS2 has been suggested to be linked to the fact that men are at higher risk than women to become seriously ill with COVID-19. (19) TMPRSS2 knockout in mice is not lethal. In contrast, humans are intolerant to the loss of function of ACE2. (19) Concerns about the effect of ACEI and AT receptor blockers in COVID-19 patients are actively being investigated in the clinic, with the most recent reports offering encouragement that they may have a beneficial effect.

Potential Drug Targets

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SARS-CoV-2 viral RNA encodes several proteins that are potentially druggable targets (Figure 1 and Table S2), including four structural proteins: the Spike (S), Envelope (E), Membrane (M), and Nucleocapsid (N). (1) The 1273 amino acid, 141 kDa, Spike protein is heavily N-glycosylated and is a major inducer of host immune responses. The 222 amino acid M protein has three transmembrane domains and is the most abundant structural protein in the virion. The 75 amino acid E protein is important for assembly and release of the virus. The 419 amino acid nucleocapsid protein forms a protective protein shell around the virus genetic material and is encased in a lipid envelope that is usurped from the host cell. Matrix protein connects the membrane to the nucleocapsid protein. There are also 16 nonstructural proteins (nsp1–16) (1) including several for which there are X-ray crystallography-derived structural data: RNA dependent RNA polymerase (nsp12, RdRp), a papain-like protease (nsp3, PLpro), the main protease (nsp5, 3CLpro, or Mpro), and exonuclease/N7-methyltransferase (nsp14, ExoN). RdRp catalyzes synthesis of the full length negative-strand RNA template used by RdRp to make more viral genomic RNA. The SARS-CoV-2 genome also contains a number of open reading frames (ORFs): namely, ORF 1a proposed to encode nsp1 to nsp11; ORF1b, is proposed to encode nsp12 to nsp16, essential for viral replication, and ORFs 3a, 3b, 6, 7a, 7b, 8, 9a, 9b, and 10, which encode for accessory proteins (1) (Table S2).

Figure 1

Figure 1. SARS-CoV-2 encoded proteins.

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Treating Viral Infection

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Immunization against SARS-CoV-2

The development of a manufacturable, safe, and effective vaccine may take 12–18 months. Several phase I clinical trials are currently recruiting participants to test the safety, reactogenicity, and immunogenicity of several investigational SARS-CoV-2 vaccines (Tables S3 and S4). An mRNA vaccine based on the Spike protein began human clinical trials within a record 63 days from first publication of the SARS-CoV-2 sequence (NCT04283461). It has been suggested that the mutation rate for SARS-CoV-2 is expected to be low, raising hope that a successful vaccine will provide life-long immunity. (20) Hyperimmune globulin isolated from the sera of convalescent patients having high titers of antibodies against SARS-CoV-2 or even their whole blood may provide instant “passive” short-lived immunity mainly via viral neutralization. Antibody dependent therapy, for example targeting the Spike protein might represent the most efficient, near-term therapeutic intervention if regulatory and safety requirements can be addressed. With over 1.3 million positive cases of COVID-19 in the US based solely on the results of RNA molecular tests, large-scale antibody testing should be expedited to identify individuals who have been exposed to the virus but were never officially confirmed to have COVID-19. An understanding what levels of antibody confer immunity postinfection could be used to determine who may be less likely to transmit the virus and thus may be able to go back safely to work.

Drug Repurposing

Developing highly selective SARS-CoV-2 specific new drugs will take many years. Alternatively, repurposing of existing, approved drugs can present a more rapid strategy to identifying drugs effective in treating COVID-19 (Tables S3 and S4 and Figure S1). (11) Repurposing of drugs that would block SARS-CoV-2 entry and/or replication are urgently needed to mitigate the symptomatic burden of the disease. Unfortunately, the HIV protease inhibitors ritonavir/liponavir failed to show efficacy in SARS-CoV-2 infected patients. (21) Hydroxychloroquine, which may act by increasing the pH within lysosomes, was granted FDA authorization for use in emergency cases. Several antiviral agents are being tested such as the RdRp inhibitor remdesivir and the approved anti-influenza drug faviprivir. (8) Remdesivir was previously tested in humans with Ebola virus disease and also in animal models of MERS and SARS-CoV. (11) At least six clinical trials are evaluating remdesivir in SARS-CoV-2 patients. Other drugs that might inhibit RdRp include the broad-spectrum antiviral drug ribavirin. RdRp conservation among RNA virus families makes it an exciting target for the discovery of newer agents. The Spike protein, ACE2, and TMPRSS2 may also represent interesting therapeutic targets for current drug repurposing efforts. Camostat mesylate, approved in Japan for treatment of pancreatic inflammation, has been shown to block TMPRSS2 activity. (22) Arbidol, which is hypothesized to block Spike/ACE2 binding, is being investigated clinically, and a clinical trial was recently launched to study the effect of thiazide, thiazide-like diuretics, calcium channel blockers, ACE inhibitors, and angiotensin receptor blockers in COVID-19 (NCT04330300). The availability of soluble recombinant hACE2 encouraged its testing in two clinical trials; although one was terminated (NCT04287686) the other is currently active (NCT04335136). Monoclonal antibodies, especially for interleukin-6 (IL-6) or its receptor, are also being considered for the control of SARS-CoV-2 associated respiratory exacerbations. (11) Interestingly, several Janus Kinase (JAK) inhibitors such as baricitinib and ruxolitinib are currently being evaluated given their involvement in interleukin signaling pathways. Another currently recruiting clinical trial is testing quinolone, macrolide, and β-lactam antibiotics against COVID-19 (NCT02735707). Multiple groups have tested FDA approved drugs in various in vitro assays as well as in computational screens. Many of these drugs show inhibitory activities, although not always at a concentration that may be safely achieved in patients. (23) Controlled clinical trials of these agents are mandatory to assess their efficacy and safety without creating false positive hope or depleting the supplies of drugs needed to treat the diseases for which they were initially approved.

Novel Agents

Mpro and PLpro are cysteine proteases responsible for the cleavage of viral polypeptides into functional proteins for virus replication and packaging within host cells. (24) These enzymes represent the best characterized drug targets among coronaviruses and are currently the focus of attention among scientists seeking novel coronavirus small molecule therapeutics. (25) Mpro is shared by all coronavirus genera and has similarity to the 3Cpro of the Enterovirus genus in the picornavirus family. (24) Mpro contains a Cys···His catalytic dyad with an additional α-helical domain involved in the dimerization of the protease, which is essential for its catalytic activity. (25) The enteroviral 3Cpro functions as a monomer featuring a classical Cys···His···Glu/Asp catalytic triad. (24) Yet, they share the almost absolute requirement for Gln in the P1 position of the substrate and space for only small residues such as Gly, Ala, or Ser in the P1′ position. Since no human proteases with a similar cleavage specificity are known, it may be possible to identify highly selective Mpro/3Cpro inhibitors, which display minimal inhibition of host proteases. (26) The 3-D structures of unliganded SARS-CoV-2 Mpro and of its complex with a peptidomimetic α-ketoamide inhibitor (11r) have been solved (26) and were used to support the design of an optimized derivative (13b) through docking studies (Figure S2). α-Ketoamides can interact with the catalytic center of Mpro through two hydrogen bonding interactions rather than only one as with other warheads such as aldehydes or Michael acceptors. (24) Nucleophilic attack of the α-keto group by the catalytic Cys residue results in reversible formation of a thiohemiketal. These α-ketoamides feature a 5-membered rigid γ-lactam as a mimic of the P1 residue, glutamine, required for Mpro specificity, with the advantage of reducing the loss of entropy upon binding. (24) Follow up optimization efforts guided by docking to the SARS-CoV-2 Mpro co-crystal structure with 11r, included incorporation of the P3-P2 amide bond into a pyridone ring as in 13a. The resulting half-life of 13a in plasma was enhanced by 3 fold relative to 11r, in vitro kinetic plasma solubility improved by a factor of ∼19 and thermodynamic solubility by a factor of ∼13. 13a inhibited purified recombinant SARS-CoV-2 Mpro, SARS-CoV Mpro, and MERS-CoV Mpro in the submicromolar range. (26) Modification of the P1′ and P3 moieties of 13a afforded an optimized derivative 13b which was crystallized with SARS-CoV-2 Mpro (PDB: 6Y2G and 6Y2F). Both 13a and 13b displayed good stability in mouse and human microsomes. 13b (3 mg/kg) showed longer t1/2, tmax, and residence time compared to 13a (20 mg/kg) in CD-1 mice. Both compounds showed lung tropism which is thought to be beneficial. While the development of these ketoamides into clinical candidates requires additional safety studies, the availability of their crystal structures is of great importance in facilitating the discovery and development of other Mpro inhibitors. One of the suggested agents for testing is the previously reported Rhinovirus and SARS-CoV Mpro inhibitor clinical candidate rupintrivir (AG-7088) (Figure S2). In addition, other groups recently reported Mpro crystal structures with inhibitors such as the peptidomimetic Michael acceptor N3 (PDB: 6LU7) and the reversible inhibitor X77 (PDB: 6W63) (Figure S2). (27) A large array of Mpro crystal structures with multiple covalent and noncovalent fragments were solved through an exceptionally large screen with vast opportunities for fragment growing and merging. The cryo EM structure of SARS-CoV-2 RdRp was recently solved, showing nearly an identical sequence to its SARS-CoV homologue. (28) RdRp should be another high priority target for therapeutic intervention given that lead inhibitors such as remdesivir already exist.

Conclusions

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Since 2003, the three pandemics caused by SARS, MERS, and SARS-CoV-2 are believed to have initiated as a result of bat coronaviruses crossing the species barrier. Therefore, other epidemics are likely to occur in the future due to the effectively unlimited supply of coronaviruses present in the bat population. Equally concerning is the fact that RNA viruses lack a genomic proof-reading mechanism and therefore are prone to mutation, raising the specter that once a new coronavirus begins circulating in the human population it will be extremely difficult to eliminate. Finally, for a drug to be most effective, it must reach its site of action (e.g., lung tissues) in sufficient quantity to clear the virus. With nearly three million reported cases, >260,000 deaths, millions out of work, and billions of dollars in lost revenue, it appears that SARS-CoV-2 has altered daily life for a sustained period of time. This cascading effect has generated unprecedented momentum and scientific effort around the globe to fight this virus. Success will require creative thinking, new technologies, innovative approaches, particularly focused on speed to market, and combinations of different modalities to effectively combat not just the current foe but also future coronaviruses. We remain hopeful that we will be more prepared for the emergence of a potential “SARS-CoV-3”.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsinfecdis.0c00224.

  • Tables showing viral outbreaks since year 2000, different targets expressed in SARS-CoV-2 proteome, unique therapeutic interventions in recruiting and nonrecruiting clinical studies for COVID-19, and structures of select approved or investigational drugs tested for drug repurposing against SARS-CoV-2; structures of the novel inhibitors obtained from the PDB for SARS-CoV-2 Mpro (PDF)

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Author Information

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  • Corresponding Author
  • Authors
    • Essam Eldin A. Osman - Department of Medicinal Chemistry, College of Pharmacy and , University of Michigan, Ann Arbor, Michigan 48109, United States;  Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
    • Peter L. Toogood - Department of Medicinal Chemistry, College of Pharmacy  and  Michigan Drug Discovery, Life Sciences Institute and , University of Michigan, Ann Arbor, Michigan 48109, United States
  • Notes
    The authors declare no competing financial interest.

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    Li, W., Shi, Z., Yu, M., Ren, W., Smith, C., Epstein, J. H., Wang, H., Crameri, G., Hu, Z., Zhang, H., Zhang, J., McEachern, J., Field, H., Daszak, P., Eaton, B. T., Zhang, S., and Wang, L. F. (2005) Bats are natural reservoirs of SARS-like coronaviruses. Science 310 (5748), 676– 679,  DOI: 10.1126/science.1118391
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    Bats are natural reservoirs of SARS-like coronaviruses
    Li, Wendong; Shi, Zhengli; Yu, Meng; Ren, Wuze; Smith, Craig; Epstein, Jonathan H.; Wang, Hanzhong; Crameri, Gary; Hu, Zhihong; Zhang, Huajun; Zhang, Jianhong; McEachern, Jennifer; Field, Hume; Daszak, Peter; Eaton, Bryan T.; Zhang, Shuyi; Wang, Lin-Fa
    Science (Washington, DC, United States) (2005), 310 (5748), 676-679CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Severe acute respiratory syndrome (SARS) emerged in 2002 to 2003 in southern China. The origin of its etiol. agent, the SARS coronavirus (SARS-CoVs), remains elusive. Here, the authors report that species of bats are a natural host of coronaviruses closely related to those responsible for the SARS outbreak. These viruses, termed SARS-like coronaviruses (SL-CoV), display greater genetic variation than SARS-CoV isolated from humans or from civets. The human and civet isolates of SARS-CoV nestle phylogenetically within the spectrum of SL-CoVs, indicating that the virus responsible for the SARS outbreak was a member of this coronavirus group.
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  6. 6
    Ejima, K., Omori, R., Cowling, B. J., Aihara, K., and Nishiura, H. (2012) The time required to estimate the case fatality ratio of influenza using only the tip of an iceberg: joint estimation of the virulence and the transmission potential. Comput. Math Methods Med. 2012, 978901,  DOI: 10.1155/2012/978901
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    The time required to estimate the case fatality ratio of influenza using only the tip of an iceberg: joint estimation of the virulence and the transmission potential
    Ejima Keisuke; Omori Ryosuke; Cowling Benjamin J; Aihara Kazuyuki; Nishiura Hiroshi
    Computational and mathematical methods in medicine (2012), 2012 (), 978901 ISSN:.
    Estimating the case fatality ratio (CFR) of a novel strain of influenza virus during the early stage of the pandemic is one of key epidemiological tasks to be conducted as rapid research response. Past experience during the epidemics of severe acute respiratory syndrome (SARS) and influenza A (H1N1-2009) posed several technical challenges in estimating the CFR in real time. The present study aimed to develop a simple method to estimate the CFR based on readily available datasets, that is, confirmed cases and deaths, while addressing some of the known technical issues. To assess the reliability and validity of the proposed method, we examined the minimum length of time required for the assigned CFR to be included within the 95% confidence intervals and for the estimated CFR to be below a prespecified cut-off value by means of Monte Carlo simulations. Overall, the smaller the transmission potential was, the longer it took to compare the estimated CFR against the cut-off value. If policymaking and public health response have to be made based on the CFR estimate derived from the proposed method and readily available data, it should be noted that the successful estimation may take longer than a few months.
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  7. 7
    Coronaviridae Study Group of the International Committee on Taxonomy of Viruses (2020) The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 5 (4), 536– 544,  DOI: 10.1038/s41564-020-0695-z
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    The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2
    Coronaviridae Study Group of the International Committee on Taxonomy of Viruses
    Nature Microbiology (2020), 5 (4), 536-544CODEN: NMAICH; ISSN:2058-5276. (Nature Research)
    A review. The present outbreak of a coronavirus-assocd. acute respiratory disease called coronavirus disease 19 (COVID-19) is the third documented spillover of an animal coronavirus to humans in only two decades that has resulted in a major epidemic. The Coronaviridae Study Group (CSG) of the International Committee on Taxonomy of Viruses, which is responsible for developing the classification of viruses and taxon nomenclature of the family Coronaviridae, has assessed the placement of the human pathogen, tentatively named 2019-nCoV, within the Coronaviridae. Based on phylogeny, taxonomy and established practice, the CSG recognizes this virus as forming a sister clade to the prototype human and bat severe acute respiratory syndrome coronaviruses (SARS-CoVs) of the species Severe acute respiratory syndrome-related coronavirus, and designates it as SARS-CoV-2. In order to facilitate communication, the CSG proposes to use the following naming convention for individual isolates: SARS-CoV-2/host/location/isolate/date. While the full spectrum of clin. manifestations assocd. with SARS-CoV-2 infections in humans remains to be detd., the independent zoonotic transmission of SARS-CoV and SARS-CoV-2 highlights the need for studying viruses at the species level to complement research focused on individual pathogenic viruses of immediate significance. This will improve our understanding of virus-host interactions in an ever-changing environment and enhance our preparedness for future outbreaks.
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  8. 8
    Hoffmann, M., Kleine-Weber, H., Schroeder, S., Kruger, N., Herrler, T., Erichsen, S., Schiergens, T. S., Herrler, G., Wu, N. H., Nitsche, A., Muller, M. A., Drosten, C., and Pohlmann, S. (2020) SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 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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  9. 9
    Knoops, K., Kikkert, M., Worm, S. H., Zevenhoven-Dobbe, J. C., van der Meer, Y., Koster, A. J., Mommaas, A. M., and Snijder, E. J. (2008) SARS-coronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum. PLoS Biol. 6 (9), e226  DOI: 10.1371/journal.pbio.0060226
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    Hagemeijer, M. C., Verheije, M. H., Ulasli, M., Shaltiel, I. A., de Vries, L. A., Reggiori, F., Rottier, P. J., and de Haan, C. A. (2010) Dynamics of coronavirus replication-transcription complexes. J. Virol. 84 (4), 2134– 2149,  DOI: 10.1128/JVI.01716-09
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    Dynamics of coronavirus replication-transcription complexes
    Hagemeijer Marne C; Verheije Monique H; Ulasli Mustafa; Shaltiel Indra A; de Vries Lisa A; Reggiori Fulvio; Rottier Peter J M; de Haan Cornelis A M
    Journal of virology (2010), 84 (4), 2134-49 ISSN:.
    Coronaviruses induce in infected cells the formation of double-membrane vesicles (DMVs) in which the replication-transcription complexes (RTCs) are anchored. To study the dynamics of these coronavirus replicative structures, we generated recombinant murine hepatitis coronaviruses that express tagged versions of the nonstructural protein nsp2. We demonstrated by using immunofluorescence assays and electron microscopy that this protein is recruited to the DMV-anchored RTCs, for which its C terminus is essential. Live-cell imaging of infected cells demonstrated that small nsp2-positive structures move through the cytoplasm in a microtubule-dependent manner. In contrast, large fluorescent structures are rather immobile. Microtubule-mediated transport of DMVs, however, is not required for efficient replication. Biochemical analyses indicated that the nsp2 protein is associated with the cytoplasmic side of the DMVs. Yet, no recovery of fluorescence was observed when (part of) the nsp2-positive foci were bleached. This result was confirmed by the observation that preexisting RTCs did not exchange fluorescence after fusion of cells expressing either a green or a red fluorescent nsp2. Apparently, nsp2, once recruited to the RTCs, is not exchanged with nsp2 present in the cytoplasm or at other DMVs. Our data show a remarkable resemblance to results obtained recently by others with hepatitis C virus. The observations point to intriguing and as yet unrecognized similarities between the RTC dynamics of different plus-strand RNA viruses.
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  11. 11
    Liu, C., Zhou, Q., Li, Y., Garner, L. V., Watkins, S. P., Carter, L. J., Smoot, J., Gregg, A. C., Daniels, A. D., Jervey, S., and Albaiu, D. (2020) Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases. ACS Cent. Sci. 6 (3), 315– 331,  DOI: 10.1021/acscentsci.0c00272
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    Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases
    Liu, Cynthia; Zhou, Qiongqiong; Li, Yingzhu; Garner, Linda V.; Watkins, Steve P.; Carter, Linda J.; Smoot, Jeffrey; Gregg, Anne C.; Daniels, Angela D.; Jervey, Susan; Albaiu, Dana
    ACS Central Science (2020), 6 (3), 315-331CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
    A review. Since the outbreak of the novel coronavirus disease COVID-19, caused by the SARS-CoV-2 virus, this disease has spread rapidly around the globe. Considering the potential threat of a pandemic, scientists and physicians have been racing to understand this new virus and the pathophysiol. of this disease to uncover possible treatment regimens and discover effective therapeutic agents and vaccines. To support the current research and development, CAS has produced a special report to provide an overview of published scientific information with an emphasis on patents in the CAS content collection. It highlights antiviral strategies involving small mols. and biologics targeting complex mol. interactions involved in coronavirus infection and replication. The drug-repurposing effort documented herein focuses primarily on agents known to be effective against other RNA viruses including SARS-CoV and MERS-CoV. The patent anal. of coronavirus-related biologics includes therapeutic antibodies, cytokines, and nucleic acid-based therapies targeting virus gene expression as well as various types of vaccines. More than 500 patents disclose methodologies of these four biologics with the potential for treating and preventing coronavirus infections, which may be applicable to COVID-19. The information included in this report provides a strong intellectual groundwork for the ongoing development of therapeutic agents and vaccines.
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  12. 12
    de Haan, C. A., Kuo, L., Masters, P. S., Vennema, H., and Rottier, P. J. (1998) Coronavirus particle assembly: primary structure requirements of the membrane protein. J. Virol. 72 (8), 6838– 6850,  DOI: 10.1128/JVI.72.8.6838-6850.1998
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    12
    Coronavirus particle assembly: primary structure requirements of the membrane protein
    De Haan, Cornelis A. M.; Kuo, Lili; Masters, Paul S.; Vennema, Harry; Rottier, Peter J. M.
    Journal of Virology (1998), 72 (8), 6838-6850CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
    Coronavirus-like particles morphol. similar to normal virions are assembled when genes encoding the viral membrane proteins M and E are co-expressed in eukaryotic cells. Using this envelope assembly assay, we have studied the primary sequence requirements for particle formation of the mouse hepatitis virus (MHV) M protein, the major protein of the coronavirion membrane. Our results show that each of the different domains of the protein is important. Mutations (deletions, insertions, point mutations) in the luminal domain, the transmembrane domains, the amphiphilic domain, or the carboxy-terminal domain had effects on the assembly of M into enveloped particles. Strikingly, the extreme carboxy-terminal residue is crucial. Deletion of this single residue abolished particle assembly almost completely; most substitutions were strongly inhibitory. Site-directed mutations in the carboxy terminus of M were also incorporated into the MHV genome by targeted recombination. The results supported a crit. role for this domain of M in viral assembly, although the M carboxy terminus was more tolerant of alteration in the complete virion than in virus-like particles, likely because of the stabilization of virions by addnl. intermol. interactions. Interestingly, glycosylation of M appeared not to be essential for assembly. Mutations in the luminal domain that abolished the normal O glycosylation of the protein or created an N-glycosylated form had no effect. Mutant M proteins unable to form virus-like particles were found to inhibit the budding of assembly-competent M in a concn.-dependent manner. However, assembly-competent M was able to rescue assembly-incompetent M when the latter was present in low amts. These observations support the existence of interactions between M mols. that are thought to be the driving force in coronavirus envelope assembly.
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    Wu, Z. and McGoogan, J. M. J. J. (2020) Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 323 (13), 1239– 1242,  DOI: 10.1001/jama.2020.2648
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    13
    Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China summary of a report of 72,314 cases from the Chinese center for disease control and prevention
    Wu, Zunyou; McGoogan, Jennifer M.
    JAMA, the Journal of the American Medical Association (2020), 323 (13), 1239-1242CODEN: JAMAAP; ISSN:1538-3598. (American Medical Association)
    The Chinese Center for Disease Control and Prevention recently published the largest case series to date of coronavirus disease 2019 (COVID-19) in mainland China (72,314 cases, updated through Feb. 11, 2020). This Viewpoint summarizes key findings from this report and discusses emerging understanding of and lessons from the COVID-19 epidemic.
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  14. 14
    Yang, X., Yu, Y., Xu, J., Shu, H., Xia, J., Liu, H., Wu, Y., Zhang, L., Yu, Z., Fang, M., Yu, T., Wang, Y., Pan, S., Zou, X., Yuan, S., and Shang, Y. (2020) Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir. Med.  DOI: 10.1016/S2213-2600(20)30079-5
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    Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., Xiang, J., Wang, Y., Song, B., Gu, X., Guan, L., Wei, Y., Li, H., Wu, X., Xu, J., Tu, S., Zhang, Y., Chen, H., and Cao, B. (2020) Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395 (10229), 1054– 1062,  DOI: 10.1016/S0140-6736(20)30566-3
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    15
    Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study
    Zhou, Fei; Yu, Ting; Du, Ronghui; Fan, Guohui; Liu, Ying; Liu, Zhibo; Xiang, Jie; Wang, Yeming; Song, Bin; Gu, Xiaoying; Guan, Lulu; Wei, Yuan; Li, Hui; Wu, Xudong; Xu, Jiuyang; Tu, Shengjin; Zhang, Yi; Chen, Hua; Cao, Bin
    Lancet (2020), 395 (10229), 1054-1062CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)
    Since Dec., 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiol. and clin. characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clin. course of illness, including viral shedding, have not been well described. In this retrospective, multicenter cohort study, we included all adult inpatients (≥18 yr old) with lab.-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demog., clin., treatment, and lab. data, including serial samples for viral RNA detection, were extd. from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors assocd. with in-hospital death. One hundred ninety-one patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. Ninety-one (48%) patients had a comorbidity, with hypertension being the most common (58 patients), followed by diabetes (36 patients) and coronary heart disease (15 patients). Multivariable regression showed increasing odds of in-hospital death assocd. with older age, higher Sequential Organ Failure Assessment (SOFA) score, and d-dimer >1μg/L on admission. Median duration of viral shedding was 20·0 days (IQR 17·0-24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest obsd. duration of viral shedding in survivors was 37 days. The potential risk factors of older age, high SOFA score, and d-dimer >1μg/L could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.
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    Jiang, F., Deng, L., Zhang, L., Cai, Y., Cheung, C. W., and Xia, Z. (2020) Review of the clinical characteristics of coronavirus disease 2019 (COVID-19). J. Gen Intern Med. 1– 5,  DOI: 10.1007/s11606-020-05762-w
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    Kuba, K., Imai, Y., Rao, S., Gao, H., Guo, F., Guan, B., Huan, Y., Yang, P., Zhang, Y., Deng, W., Bao, L., Zhang, B., Liu, G., Wang, Z., Chappell, M., Liu, Y., Zheng, D., Leibbrandt, A., Wada, T., Slutsky, A. S., Liu, D., Qin, C., Jiang, C., and Penninger, J. M. (2005) A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat. Med. 11 (8), 875– 879,  DOI: 10.1038/nm1267
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    A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury
    Kuba, Keiji; Imai, Yumiko; Rao, Shuan; Gao, Hong; Guo, Feng; Guan, Bin; Huan, Yi; Yang, Peng; Zhang, Yanli; Deng, Wei; Bao, Linlin; Zhang, Binlin; Liu, Guang; Wang, Zhong; Chappell, Mark; Liu, Yanxin; Zheng, Dexian; Leibbrandt, Andreas; Wada, Teiji; Slutsky, Arthur S.; Liu, Depei; Qin, Chuan; Jiang, Chengyu; Penninger, Josef M.
    Nature Medicine (New York, NY, United States) (2005), 11 (8), 875-879CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
    During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world. A new coronavirus (SARS-CoV) was identified as the SARS pathogen, which triggered severe pneumonia and acute, often lethal, lung failure. Moreover, among infected individuals influenza such as the Spanish flu and the emergence of new respiratory disease viruses have caused high lethality resulting from acute lung failure. In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor. The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biol. weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a mol. explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses.
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    Zhang, H., Penninger, J. M., Li, Y., Zhong, N., and Slutsky, A. S. (2020) Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 46 (4), 586– 590,  DOI: 10.1007/s00134-020-05985-9
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    18
    Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target
    Zhang, Haibo; Penninger, Josef M.; Li, Yimin; Zhong, Nanshan; Slutsky, Arthur S.
    Intensive Care Medicine (2020), 46 (4), 586-590CODEN: ICMED9; ISSN:0342-4642. (Springer)
    A review. A novel infectious disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was detected in Wuhan, China, in Dec. 2019. The disease (COVID-19) spread rapidly, reaching epidemic proportions in China, and has been found in 27 other countries. As of Feb. 27, 2020, over 82,000 cases of COVID-19 were reported, with > 2800 deaths. No specific therapeutics are available, and current management includes travel restrictions, patient isolation, and supportive medical care. There are a no. of pharmaceuticals already being tested, but a better understanding of the underlying pathobiol. is required. In this context, this article will brief review the rationale for angiotensin-converting enzyme 2 (ACE2) receptor as a specific target.
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    Wang, X., Dhindsa, R., Povysil, G., Zoghbi, A., Motelow, J., Hostyk, J., and Goldstein, D. (2020) Transcriptional inhibition of host viral entry proteins as a therapeutic strategy for SARS-CoV-2. Preprints, 2020030360,  DOI: 10.20944/preprints202003.0360.v1 .
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    Andersen, K. G., Rambaut, A., Lipkin, W. I., Holmes, E. C., and Garry, R. F. (2020) The proximal origin of SARS-CoV-2. Nat. Med. 26 (4), 450– 452,  DOI: 10.1038/s41591-020-0820-9
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    The proximal origin of SARS-CoV-2
    Andersen, Kristian G.; Rambaut, Andrew; Lipkin, W. Ian; Holmes, Edward C.; Garry, Robert F.
    Nature Medicine (New York, NY, United States) (2020), 26 (4), 450-452CODEN: NAMEFI; ISSN:1078-8956. (Nature Research)
    There is no expanded citation for this reference.
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    Cao, B., Wang, Y., Wen, D., Liu, W., Wang, J., Fan, G., Ruan, L., Song, B., Cai, Y., Wei, M., Li, X., Xia, J., Chen, N., Xiang, J., Yu, T., Bai, T., Xie, X., Zhang, L., Li, C., Yuan, Y., Chen, H., Li, H., Huang, H., Tu, S., Gong, F., Liu, Y., Wei, Y., Dong, C., Zhou, F., Gu, X., Xu, J., Liu, Z., Zhang, Y., Li, H., Shang, L., Wang, K., Li, K., Zhou, X., Dong, X., Qu, Z., Lu, S., Hu, X., Ruan, S., Luo, S., Wu, J., Peng, L., Cheng, F., Pan, L., Zou, J., Jia, C., Wang, J., Liu, X., Wang, S., Wu, X., Ge, Q., He, J., Zhan, H., Qiu, F., Guo, L., Huang, C., Jaki, T., Hayden, F. G., Horby, P. W., Zhang, D., and Wang, C. (2020) A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N. Engl. J. Med.  DOI: 10.1056/NEJMoa2001282
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    Kawase, M., Shirato, K., van der Hoek, L., Taguchi, F., and Matsuyama, S. (2012) Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry. J. Virol 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)
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      Bats are natural reservoirs of SARS-like coronaviruses
      Li, Wendong; Shi, Zhengli; Yu, Meng; Ren, Wuze; Smith, Craig; Epstein, Jonathan H.; Wang, Hanzhong; Crameri, Gary; Hu, Zhihong; Zhang, Huajun; Zhang, Jianhong; McEachern, Jennifer; Field, Hume; Daszak, Peter; Eaton, Bryan T.; Zhang, Shuyi; Wang, Lin-Fa
      Science (Washington, DC, United States) (2005), 310 (5748), 676-679CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      Severe acute respiratory syndrome (SARS) emerged in 2002 to 2003 in southern China. The origin of its etiol. agent, the SARS coronavirus (SARS-CoVs), remains elusive. Here, the authors report that species of bats are a natural host of coronaviruses closely related to those responsible for the SARS outbreak. These viruses, termed SARS-like coronaviruses (SL-CoV), display greater genetic variation than SARS-CoV isolated from humans or from civets. The human and civet isolates of SARS-CoV nestle phylogenetically within the spectrum of SL-CoVs, indicating that the virus responsible for the SARS outbreak was a member of this coronavirus group.
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    6. 6
      Ejima, K., Omori, R., Cowling, B. J., Aihara, K., and Nishiura, H. (2012) The time required to estimate the case fatality ratio of influenza using only the tip of an iceberg: joint estimation of the virulence and the transmission potential. Comput. Math Methods Med. 2012, 978901,  DOI: 10.1155/2012/978901
      6
      The time required to estimate the case fatality ratio of influenza using only the tip of an iceberg: joint estimation of the virulence and the transmission potential
      Ejima Keisuke; Omori Ryosuke; Cowling Benjamin J; Aihara Kazuyuki; Nishiura Hiroshi
      Computational and mathematical methods in medicine (2012), 2012 (), 978901 ISSN:.
      Estimating the case fatality ratio (CFR) of a novel strain of influenza virus during the early stage of the pandemic is one of key epidemiological tasks to be conducted as rapid research response. Past experience during the epidemics of severe acute respiratory syndrome (SARS) and influenza A (H1N1-2009) posed several technical challenges in estimating the CFR in real time. The present study aimed to develop a simple method to estimate the CFR based on readily available datasets, that is, confirmed cases and deaths, while addressing some of the known technical issues. To assess the reliability and validity of the proposed method, we examined the minimum length of time required for the assigned CFR to be included within the 95% confidence intervals and for the estimated CFR to be below a prespecified cut-off value by means of Monte Carlo simulations. Overall, the smaller the transmission potential was, the longer it took to compare the estimated CFR against the cut-off value. If policymaking and public health response have to be made based on the CFR estimate derived from the proposed method and readily available data, it should be noted that the successful estimation may take longer than a few months.
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    7. 7
      Coronaviridae Study Group of the International Committee on Taxonomy of Viruses (2020) The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 5 (4), 536– 544,  DOI: 10.1038/s41564-020-0695-z
      7
      The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2
      Coronaviridae Study Group of the International Committee on Taxonomy of Viruses
      Nature Microbiology (2020), 5 (4), 536-544CODEN: NMAICH; ISSN:2058-5276. (Nature Research)
      A review. The present outbreak of a coronavirus-assocd. acute respiratory disease called coronavirus disease 19 (COVID-19) is the third documented spillover of an animal coronavirus to humans in only two decades that has resulted in a major epidemic. The Coronaviridae Study Group (CSG) of the International Committee on Taxonomy of Viruses, which is responsible for developing the classification of viruses and taxon nomenclature of the family Coronaviridae, has assessed the placement of the human pathogen, tentatively named 2019-nCoV, within the Coronaviridae. Based on phylogeny, taxonomy and established practice, the CSG recognizes this virus as forming a sister clade to the prototype human and bat severe acute respiratory syndrome coronaviruses (SARS-CoVs) of the species Severe acute respiratory syndrome-related coronavirus, and designates it as SARS-CoV-2. In order to facilitate communication, the CSG proposes to use the following naming convention for individual isolates: SARS-CoV-2/host/location/isolate/date. While the full spectrum of clin. manifestations assocd. with SARS-CoV-2 infections in humans remains to be detd., the independent zoonotic transmission of SARS-CoV and SARS-CoV-2 highlights the need for studying viruses at the species level to complement research focused on individual pathogenic viruses of immediate significance. This will improve our understanding of virus-host interactions in an ever-changing environment and enhance our preparedness for future outbreaks.
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    8. 8
      Hoffmann, M., Kleine-Weber, H., Schroeder, S., Kruger, N., Herrler, T., Erichsen, S., Schiergens, T. S., Herrler, G., Wu, N. H., Nitsche, A., Muller, M. A., Drosten, C., and Pohlmann, S. (2020) SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181 (2), 271– 280,  DOI: 10.1016/j.cell.2020.02.052
      8
      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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    9. 9
      Knoops, K., Kikkert, M., Worm, S. H., Zevenhoven-Dobbe, J. C., van der Meer, Y., Koster, A. J., Mommaas, A. M., and Snijder, E. J. (2008) SARS-coronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum. PLoS Biol. 6 (9), e226  DOI: 10.1371/journal.pbio.0060226
      There is no corresponding record for this reference.
    10. 10
      Hagemeijer, M. C., Verheije, M. H., Ulasli, M., Shaltiel, I. A., de Vries, L. A., Reggiori, F., Rottier, P. J., and de Haan, C. A. (2010) Dynamics of coronavirus replication-transcription complexes. J. Virol. 84 (4), 2134– 2149,  DOI: 10.1128/JVI.01716-09
      10
      Dynamics of coronavirus replication-transcription complexes
      Hagemeijer Marne C; Verheije Monique H; Ulasli Mustafa; Shaltiel Indra A; de Vries Lisa A; Reggiori Fulvio; Rottier Peter J M; de Haan Cornelis A M
      Journal of virology (2010), 84 (4), 2134-49 ISSN:.
      Coronaviruses induce in infected cells the formation of double-membrane vesicles (DMVs) in which the replication-transcription complexes (RTCs) are anchored. To study the dynamics of these coronavirus replicative structures, we generated recombinant murine hepatitis coronaviruses that express tagged versions of the nonstructural protein nsp2. We demonstrated by using immunofluorescence assays and electron microscopy that this protein is recruited to the DMV-anchored RTCs, for which its C terminus is essential. Live-cell imaging of infected cells demonstrated that small nsp2-positive structures move through the cytoplasm in a microtubule-dependent manner. In contrast, large fluorescent structures are rather immobile. Microtubule-mediated transport of DMVs, however, is not required for efficient replication. Biochemical analyses indicated that the nsp2 protein is associated with the cytoplasmic side of the DMVs. Yet, no recovery of fluorescence was observed when (part of) the nsp2-positive foci were bleached. This result was confirmed by the observation that preexisting RTCs did not exchange fluorescence after fusion of cells expressing either a green or a red fluorescent nsp2. Apparently, nsp2, once recruited to the RTCs, is not exchanged with nsp2 present in the cytoplasm or at other DMVs. Our data show a remarkable resemblance to results obtained recently by others with hepatitis C virus. The observations point to intriguing and as yet unrecognized similarities between the RTC dynamics of different plus-strand RNA viruses.
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    11. 11
      Liu, C., Zhou, Q., Li, Y., Garner, L. V., Watkins, S. P., Carter, L. J., Smoot, J., Gregg, A. C., Daniels, A. D., Jervey, S., and Albaiu, D. (2020) Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases. ACS Cent. Sci. 6 (3), 315– 331,  DOI: 10.1021/acscentsci.0c00272
      11
      Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases
      Liu, Cynthia; Zhou, Qiongqiong; Li, Yingzhu; Garner, Linda V.; Watkins, Steve P.; Carter, Linda J.; Smoot, Jeffrey; Gregg, Anne C.; Daniels, Angela D.; Jervey, Susan; Albaiu, Dana
      ACS Central Science (2020), 6 (3), 315-331CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
      A review. Since the outbreak of the novel coronavirus disease COVID-19, caused by the SARS-CoV-2 virus, this disease has spread rapidly around the globe. Considering the potential threat of a pandemic, scientists and physicians have been racing to understand this new virus and the pathophysiol. of this disease to uncover possible treatment regimens and discover effective therapeutic agents and vaccines. To support the current research and development, CAS has produced a special report to provide an overview of published scientific information with an emphasis on patents in the CAS content collection. It highlights antiviral strategies involving small mols. and biologics targeting complex mol. interactions involved in coronavirus infection and replication. The drug-repurposing effort documented herein focuses primarily on agents known to be effective against other RNA viruses including SARS-CoV and MERS-CoV. The patent anal. of coronavirus-related biologics includes therapeutic antibodies, cytokines, and nucleic acid-based therapies targeting virus gene expression as well as various types of vaccines. More than 500 patents disclose methodologies of these four biologics with the potential for treating and preventing coronavirus infections, which may be applicable to COVID-19. The information included in this report provides a strong intellectual groundwork for the ongoing development of therapeutic agents and vaccines.
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    12. 12
      de Haan, C. A., Kuo, L., Masters, P. S., Vennema, H., and Rottier, P. J. (1998) Coronavirus particle assembly: primary structure requirements of the membrane protein. J. Virol. 72 (8), 6838– 6850,  DOI: 10.1128/JVI.72.8.6838-6850.1998
      12
      Coronavirus particle assembly: primary structure requirements of the membrane protein
      De Haan, Cornelis A. M.; Kuo, Lili; Masters, Paul S.; Vennema, Harry; Rottier, Peter J. M.
      Journal of Virology (1998), 72 (8), 6838-6850CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
      Coronavirus-like particles morphol. similar to normal virions are assembled when genes encoding the viral membrane proteins M and E are co-expressed in eukaryotic cells. Using this envelope assembly assay, we have studied the primary sequence requirements for particle formation of the mouse hepatitis virus (MHV) M protein, the major protein of the coronavirion membrane. Our results show that each of the different domains of the protein is important. Mutations (deletions, insertions, point mutations) in the luminal domain, the transmembrane domains, the amphiphilic domain, or the carboxy-terminal domain had effects on the assembly of M into enveloped particles. Strikingly, the extreme carboxy-terminal residue is crucial. Deletion of this single residue abolished particle assembly almost completely; most substitutions were strongly inhibitory. Site-directed mutations in the carboxy terminus of M were also incorporated into the MHV genome by targeted recombination. The results supported a crit. role for this domain of M in viral assembly, although the M carboxy terminus was more tolerant of alteration in the complete virion than in virus-like particles, likely because of the stabilization of virions by addnl. intermol. interactions. Interestingly, glycosylation of M appeared not to be essential for assembly. Mutations in the luminal domain that abolished the normal O glycosylation of the protein or created an N-glycosylated form had no effect. Mutant M proteins unable to form virus-like particles were found to inhibit the budding of assembly-competent M in a concn.-dependent manner. However, assembly-competent M was able to rescue assembly-incompetent M when the latter was present in low amts. These observations support the existence of interactions between M mols. that are thought to be the driving force in coronavirus envelope assembly.
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    13. 13
      Wu, Z. and McGoogan, J. M. J. J. (2020) Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 323 (13), 1239– 1242,  DOI: 10.1001/jama.2020.2648
      13
      Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China summary of a report of 72,314 cases from the Chinese center for disease control and prevention
      Wu, Zunyou; McGoogan, Jennifer M.
      JAMA, the Journal of the American Medical Association (2020), 323 (13), 1239-1242CODEN: JAMAAP; ISSN:1538-3598. (American Medical Association)
      The Chinese Center for Disease Control and Prevention recently published the largest case series to date of coronavirus disease 2019 (COVID-19) in mainland China (72,314 cases, updated through Feb. 11, 2020). This Viewpoint summarizes key findings from this report and discusses emerging understanding of and lessons from the COVID-19 epidemic.
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    14. 14
      Yang, X., Yu, Y., Xu, J., Shu, H., Xia, J., Liu, H., Wu, Y., Zhang, L., Yu, Z., Fang, M., Yu, T., Wang, Y., Pan, S., Zou, X., Yuan, S., and Shang, Y. (2020) Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir. Med.  DOI: 10.1016/S2213-2600(20)30079-5
      There is no corresponding record for this reference.
    15. 15
      Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., Xiang, J., Wang, Y., Song, B., Gu, X., Guan, L., Wei, Y., Li, H., Wu, X., Xu, J., Tu, S., Zhang, Y., Chen, H., and Cao, B. (2020) Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395 (10229), 1054– 1062,  DOI: 10.1016/S0140-6736(20)30566-3
      15
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study
      Zhou, Fei; Yu, Ting; Du, Ronghui; Fan, Guohui; Liu, Ying; Liu, Zhibo; Xiang, Jie; Wang, Yeming; Song, Bin; Gu, Xiaoying; Guan, Lulu; Wei, Yuan; Li, Hui; Wu, Xudong; Xu, Jiuyang; Tu, Shengjin; Zhang, Yi; Chen, Hua; Cao, Bin
      Lancet (2020), 395 (10229), 1054-1062CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)
      Since Dec., 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiol. and clin. characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clin. course of illness, including viral shedding, have not been well described. In this retrospective, multicenter cohort study, we included all adult inpatients (≥18 yr old) with lab.-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demog., clin., treatment, and lab. data, including serial samples for viral RNA detection, were extd. from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors assocd. with in-hospital death. One hundred ninety-one patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. Ninety-one (48%) patients had a comorbidity, with hypertension being the most common (58 patients), followed by diabetes (36 patients) and coronary heart disease (15 patients). Multivariable regression showed increasing odds of in-hospital death assocd. with older age, higher Sequential Organ Failure Assessment (SOFA) score, and d-dimer >1μg/L on admission. Median duration of viral shedding was 20·0 days (IQR 17·0-24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest obsd. duration of viral shedding in survivors was 37 days. The potential risk factors of older age, high SOFA score, and d-dimer >1μg/L could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.
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    16. 16
      Jiang, F., Deng, L., Zhang, L., Cai, Y., Cheung, C. W., and Xia, Z. (2020) Review of the clinical characteristics of coronavirus disease 2019 (COVID-19). J. Gen Intern Med. 1– 5,  DOI: 10.1007/s11606-020-05762-w
      There is no corresponding record for this reference.
    17. 17
      Kuba, K., Imai, Y., Rao, S., Gao, H., Guo, F., Guan, B., Huan, Y., Yang, P., Zhang, Y., Deng, W., Bao, L., Zhang, B., Liu, G., Wang, Z., Chappell, M., Liu, Y., Zheng, D., Leibbrandt, A., Wada, T., Slutsky, A. S., Liu, D., Qin, C., Jiang, C., and Penninger, J. M. (2005) A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat. Med. 11 (8), 875– 879,  DOI: 10.1038/nm1267
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      A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury
      Kuba, Keiji; Imai, Yumiko; Rao, Shuan; Gao, Hong; Guo, Feng; Guan, Bin; Huan, Yi; Yang, Peng; Zhang, Yanli; Deng, Wei; Bao, Linlin; Zhang, Binlin; Liu, Guang; Wang, Zhong; Chappell, Mark; Liu, Yanxin; Zheng, Dexian; Leibbrandt, Andreas; Wada, Teiji; Slutsky, Arthur S.; Liu, Depei; Qin, Chuan; Jiang, Chengyu; Penninger, Josef M.
      Nature Medicine (New York, NY, United States) (2005), 11 (8), 875-879CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
      During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world. A new coronavirus (SARS-CoV) was identified as the SARS pathogen, which triggered severe pneumonia and acute, often lethal, lung failure. Moreover, among infected individuals influenza such as the Spanish flu and the emergence of new respiratory disease viruses have caused high lethality resulting from acute lung failure. In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor. The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biol. weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a mol. explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses.
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    18. 18
      Zhang, H., Penninger, J. M., Li, Y., Zhong, N., and Slutsky, A. S. (2020) Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 46 (4), 586– 590,  DOI: 10.1007/s00134-020-05985-9
      18
      Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target
      Zhang, Haibo; Penninger, Josef M.; Li, Yimin; Zhong, Nanshan; Slutsky, Arthur S.
      Intensive Care Medicine (2020), 46 (4), 586-590CODEN: ICMED9; ISSN:0342-4642. (Springer)
      A review. A novel infectious disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was detected in Wuhan, China, in Dec. 2019. The disease (COVID-19) spread rapidly, reaching epidemic proportions in China, and has been found in 27 other countries. As of Feb. 27, 2020, over 82,000 cases of COVID-19 were reported, with > 2800 deaths. No specific therapeutics are available, and current management includes travel restrictions, patient isolation, and supportive medical care. There are a no. of pharmaceuticals already being tested, but a better understanding of the underlying pathobiol. is required. In this context, this article will brief review the rationale for angiotensin-converting enzyme 2 (ACE2) receptor as a specific target.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXkt1erurY%253D&md5=705f72887420f24bdc15084bb6fdf193
    19. 19
      Wang, X., Dhindsa, R., Povysil, G., Zoghbi, A., Motelow, J., Hostyk, J., and Goldstein, D. (2020) Transcriptional inhibition of host viral entry proteins as a therapeutic strategy for SARS-CoV-2. Preprints, 2020030360,  DOI: 10.20944/preprints202003.0360.v1 .
      There is no corresponding record for this reference.
    20. 20
      Andersen, K. G., Rambaut, A., Lipkin, W. I., Holmes, E. C., and Garry, R. F. (2020) The proximal origin of SARS-CoV-2. Nat. Med. 26 (4), 450– 452,  DOI: 10.1038/s41591-020-0820-9
      20
      The proximal origin of SARS-CoV-2
      Andersen, Kristian G.; Rambaut, Andrew; Lipkin, W. Ian; Holmes, Edward C.; Garry, Robert F.
      Nature Medicine (New York, NY, United States) (2020), 26 (4), 450-452CODEN: NAMEFI; ISSN:1078-8956. (Nature Research)
      There is no expanded citation for this reference.
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    21. 21
      Cao, B., Wang, Y., Wen, D., Liu, W., Wang, J., Fan, G., Ruan, L., Song, B., Cai, Y., Wei, M., Li, X., Xia, J., Chen, N., Xiang, J., Yu, T., Bai, T., Xie, X., Zhang, L., Li, C., Yuan, Y., Chen, H., Li, H., Huang, H., Tu, S., Gong, F., Liu, Y., Wei, Y., Dong, C., Zhou, F., Gu, X., Xu, J., Liu, Z., Zhang, Y., Li, H., Shang, L., Wang, K., Li, K., Zhou, X., Dong, X., Qu, Z., Lu, S., Hu, X., Ruan, S., Luo, S., Wu, J., Peng, L., Cheng, F., Pan, L., Zou, J., Jia, C., Wang, J., Liu, X., Wang, S., Wu, X., Ge, Q., He, J., Zhan, H., Qiu, F., Guo, L., Huang, C., Jaki, T., Hayden, F. G., Horby, P. W., Zhang, D., and Wang, C. (2020) A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N. Engl. J. Med.  DOI: 10.1056/NEJMoa2001282
      There is no corresponding record for this reference.
    22. 22
      Kawase, M., Shirato, K., van der Hoek, L., Taguchi, F., and Matsuyama, S. (2012) Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry. J. Virol 86 (12), 6537– 6545,  DOI: 10.1128/JVI.00094-12
      22
      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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    23. 23
      Jeon, S., Ko, M., Lee, J., Choi, I., Byun, S. Y., Park, S., Shum, D., and Kim, S. (2020) Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs. bioRxiv,  DOI: 10.1101/2020.03.20.999730 .
      There is no corresponding record for this reference.
    24. 24
      Zhang, L., Lin, D., Kusov, Y., Nian, Y., Ma, Q., Wang, J., von Brunn, A., Leyssen, P., Lanko, K., Neyts, J., de Wilde, A., Snijder, E. J., Liu, H., and Hilgenfeld, R. (2020) Alpha-ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication: structure-based design, synthesis, and activity assessment. J. Med. Chem.  DOI: 10.1021/acs.jmedchem.9b01828
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      Hilgenfeld, R. (2014) From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design. FEBS J. 281 (18), 4085– 4096,  DOI: 10.1111/febs.12936
      25
      From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design
      Hilgenfeld, Rolf
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      A review. Here, the author focuses on the important contributions that macromol. crystallog. has made over the past 12 yr to elucidating structures and mechanisms of the essential proteases of coronaviruses, the main protease (Mpro) and the papain-like protease (PLpro). The role of x-ray crystallog. in structure-assisted drug discovery against these targets is discussed. Aspects dealt with in this review include the emergence of the SARS coronavirus in 2002-2003 and of the MERS coronavirus 10 yr later and the origins of these viruses. The crystal structure of the free SARS coronavirus Mpro and its dependence on pH is discussed, as are efforts to design inhibitors on the basis of these structures. The mechanism of maturation of the enzyme from the viral polyprotein is still a matter of debate. The crystal structure of the SARS coronavirus PLpro and its complex with ubiquitin is also discussed, as is its ortholog from MERS coronavirus. Efforts at predictive structure-based inhibitor development for bat coronavirus Mpros to increase the preparedness against zoonotic transmission to man are described as well. The paper closes with a brief discussion of structure-based discovery of antivirals in an academic setting.
      >> More from SciFinder ®
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      Gao, Y., Yan, L., Huang, Y., Liu, F., Zhao, Y., Cao, L., Wang, T., Sun, Q., Ming, Z., Zhang, L., Ge, J., Zheng, L., Zhang, Y., Wang, H., Zhu, Y., Zhu, C., Hu, T., Hua, T., Zhang, B., Yang, X., Li, J., Yang, H., Liu, Z., Xu, W., Guddat, L. W., Wang, Q., Lou, Z., and Rao, Z. (2020) Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science eabb7498  DOI: 10.1126/science.abb7498
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  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsinfecdis.0c00224.

    • Tables showing viral outbreaks since year 2000, different targets expressed in SARS-CoV-2 proteome, unique therapeutic interventions in recruiting and nonrecruiting clinical studies for COVID-19, and structures of select approved or investigational drugs tested for drug repurposing against SARS-CoV-2; structures of the novel inhibitors obtained from the PDB for SARS-CoV-2 Mpro (PDF)


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