Cannabinoids Block Cellular Entry of SARS-CoV-2 and the Emerging Variants

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This article references 49 other publications.

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   Journal of pharmaceutical analysis (2020), 10 (4), 313-319 ISSN:.

   The recent pandemic of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has raised global health concerns. The viral 3-chymotrypsin-like cysteine protease (3CL(pro)) enzyme controls coronavirus replication and is essential for its life cycle. 3CL(pro) is a proven drug discovery target in the case of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Recent studies revealed that the genome sequence of SARS-CoV-2 is very similar to that of SARS-CoV. Therefore, herein, we analysed the 3CL(pro) sequence, constructed its 3D homology model, and screened it against a medicinal plant library containing 32,297 potential anti-viral phytochemicals/traditional Chinese medicinal compounds. Our analyses revealed that the top nine hits might serve as potential anti- SARS-CoV-2 lead molecules for further optimisation and drug development process to combat COVID-19.
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   Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; Cheng, Z.; Yu, T.; Xia, J.; Wei, Y.; Wu, W.; Xie, X.; Yin, W.; Li, H.; Liu, M.; Xiao, Y.; Gao, H.; Guo, L.; Xie, J.; Wang, G.; Jiang, R.; Gao, Z.; Jin, Q.; Wang, J.; Cao, B. Lancet 2020, 395, 497– 506,  DOI: 10.1016/S0140-6736(20)30183-5

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   Lancet (2020), 395 (10223), 497-506CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)

   A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiol., clin., lab., and radiol. characteristics and treatment and clin. outcomes of these patients. All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analyzed data on patients with lab.-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiol. and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. By Jan 2, 2020, 41 admitted hospital patients had been identified as having lab.-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0-58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum prodn. (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0-13·0]). 26 (63%) Of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was assocd. with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiol., duration of human transmission, and clin. spectrum of disease need fulfilment by future studies. Ministry of Science and Technol., Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technol. Commission.
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   Nature (London, United Kingdom) (2020), 579 (7798), 265-269CODEN: NATUAS; ISSN:0028-0836. (Nature Research)

   Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health. Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 Jan. 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 Dec. 2019. Epidemiol. investigations have suggested that the outbreak was assocd. with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 Dec. 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here 'WH-Human 1' coronavirus (and has also been referred to as '2019-nCoV'). Phylogenetic anal. of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China. This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.
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   Neutralizing Antibodies against SARS-CoV-2 and Other Human Coronaviruses

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   Trends in Immunology (2020), 41 (5), 355-359CODEN: TIRMAE; ISSN:1471-4906. (Elsevier Ltd.)

   A review. Coronavirus (CoV) disease 2019 (COVID-19) caused by severe acute respiratory syndrome (SARS)-CoV-2 (also known as 2019-nCoV) is threatening global public health, social stability, and economic development. To meet this challenge, this article discusses advances in the research and development of neutralizing antibodies (nAbs) for the prevention and treatment of infection by SARS-CoV-2 and other human CoVs.
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   Pathogens (2020), 9 (3), 231CODEN: PATHCD; ISSN:2076-0817. (MDPI AG)

   In Dec. 2019, a cluster of fatal pneumonia cases presented in Wuhan, China. They were caused by a previously unknown coronavirus. All patients had been assocd. with the Wuhan Wholefood market, where seafood and live animals are sold. The virus spread rapidly and public health authorities in China initiated a containment effort. However, by that time, travelers had carried the virus to many countries, sparking memories of the previous coronavirus epidemics, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), and causing widespread media attention and panic. Based on clin. criteria and available serol. and mol. information, the new disease was called coronavirus disease of 2019 (COVID-19), and the novel coronavirus was called SARS Coronavirus-2 (SARS-CoV-2), emphasizing its close relationship to the 2002 SARS virus (SARS-CoV). The scientific community raced to uncover the origin of the virus, understand the pathogenesis of the disease, develop treatment options, define the risk factors, and work on vaccine development. Here we present a summary of current knowledge regarding the novel coronavirus and the disease it causes.
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   Cellular & Molecular Immunology (2020), 17 (6), 613-620CODEN: CMIEAO; ISSN:1672-7681. (Nature Research)

   The outbreak of Coronavirus Disease 2019 (COVID-19) has posed a serious threat to global public health, calling for the development of safe and effective prophylactics and therapeutics against infection of its causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as 2019 novel coronavirus (2019-nCoV). The CoV spike (S) protein plays the most important roles in viral attachment, fusion and entry, and serves as a target for development of antibodies, entry inhibitors and vaccines. Here, we identified the receptor-binding domain (RBD) in SARS-CoV-2 S protein and found that the RBD protein bound strongly to human and bat angiotensin-converting enzyme 2 (ACE2) receptors. SARS-CoV-2 RBD exhibited significantly higher binding affinity to ACE2 receptor than SARS-CoV RBD and could block the binding and, hence, attachment of SARS-CoV-2 RBD and SARS-CoV RBD to ACE2-expressing cells, thus inhibiting their infection to host cells. SARS-CoV RBD-specific antibodies could cross-react with SARS-CoV-2 RBD protein, and SARS-CoV RBD-induced antisera could cross-neutralize SARS-CoV-2, suggesting the potential to develop SARS-CoV RBD-based vaccines for prevention of SARS-CoV-2 and SARS-CoV infection.
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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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    Guo, Yan-Rong; Cao, Qing-Dong; Hong, Zhong-Si; Tan, Yuan-Yang; Chen, Shou-Deng; Jin, Hong-Jun; Tan, Kai-Sen; Wang, De-Yun; Yan, Yan

    Military Medical Research (2020), 7 (1), 11CODEN: MMRICN; ISSN:2054-9369. (BioMed Central Ltd.)

    A review. An acute respiratory disease, caused by a novel coronavirus (SARS-CoV-2, previously known as 2019-nCoV), the coronavirus disease 2019 (COVID-19) has spread throughout China and received worldwide attention. On 30 Jan. 2020, World Health Organization (WHO) officially declared the COVID-19 epidemic as a public health emergency of international concern. The emergence of SARS-CoV-2, since the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, marked the 3rd introduction of a highly pathogenic and large-scale epidemic coronavirus into the human population in the 21st century. As of 1 March 2020, a total of 87,137 confirmed cases globally, 79,968 confirmed in China and 7169 outside of China, with 2977 deaths (3.4%) had been reported by WHO. Meanwhile, several independent research groups have identified that SARS-CoV-2 belongs to β-coronavirus, with highly identical genome to bat coronavirus, pointing to bat as the natural host. The novel coronavirus uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as that for SARS-CoV, and mainly spreads through the respiratory tract. Importantly, increasingly evidence showed sustained human-to-human transmission, along with many exported cases across the globe. The clin. symptoms of COVID-19 patients include fever, cough, fatigue, and a small population of patients appeared gastrointestinal infection symptoms. The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes, which may be assocd. with acute respiratory distress syndrome (ARDS) and cytokine storm. Currently, there are few specific antiviral strategies, but several potent candidates of antivirals and repurposed drugs are under urgent investigation. We summarized the latest research progress of the epidemiol., pathogenesis, and clin. characteristics of COVID-19, and discussed the current treatment and scientific advancements to combat the epidemic novel coronavirus.
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    A review. Severe acute respiratory syndrome (SARS) is a newly emerging infectious disease caused by a novel coronavirus, SARS-coronavirus (SARS-CoV). The SARS-CoV spike (S) protein is composed of two subunits; the S1 subunit contains a receptor-binding domain that engages with the host cell receptor angiotensin-converting enzyme 2 and the S2 subunit mediates fusion between the viral and host cell membranes. The S protein plays key parts in the induction of neutralizing-antibody and T-cell responses, as well as protective immunity, during infection with SARS-CoV. In this Review, we highlight recent advances in the development of vaccines and therapeutics based on the S protein.
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    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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    Yuan, K.; Yi, L.; Chen, J.; Qu, X.; Qing, T.; Rao, X.; Jiang, P.; Hu, J.; Xiong, Z.; Nie, Y.; Shi, X.; Wang, W.; Ling, C.; Yin, X.; Fan, K.; Lai, L.; Ding, M.; Deng, H. Biochem. Biophys. Res. Commun. 2004, 319, 746– 752,  DOI: 10.1016/j.bbrc.2004.05.046

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    Suppression of SARS-CoV entry by peptides corresponding to heptad regions on spike glycoprotein

    Yuan, Kehu; Yi, Ling; Chen, Jian; Qu, Xiuxia; Qing, Tingting; Rao, Xi; Jiang, Pengfei; Hu, Jianhe; Xiong, Zikai; Nie, Yuchun; Shi, Xuanling; Wang, Wei; Chen, Ling; Yin, Xiaolei; Fan, Keqiang; Lai, Luhua; Ding, Mingxiao; Deng, Hongkui

    Biochemical and Biophysical Research Communications (2004), 319 (3), 746-752CODEN: BBRCA9; ISSN:0006-291X. (Elsevier Science)

    Heptad repeat regions (HR1 and HR2) are highly conserved sequences located in the glycoproteins of enveloped viruses. They form a six-helix bundle structure and are important in the process of virus fusion. Peptides derived from the HR regions of some viruses have been shown to inhibit the entry of these viruses. SARS-CoV was also predicted to have HR1 and HR2 regions in the S2 protein. Based on this prediction, we designed 25 peptides and screened them using a HIV-luc/SARS pseudotyped virus assay. Two peptides, HR1-1 and HR2-18, were identified as potential inhibitors, with EC50 values of 0.14 and 1.19 μM, resp. The inhibitory effects of these peptides were validated by the wild-type SARS-CoV assay. HR1-1 and HR2-18 can serve as functional probes for dissecting the fusion mechanism of SARS-CoV and also provide the potential of further identifying potent inhibitors for SARS-CoV entry.
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    Antiviral drugs: current state of the art

    De Clercq, E.

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    A review. The chemotherapy of virus infections has definitely come of age. There are now 15 antiviral agents that have been formally licensed for the treatment of human immunodeficiency virus infections (zidovudine, didanosine, zalcitabine, stavudine, Lamivudine, Abacavir, Nevirapine, Delavirdine, Efavirenz, Saquinavir, Ritonavir, Indinavir, Nelfinavir, Amprenavir, Lopinavir) and several others, such as Tenofovir Disoproxil, Emtricitabine, Capravirine, Emivirine, T-20 (Pentafuside), and AMD3100 (bicyclam), are under clin. development. Lamivudine has been approved, and several other compds. (such as Adefovir Dipivoxil, Emtricitabine, and Entecavir) are under clin. development, for the treatment of hepatitis B virus infections. Among the anti-herpesvirus agents, Aciclovir, Valaciclovir, Penciclovir, Famciclovir, Idoxuridine, Trifluridine, and Brivudin are used in the treatment of herpes simplex virus and varicella-zoster virus infections, and Ganciclovir, Foscarnet, Cidofovir, Fomivirsen, and Maribavir (the latter in the developmental stage) are used in the treatment of cytomegalovirus infections. Following amantadine and Rimantadine, the neuraminidase inhibitors, Zanamivir and Oseltamivir, have now become available for the therapy and prophylaxis of influenza virus infections, and so is Ribavirin for the treatment of respiratory syncytial virus infections and the combination of Ribavirin with interferon-α for the treatment of hepatitis C virus infections.
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    VanCompernolle, S. E.; Wiznycia, A. V.; Rush, J. R.; Dhanasekaran, M.; Baures, P. W.; Todd, S. C. Virology 2003, 314, 371– 380,  DOI: 10.1016/S0042-6822(03)00406-9

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    Virology (2003), 314 (1), 371-380CODEN: VIRLAX; ISSN:0042-6822. (Elsevier Science)

    The hepatitis C virus (HCV) is a causal agent of chronic liver infection, cirrhosis, and hepatocellular carcinoma infecting more than 170 million people. CD81 is a receptor for HCV envelope glycoprotein E2. Although the binding of HCV-E2 with CD81 is well documented the role of this interaction in the viral life cycle remains unclear. Host specificity and mutagenesis studies suggest that the helix D region of CD81 mediates binding to HCV-E2. Structural anal. of CD81 has enabled the synthesis of small mols. designed to mimic the space and hydrophobic features of the solvent-exposed face on helix D. Utilizing a novel bis-imidazole scaffold a series of over 100 compds. has been synthesized. Seven related, imidazole-based compds. were identified that inhibit binding of HCV-E2 to CD81. The inhibitory compds. have no short-term effect on cellular expression of CD81 or other tetraspanins, do not disrupt CD81 assocns. with other cell surface proteins, and bind reversibly to HCV-E2. These results provide an important proof of concept that CD81-based mimics can disrupt binding of HCV-E2 to CD81.
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    A review. Nature has been a source of medicinal agents for thousands of years and continues to be an abundant source of novel chemotypes and pharmacophores. With only 5 to 15% of the approx. 250 000 species of higher plants systematically investigated, and the potential of the marine environment barely tapped, these areas will remain a rich source of novel bioactive compds. Less than 1% of bacterial and 5% of fungal species are currently known, and the potential of novel microbial sources, particularly those found in extreme environments, seems unbounded. To these natural sources can be added the potential to investigate the rational design of novel structure types within certain classes of microbial metabolites through genetic engineering. It is apparent that Nature can provide the novel chem. scaffolds for elaboration by combinatorial approaches (chem. and biochem.), thus leading to agents that have been optimized on the basis of their pharmacol. activities. The proven natural product drug discovery track record, coupled with the continuing threat to biodiversity through the destruction of terrestrial and marine ecosystems and the current low no. of new chem. entities in pharmaceutical industry pipelines, provides a compelling argument in favor of expanded multidisciplinary and international collaboration in the exploration of Nature as a source of novel leads for the development of drugs and other valuable bioactive agents.
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    Metabolites (2012), 2 (2), 303-336CODEN: METALU; ISSN:2218-1989. (MDPI AG)

    A review. Historically, natural products have been used since ancient times and in folklore for the treatment of many diseases and illnesses. Classical natural product chem. methodologies enabled a vast array of bioactive secondary metabolites from terrestrial and marine sources to be discovered. Many of these natural products have gone on to become current drug candidates. This brief review aims to highlight historically significant bioactive marine and terrestrial natural products, their use in folklore and dereplication techniques to rapidly facilitate their discovery. Furthermore a discussion of how natural product chem. has resulted in the identification of many drug candidates; the application of advanced hyphenated spectroscopic techniques to aid in their discovery, the future of natural product chem. and finally adopting metabolomic profiling and dereplication approaches for the comprehensive study of natural product exts. will be discussed.
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    Antibacterial natural products in medicinal chemistry - exodus or revival?

    von Nussbaum, Franz; Brands, Michael; Hinzen, Berthold; Weigand, Stefan; Haebich, Dieter

    Angewandte Chemie, International Edition (2006), 45 (31), 5072-5129CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

    A review. To create a drug, nature's blueprints often have to be improved through semi-synthesis or total synthesis (chem. post-evolution). Selected contributions from industrial and academic groups highlight the arduous but rewarding path from natural products to drugs. Principle modification types for natural products to drugs. Principle modification types for natural products are discussed herein, such as decoration, substitution, and degrdn. The biol., chem., and socioeconomic environments of antibacterial research are dealt with in context. Natural products, many from soil organisms, have provided the majority of lead structures for marketed anti-infectives. Surprisingly, numerous "old" classes of antibacterial natural products have never been intensively explored by medical chemists. Nevertheless, research on antibacterial natural products is flagging. Apparently, the "old fashioned" natural products no longer fit into modern drug discovery. The handling of natural products is cumbersome, requiring nonstandardized workflows and extended timelines. Revisiting natural products with modern chem. and target-finding tools from biol. (reversed genomics) is one option for their revival.
21. 21

    Mishra, B. B.; Tiwari, V. K. Eur. J. Med. Chem. 2011, 46, 4769– 4807,  DOI: 10.1016/j.ejmech.2011.07.057

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    21

    Natural products: An evolving role in future drug discovery

    Mishra, Bhuwan B.; Tiwari, Vinod K.

    European Journal of Medicinal Chemistry (2011), 46 (10), 4769-4807CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)

    A review. The therapeutic areas of infectious diseases and oncol. have benefited from abundant scaffold diversity in natural products, able to interact with many specific targets within the cell and indeed for many years have been source or inspiration for the majority of FDA approved drugs. The present review describes natural products (NPs), semi-synthetic NPs and NP-derived compds. that have undergone clin. evaluation or registration from 2005 to 2010 by disease area i.e. infectious (bacterial, fungal, parasitic and viral), immunol., cardiovascular, neurol., inflammatory and related diseases and oncol.
22. 22

    Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2016, 79, 629– 661,  DOI: 10.1021/acs.jnatprod.5b01055

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    Natural Products as Sources of New Drugs from 1981 to 2014

    Newman, David J.; Cragg, Gordon M.

    Journal of Natural Products (2016), 79 (3), 629-661CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)

    This contribution is a completely updated and expanded version of the four prior analogous reviews that were published in this journal in 1997, 2003, 2007, and 2012. In the case of all approved therapeutic agents, the time frame has been extended to cover the 34 years from Jan. 1, 1981, to Dec. 31, 2014, for all diseases worldwide, and from 1950 (earliest so far identified) to Dec. 2014 for all approved antitumor drugs worldwide. As mentioned in the 2012 review, we have continued to utilize our secondary subdivision of a "natural product mimic", or "NM", to join the original primary divisions and the designation "natural product botanical", or "NB", to cover those botanical "defined mixts." now recognized as drug entities by the U.S. FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over the time frame from around the 1940s to the end of 2014, of the 175 small mols. approved, 131, or 75%, are other than "S" (synthetic), with 85, or 49%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. We wish to draw the attention of readers to the rapidly evolving recognition that a significant no. of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore it is considered that this area of natural product research should be expanded significantly.
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    Kanjanasirirat, P.; Suksatu, A.; Manopwisedjaroen, S.; Munyoo, B.; Tuchinda, P.; Jearawuttanakul, K.; Seemakhan, S.; Charoensutthivarakul, S.; Wongtrakoongate, P.; Rangkasenee, N.; Pitiporn, S.; Waranuch, N.; Chabang, N.; Khemawoot, P.; Sa-Ngiamsuntorn, K.; Pewkliang, Y.; Thongsri, P.; Chutipongtanate, S.; Hongeng, S.; Borwornpinyo, S.; Thitithanyanont, A. Sci. Rep. 2020, 10, 19963,  DOI: 10.1038/s41598-020-77003-3

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    High-content screening of Thai medicinal plants reveals Boesenbergia rotunda extract and its component Panduratin A as anti-SARS-CoV-2 agents

    Kanjanasirirat, Phongthon; Suksatu, Ampa; Manopwisedjaroen, Suwimon; Munyoo, Bamroong; Tuchinda, Patoomratana; Jearawuttanakul, Kedchin; Seemakhan, Sawinee; Charoensutthivarakul, Sitthivut; Wongtrakoongate, Patompon; Rangkasenee, Noppawan; Pitiporn, Supaporn; Waranuch, Neti; Chabang, Napason; Khemawoot, Phisit; Sa-ngiamsuntorn, Khanit; Pewkliang, Yongyut; Thongsri, Piyanoot; Chutipongtanate, Somchai; Hongeng, Suradej; Borwornpinyo, Suparerk; Thitithanyanont, Arunee

    Scientific Reports (2020), 10 (1), 19963CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)

    Abstr.: Since Dec. 2019, the emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused severe pneumonia, a disease named COVID-19, that became pandemic and created an acute threat to public health. The effective therapeutics are in urgent need. Here, we developed a high-content screening for the antiviral candidates using fluorescence-based SARS-CoV-2 nucleoprotein detection in Vero E6 cells coupled with plaque redn. assay. Among 122 Thai natural products, we found that Boesenbergia rotunda ext. and its phytochem. compd., panduratin A, exhibited the potent anti-SARS-CoV-2 activity. Treatment with B. rotunda ext. and panduratin A after viral infection drastically suppressed SARS-CoV-2 infectivity in Vero E6 cells with IC50 of 3.62μg/mL (CC50 = 28.06μg/mL) and 0.81μΜ (CC50 = 14.71μM), resp. Also, the treatment of panduratin A at the pre-entry phase inhibited SARS-CoV-2 infection with IC50 of 5.30μM (CC50 = 43.47μM). Our study demonstrated, for the first time, that panduratin A exerts the inhibitory effect against SARS-CoV-2 infection at both pre-entry and post-infection phases. Apart from Vero E6 cells, treatment with this compd. was able to suppress viral infectivity in human airway epithelial cells. This result confirmed the potential of panduratin A as the anti-SARS-CoV-2 agent in the major target cells in human. Since B. rotunda is a culinary herb generally grown in China and Southeast Asia, its ext. and the purified panduratin A may serve as the promising candidates for therapeutic purposes with economic advantage during COVID-19 situation.
24. 24

    Muchiri, R. N.; van Breemen, R. B. J. Mass Spectrom. 2021, 56, e4647,  DOI: 10.1002/jms.4647

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    Affinity selection-mass spectrometry for the discovery of pharmacologically active compounds from combinatorial libraries and natural products

    Muchiri, Ruth N.; van Breemen, Richard B.

    Journal of Mass Spectrometry (2021), 56 (5), e4647CODEN: JMSPFJ; ISSN:1076-5174. (John Wiley & Sons Ltd.)

    A review. Invented to address the high-throughput screening (HTS) demands of combinatorial chem., affinity selection-mass spectrometry (AS-MS) utilizes binding interactions between ligands and receptors to isolate pharmacol. active compds. from mixts. of small mols. and then relies on the selectivity, sensitivity, and speed of mass spectrometry to identify them. No radiolabels, fluorophores, or chromophores are required. Although many variations of AS-MS have been devised, three approaches have emerged as the most flexible, productive, and popular, and they differ primarily in how ligand-receptor complexes are sepd. from nonbinding compds. in the mixt. These are pulsed ultrafiltration (PUF) AS-MS, size exclusion chromatog. (SEC) AS-MS, and magnetic microbead affinity selection screening (MagMASS). PUF and SEC AS-MS are soln.-phase screening approaches, and MagMASS uses receptors immobilized on magnetic microbeads. Because pools of compds. are screened using AS-MS, each contg. hundreds to thousands of potential ligands, hundreds of thousands of compds. can be screened per day. AS-MS is also compatible with complex mixts. of chem. diverse natural products in exts. of botanicals and fungi and microbial cultures, which often contain fluorophores and chromophores that can interfere with convention HTS. Unlike conventional HTS, AS-MS may be used to discover ligands binding to allosteric as well as orthosteric receptor sites, and AS-MS has been useful for discovering ligands to targets that are not easily incorporated into conventional HTS such as membrane-bound receptors.
25. 25

    van Breemen, R. B.; Huang, C. R.; Nikolic, D.; Woodbury, C. P.; Zhao, Y. Z.; Venton, D. L. Anal. Chem. 1997, 69, 2159– 2164,  DOI: 10.1021/ac970132j

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    Pulsed Ultrafiltration Mass Spectrometry: A New Method for Screening Combinatorial Libraries

    van Breemen, Richard B.; Huang, Chao-Ran; Nikolic, Dejan; Woodbury, Charles P.; Zhao, Yong-Zhong; Venton, Duane L.

    Analytical Chemistry (1997), 69 (11), 2159-2164CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)

    In response to the need for rapid screening of combinatorial libraries to identify new lead compds. during drug discovery, we have developed an online combination of ultrafiltration and electrospray mass spectrometry, called pulsed ultrafiltration mass spectrometry, which facilitates the identification of soln.-phase ligands in library mixts. that bind to soln.-phase receptors. After ligands contained in a library mixt. were bound to a macromol. receptor, e.g., human serum albumin or calf intestine adenosine deaminase, the ligand-receptor complexes were purified by ultrafiltration and then dissocd. using methanol to elute the ligands into the electrospray mass spectrometer for detection. Ligands with dissocn. consts. in the micromolar to nanomolar range were successfully bound, released, and detected using this method, including warfarin, salicylate, furosemide, and thyroxine binding to human serum albumin, and erythro-9-(2-hydroxy-3-nonyl)adenine binding to calf intestine adenosine deaminase. Repetitive bind-and-release expts. demonstrated that the receptor could be reused. Thus, pulsed ultrafiltration mass spectrometry was shown to provide a simple and powerful new method for the screening of combinatorial libraries in support of new drug discovery.
26. 26

    Kaur, S.; McGuire, L.; Tang, D.; Dollinger, G.; Huebner, V. J. Protein Chem. 1997, 16, 505– 511,  DOI: 10.1023/A:1026369729393

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    Affinity selection and mass spectrometry-based strategies to identify lead compounds in combinatorial libraries

    Kaur, Surinder; McGuire, Lisa; Tang, Dazhi; Dollinger, Gavin; Huebner, Verena

    Journal of Protein Chemistry (1997), 16 (5), 505-511CODEN: JPCHD2; ISSN:0277-8033. (Plenum)

    The screening of diverse libraries of small mols. created by combinatorial synthetic methods is a recent development which has the potential to accelerate the identification of lead compds. in drug discovery. We developed a direct and rapid method to identify lead compds. in libraries involving affinity selection and mass spectrometry. In our strategy, the receptor or target mol. of interest is used to isolate the active components from the library phys., followed by direct structural identification of the active compds. bound to the target mol. by mass spectrometry. In a drug design strategy, structurally diverse libraries can be used for the initial identification of lead compds. Once lead compds. have been identified, libraries contg. compds. chem. similar to the lead compd. can be generated and used to optimize the binding characteristics. These strategies have also been adopted for more detailed studies of protein-ligand interactions.
27. 27

    Choi, Y.; van Breemen, R. B. Combin. Chem. High Throughput Screen. 2008, 11, 1– 6,  DOI: 10.2174/138620708783398340

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    Development of a screening assay for ligands to the estrogen receptor based on magnetic microparticles and LC-MS

    Choi, Yongsoo; van Breemen, Richard B.

    Combinatorial Chemistry & High Throughput Screening (2008), 11 (1), 1-6CODEN: CCHSFU; ISSN:1386-2073. (Bentham Science Publishers Ltd.)

    A high throughput screening assay for the identification of ligands to pharmacol. significant receptors was developed based on magnetic particles contg. immobilized receptors followed by liq. chromatog.-mass spectrometry (LC-MS). This assay is suitable for the screening of complex mixts. such as botanical exts. For proof-of-principle, estrogen receptor-α (ER-α) and ER-β were immobilized on magnetic particles functionalized with aldehyde or carboxylic acid groups. Alternatively, biotinylated ER was immobilized onto streptavidin-derivitized magnetic particles. The ER that was immobilized using the streptavidin-biotin chem. showed higher activity than that immobilized on aldehyde or carboxylic acid functionalized magnetic particles. Immobilized ER was incubated with exts. of Trifolium pratense (red clover) or Humulus lupulus (hops). As a control for non-specific binding, each botanical ext. was incubated with magnetic particles contg. no ER. After magnetic sepn. of the particles contg. bound ligands from the unbound components in the ext., the particles were washed, ligands were released using methanol, and then the ligands were identified using LC-MS. The estrogens genistein and daidzein were identified in the red clover ext., and the estrogen 8-prenylnaringenin was identified in the hop ext. These screening results are consistent with those obtained using previous screening approaches.
28. 28

    Rush, M. D.; Walker, E. M.; Prehna, G.; Burton, T.; van Breemen, R. B. J. Am. Soc. Mass Spectrom. 2017, 28, 479– 448,  DOI: 10.1007/s13361-016-1564-0

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    Development of a Magnetic Microbead Affinity Selection Screen (MagMASS) Using Mass Spectrometry for Ligands to the Retinoid X Receptor-α

    Rush, Michael D.; Walker, Elisabeth M.; Prehna, Gerd; Burton, Tristesse; van Breemen, Richard B.

    Journal of the American Society for Mass Spectrometry (2017), 28 (3), 479-485CODEN: JAMSEF; ISSN:1044-0305. (Springer)

    To overcome limiting factors in mass spectrometry-based screening methods such as automation while still facilitating the screening of complex mixts. such as botanical exts., magnetic microbead affinity selection screening (MagMASS) was developed. The screening process involves immobilization of a target protein on a magnetic microbead using a variety of possible chemistries, incubation with mixts. of mols. contg. possible ligands, a washing step that removes nonbound compds. while a magnetic field retains the beads in the microtiter well, and an org. solvent release step followed by LC-MS anal. Using retinoid X receptor-α (RXRα) as an example, which is a nuclear receptor and target for anti-inflammation therapy as well as cancer treatment and prevention, a MagMASS assay was developed and compared with an existing screening assay, pulsed ultrafiltration (PUF)-MS. Optimization of MagMASS involved evaluation of multiple protein constructs and several magnetic bead immobilization chemistries. The full-length RXRα construct immobilized with amylose beads provided optimum results. Addnl. enhancements of MagMASS were the application of 96-well plates to enable automation, use of UHPLC instead of HPLC for faster MS analyses, and application of metabolomics software for faster, automated data anal. Performance of MagMASS was demonstrated using mixts. of synthetic compds. and known ligands spiked into botanical exts.
29. 29

    van Breemen, R. B. Curr. Trends Mass Spectrom. 2020, 18, 18– 25

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    Affinity selection-mass spectrometry: defining the bioactive compounds in complex mixtures of natural products and combinatorial libraries

    van Breemen, Richard

    Current Trends in Mass Spectrometry (2020), 18 (1), 18-25CODEN: CTMSAX ISSN:. (MultiMedia Pharma Sciences, LLC)

    Drug discovery from combinatorial libraries typically utilizes high-throughput screening of discreet compds., and the discovery of natural products with pharmacol. mechanisms of action relies on bioassay-guided fractionation. Both processes can be expedited through the application of affinity selection-mass spectrometry (AS-MS). AS-MS includes a family of MS-based affinity screening methods, including pulsed ultrafiltration (PUF)-AS-MS, size exclusion chromatog. AS-MS, and magnetic microbead affinity selection screening (MagMASS). All AS-MS approaches begin by incubating a pharmacol. important receptor with a mixt. of possible ligands, sepg. the ligand-receptor complexes from non-binding mols. (the approaches differ in this sepn. step), and then using LC-MS to characterize the affinity-extd. ligands. The speed, selectivity, and sensitivity of mass spectrometry and ultrahigh-pressure liq. chromatog. (UHPLC)-compatible MS ionization techniques, like electrospray and atm. pressure chem. ionization, make AS-MS ideal for characterizing ligands. Recent applications of AS-MS include allosteric as well as orthosteric ligand discovery, and finding ligands to membrane-bound proteins and RNA targets.
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    Citti, C.; Linciano, P.; Panseri, S.; Vezzalini, F.; Forni, F.; Vandelli, M. A.; Cannazza, G. Front. Plant Sci. 2019, 10, 120,  DOI: 10.3389/fpls.2019.00120

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    Cannabinoid Profiling of Hemp Seed Oil by Liquid Chromatography Coupled to High-Resolution Mass Spectrometry

    Citti Cinzia; Linciano Pasquale; Vezzalini Francesca; Forni Flavio; Vandelli Maria Angela; Cannazza Giuseppe; Citti Cinzia; Cannazza Giuseppe; Panseri Sara

    Frontiers in plant science (2019), 10 (), 120 ISSN:1664-462X.

    Hemp seed oil is well known for its nutraceutical, cosmetic and pharmaceutical properties due to a perfectly balanced content of omega 3 and omega 6 polyunsaturated fatty acids. Its importance for human health is reflected by the success on the market of organic goods in recent years. However, it is of utmost importance to consider that its healthy properties are strictly related to its chemical composition, which varies depending not only on the manufacturing method, but also on the hemp variety employed. In the present work, we analyzed the chemical profile of ten commercially available organic hemp seed oils. Their cannabinoid profile was evaluated by a liquid chromatography method coupled to high-resolution mass spectrometry. Besides tetrahydrocannabinol and cannabidiol, other 30 cannabinoids were identified for the first time in hemp seed oil. The results obtained were processed according to an untargeted metabolomics approach. The multivariate statistical analysis showed highly significant differences in the chemical composition and, in particular, in the cannabinoid content of the hemp oils under investigation.
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    Hazekamp, A.; Fischedick, J. T.; Díez, M. L.; Lubbe, A.; Ruhaak, R. L. In Comprehensive Natural Products II; Mander, L.; Lui, H.-W.; Eds.; Elsevier: Oxford, UK, 2010; pp 1033– 1084.

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    Pellesi, L.; Licata, M.; Verri, P.; Vandelli, D.; Palazzoli, F.; Marchesi, F.; Cainazzo, M. M.; Pini, L. A.; Guerzoni, S. Eur. J. Clin. Pharmacol. 2018, 74, 1427– 1436,  DOI: 10.1007/s00228-018-2516-3

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    Pharmacokinetics and tolerability of oral cannabis preparations in patients with medication overuse headache (MOH)-a pilot study

    Pellesi, Lanfranco; Licata, Manuela; Verri, Patrizia; Vandelli, Daniele; Palazzoli, Federica; Marchesi, Filippo; Cainazzo, Maria Michela; Pini, Luigi Alberto; Guerzoni, Simona

    European Journal of Clinical Pharmacology (2018), 74 (11), 1427-1436CODEN: EJCPAS; ISSN:0031-6970. (Springer)

    Purpose: The recent release of a medical cannabis strain has given a new impulse for the study of cannabis in Italy. The National Health Service advises to consume medical cannabis by vaporizing, in decoction or oil form. This is the first study that explores the pharmacokinetics and tolerability of a single oral dose of cannabis as decoction (200 mL) or in olive oil (1 mL), as a first step to improve the prescriptive recommendations. Methods: This is a single-center, open-label, two-period crossover study designed to assess the pharmacokinetics and tolerability of oral cannabis administered to 13 patients with medication overuse headache (MOH). A liq. chromatog. tandem-mass spectrometry (LC-MS/MS) method was conducted for the quantification of THC, CBD, 11-OH-THC, THC-COOH, THC-COOH-glucuronide, THCA-A, and CBDA. Blood pressure, heart rate, and a short list of symptoms by numerical rating scale (NRS) were assessed. Results: Decoctions of cannabis showed high variability in cannabinoids content, compared to cannabis oil. For both prepns., THCA-A and CBDA were the most widely absorbed cannabinoids, while THC and CBD were less absorbed. The most important differences concern the bioavailability of THC, higher in oil (AUC0-24 7.44, 95% CI 5.19, 9.68) than in decoction (AUC0-24 3.34, 95% CI 2.07, 4.60), and the bioavailability of CBDA. No serious adverse events were reported. Conclusions: Cannabis decoction and cannabis oil showed different pharmacokinetic properties, as well as distinct consequences on patients. This study was performed in a limited no. of patients; future studies should be performed to investigate the clin. efficacy in larger populations.
33. 33

    https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms.

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    There is no corresponding record for this reference.
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    Sun, Y.; Gu, C.; Liu, X.; Liang, W.; Yao, P.; Bolton, J. L.; van Breemen, R. B. J. Am. Soc. Mass Spectrom. 2005, 16, 271– 279,  DOI: 10.1016/j.jasms.2004.11.002

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    Ultrafiltration tandem mass spectrometry of estrogens for characterization of structure and affinity for human estrogen receptors

    Sun, Yongkai; Gu, Chungang; Liu, Xuemei; Liang, Wenzhong; Yao, Ping; Bolton, Judy L.; van Breemen, Richard B.

    Journal of the American Society for Mass Spectrometry (2005), 16 (2), 271-279CODEN: JAMSEF; ISSN:1044-0305. (Elsevier Inc.)

    Although hormone replacement therapy (HRT) is used by post-menopausal women for the relief of menopausal symptoms and the potential redn. of osteoporosis, HRT also increases their risk of Alzheimer's disease, stroke, breast cancer, and endometrial cancer. Since the majority of these effects are assocd. primarily with estrogen binding to only one of the estrogen receptors (ER), new assays are needed that can more efficiently evaluate ER-binding and identify ligands selective for ER-α and ER-β. HPLC-tandem mass spectrometry (LC-MS-MS) was combined with ultrafiltration as a new method to investigate the relative binding of compds. to the ERs and to evaluate the structures of these estrogens. Mixts. of estradiol and six equine estrogens, including equilin, equilenin, 8,9-dehydroestrone, and their 17β-hydroxyl derivs., were assayed simultaneously to det. their relative binding to human ER-α and ER-β. Estrogens contg. a 17β-OH group were found to have higher relative affinities for the estrogen receptors than their ketone analogs. In addn., 17β-EN showed selectivity for binding to ER-β over ER-α. The results were compared to the IC50 values obtained by using a conventional radiolabeled estradiol competitive binding assay. Finally, the utility of neg. ion electrospray tandem mass spectrometry for the unambiguous identification of these estrogen isomers was investigated. Several characteristic recyclization pathways during tandem mass spectrometry were identified, which might be useful for distinguishing related estrogens.
35. 35

    Zhao, Y. Z.; van Breemen, R. B.; Nikolic, D.; Huang, C. R.; Woodbury, C. P.; Schilling, A.; Venton, D. L. J. Med. Chem. 1997, 40, 4006– 4012,  DOI: 10.1021/jm960729b

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    Screening Solution-Phase Combinatorial Libraries Using Pulsed Ultrafiltration/Electrospray Mass Spectrometry

    Zhao, Yong-Zhong; van Breemen, Richard B.; Nikolic, Dejan; Huang, Chao-Ran; Woodbury, Charles P.; Schilling, Alexander; Venton, Duane L.

    Journal of Medicinal Chemistry (1997), 40 (25), 4006-4012CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    A method is described whereby a family of homologues is synthesized in a one-pot reaction, without isolation or purifn., and the reaction mixt. is screened using a competitive binding assay based on pulsed ultrafiltration/electrospray mass spectrometry (PUF/ESMS) to tentatively identify those derivs. having the highest affinity for a target receptor. As a model system to test this approach, a synthetic scheme designed to prep. a series of analogs of the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), as diastereomeric mixts., was carried out. Pulsed ultrafiltration screening of the crude reaction mixt. against controls without protein detected protonated mols. corresponding to EHNA-type derivs. and three of its linear, alkyl homologues but did not show protonated mols. for an iso-Bu or benzylic EHNA deriv., suggesting the latter was inactive. To verify this conclusion, we prepd. E/THNA, the linear homologues, and the benzylic deriv. (each as a diastereomeric mixt.) and bioassayed them for their adenosine deaminase inhibition index ([I]/[S]0.5). The bioassay results for the individually synthesized analogs were in good agreement with that predicted by the obsd. relative ion enhancement in the PUF expts. Thus, the PUF protocol might be used as a general method to quickly provide direction to the chemist in search of drug candidates.
36. 36

    Liu, J.; Burdette, J. E.; Xu, H.; Gu, C.; van Breemen, R. B.; Bhat, K. P.; Booth, N.; Constantinou, A. I.; Pezzuto, J. M.; Fong, H. H.; Farnsworth, N. R.; Bolton, J. L. J. Agric. Food Chem. 2001, 49, 2472– 2479,  DOI: 10.1021/jf0014157

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    Evaluation of Estrogenic Activity of Plant Extracts for the Potential Treatment of Menopausal Symptoms

    Liu, Jianghua; Burdette, Joanna E.; Xu, Haiyan; Gu, Chungang; van Breemen, Richard B.; Bhat, Krishna P. L.; Booth, Nancy; Constantinou, Andreas I.; Pezzuto, John M.; Fong, Harry H. S.; Farnsworth, Norman R.; Bolton, Judy L.

    Journal of Agricultural and Food Chemistry (2001), 49 (5), 2472-2479CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)

    Eight botanical prepns. that are commonly used for the treatment of menopausal symptoms were tested for estrogenic activity. Methanol exts. of red clover (Trifolium pratense L.), chasteberry (Vitex agnus-castus L.), and hops (Humulus lupulus L.) showed significant competitive binding to estrogen receptors α (ERα) and β (ERβ). With cultured Ishikawa (endometrial) cells, red clover and hops exhibited estrogenic activity as indicated by induction of alk. phosphatase (AP) activity and up-regulation of progesterone receptor (PR) mRNA. Chasteberry also stimulated PR expression, but no induction of AP activity was obsd. In S30 breast cancer cells, pS2 (presenelin-2), another estrogen-inducible gene, was up-regulated in the presence of red clover, hops, and chasteberry. Interestingly, exts. of Asian ginseng (Panax ginseng C.A. Meyer) and North American ginseng (Panax quinquefolius L.) induced pS2 mRNA expression in S30 cells, but no significant ER binding affinity, AP induction, or PR expression was noted in Ishikawa cells. Dong quai [Angelica sinensis (Oliv.) Diels] and licorice (Glycyrrhiza glabra L.) showed only weak ER binding and PR and pS2 mRNA induction. Black cohosh [Cimicifuga racemosa (L.) Nutt.] showed no activity in any of the above in vitro assays. Bioassay-guided isolation utilizing ER competitive binding as a monitor and screening using ultrafiltration LC-MS revealed that genistein was the most active component of red clover. Consistent with this observation, genistein was the most effective of four red clover isoflavones tested in the above in vitro assays. Therefore, estrogenic components of plant exts. can be identified using assays for estrogenic activity along with screening and identification of the active components using ultrafiltration LC-MS. These data suggest a potential use for some dietary supplements, ingested by human beings, in the treatment of menopausal symptoms.
37. 37

    Rush, M. D.; Walker, E. M.; Burton, T.; van Breemen, R. B. J. Nat. Prod. 2016, 79, 2898– 2902,  DOI: 10.1021/acs.jnatprod.6b00693

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    Magnetic Microbead Affinity Selection Screening (MagMASS) of Botanical Extracts for Inhibitors of 15-Lipoxygenase

    Rush, Michael D.; Walker, Elisabeth M.; Burton, Tristesse; van Breemen, Richard B.

    Journal of Natural Products (2016), 79 (11), 2898-2902CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)

    To expedite the identification of active natural products in complex mixts. such as botanical exts., a Magnetic Microbead Affinity Selection Screening (MagMASS) procedure was developed. This technique utilizes target proteins immobilized on magnetic beads for rapid bioaffinity isolation of ligands from complex mixts. A MagMASS method was developed and validated for 15-lipoxygenase. As a proof of concept, several North American prairie plants used medicinally by Native Americans were extd. with MeOH and screened. A hit from an ext. of Proserpinaca palustris, also known as mermaid weed, was flagged for further characterization using high-resoln. tandem mass spectrometry, dereplication, and identification using XCMS online. Through the application of high-resoln. product ion tandem mass spectrometry, comparison with natural product databases and confirmation using stds., the hit was identified as quercitrin, which is a known inhibitor of 15-lipoxygenase. The overall workflow of MagMASS is faster and more amendable to automation than alternative methods designed for screening botanical exts. or complex mixts. of combinatorial libraries.
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    Wang, Q.; Zhang, Y.; Wu, L.; Niu, S.; Song, C.; Zhang, Z.; Lu, G.; Qiao, C.; Hu, Y.; Yuen, K. Y.; Wang, Q.; Zhou, H.; Yan, J.; Qi, J. Cell 2020, 181, 894– 904,  DOI: 10.1016/j.cell.2020.03.045

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    38

    Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2

    Wang, Qihui; Zhang, Yanfang; Wu, Lili; Niu, Sheng; Song, Chunli; Zhang, Zengyuan; Lu, Guangwen; Qiao, Chengpeng; Hu, Yu; Yuen, Kwok-Yung; Wang, Qisheng; Zhou, Huan; Yan, Jinghua; Qi, Jianxun

    Cell (Cambridge, MA, United States) (2020), 181 (4), 894-904.e9CODEN: CELLB5; ISSN:0092-8674. (Cell Press)

    The recent emergence of a novel coronavirus (SARS-CoV-2) in China has caused significant public health concerns. Recently, ACE2 was reported as an entry receptor for SARS-CoV-2. In this study, we present the crystal structure of the C-terminal domain of SARS-CoV-2 (SARS-CoV-2-CTD) spike (S) protein in complex with human ACE2 (hACE2), which reveals a hACE2-binding mode similar overall to that obsd. for SARS-CoV. However, at. details at the binding interface demonstrate that key residue substitutions in SARS-CoV-2-CTD slightly strengthen the interaction and lead to higher affinity for receptor binding than SARS-RBD. Addnl., a panel of murine monoclonal antibodies (mAbs) and polyclonal antibodies (pAbs) against SARS-CoV-S1/receptor-binding domain (RBD) were unable to interact with the SARS-CoV-2 S protein, indicating notable differences in antigenicity between SARS-CoV and SARS-CoV-2. These findings shed light on the viral pathogenesis and provide important structural information regarding development of therapeutic countermeasures against the emerging virus.
39. 39

    Yi, C.; Sun, X.; Ye, J.; Ding, L.; Liu, M.; Yang, Z.; Lu, X.; Zhang, Y.; Ma, L.; Gu, W.; Qu, A.; Xu, J.; Shi, Z.; Ling, Z.; Sun, B. Cell Mol. Immunol. 2020, 17, 621– 630,  DOI: 10.1038/s41423-020-0458-z

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    Key residues of the receptor binding motif in the spike protein of SARS-CoV-2 that interact with ACE2 and neutralizing antibodies

    Yi, Chunyan; Sun, Xiaoyu; Ye, Jing; Ding, Longfei; Liu, Meiqin; Yang, Zhuo; Lu, Xiao; Zhang, Yaguang; Ma, Liyang; Gu, Wangpeng; Qu, Aidong; Xu, Jianqing; Shi, Zhengli; Ling, Zhiyang; Sun, Bing

    Cellular & Molecular Immunology (2020), 17 (6), 621-630CODEN: CMIEAO; ISSN:1672-7681. (Nature Research)

    Abstr.: Coronavirus disease 2019 (COVID-19), caused by the novel human coronavirus SARS-CoV-2, is currently a major threat to public health worldwide. The viral spike protein binds the host receptor angiotensin-converting enzyme 2 (ACE2) via the receptor-binding domain (RBD), and thus is believed to be a major target to block viral entry. Both SARS-CoV-2 and SARS-CoV share this mechanism. Here we functionally analyzed the key amino acid residues located within receptor binding motif of RBD that may interact with human ACE2 and available neutralizing antibodies. The in vivo expts. showed that immunization with either the SARS-CoV RBD or SARS-CoV-2 RBD was able to induce strong clade-specific neutralizing antibodies in mice; however, the cross-neutralizing activity was much weaker, indicating that there are distinct antigenic features in the RBDs of the two viruses. This finding was confirmed with the available neutralizing monoclonal antibodies against SARS-CoV or SARS-CoV-2. It is worth noting that a newly developed SARS-CoV-2 human antibody, HA001, was able to neutralize SARS-CoV-2, but failed to recognize SARS-CoV. Moreover, the potential epitope residues of HA001 were identified as A475 and F486 in the SARS-CoV-2 RBD, representing new binding sites for neutralizing antibodies. Overall, our study has revealed the presence of different key epitopes between SARS-CoV and SARS-CoV-2, which indicates the necessity to develop new prophylactic vaccine and antibody drugs for specific control of the COVID-19 pandemic although the available agents obtained from the SARS-CoV study are unneglectable.
40. 40

    Tegally, H.; Wilkinson, E.; Giovanetti, M.; Iranzadeh, A.; Fonseca, V.; Giandhari, J.; Doolabh, D.; Pillay, S.; San, E. J.; Msomi, N.; Mlisana, K.; von Gottberg, A.; Walaza, S.; Allam, M.; Ismail, A.; Mohale, T.; Glass, A. J.; Engelbrecht, S.; Van Zyl, G.; Preiser, W.; Petruccione, F.; Sigal, A.; Hardie, D.; Marais, G.; Hsiao, N. Y.; Korsman, S.; Davies, M. A.; Tyers, L.; Mudau, I.; York, D.; Maslo, C.; Goedhals, D.; Abrahams, S.; Laguda-Akingba, O.; Alisoltani-Dehkordi, A.; Godzik, A.; Wibmer, C. K.; Sewell, B. T.; Lourenço, J.; Alcantara, L. C. J.; Kosakovsky Pond, S. L.; Weaver, S.; Martin, D.; Lessells, R. J.; Bhiman, J. N.; Williamson, C.; de Oliveira, T. Nature 2021, 592, 438– 443,  DOI: 10.1038/s41586-021-03402-9

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    Detection of a SARS-CoV-2 variant of concern in South Africa

    Tegally, Houriiyah; Wilkinson, Eduan; Giovanetti, Marta; Iranzadeh, Arash; Fonseca, Vagner; Giandhari, Jennifer; Doolabh, Deelan; Pillay, Sureshnee; San, Emmanuel James; Msomi, Nokukhanya; Mlisana, Koleka; von Gottberg, Anne; Walaza, Sibongile; Allam, Mushal; Ismail, Arshad; Mohale, Thabo; Glass, Allison J.; Engelbrecht, Susan; Van Zyl, Gert; Preiser, Wolfgang; Petruccione, Francesco; Sigal, Alex; Hardie, Diana; Marais, Gert; Hsiao, Nei-yuan; Korsman, Stephen; Davies, Mary-Ann; Tyers, Lynn; Mudau, Innocent; York, Denis; Maslo, Caroline; Goedhals, Dominique; Abrahams, Shareef; Laguda-Akingba, Oluwakemi; Alisoltani-Dehkordi, Arghavan; Godzik, Adam; Wibmer, Constantinos Kurt; Sewell, Bryan Trevor; Lourenco, Jose; Alcantara, Luiz Carlos Junior; Kosakovsky Pond, Sergei L.; Weaver, Steven; Martin, Darren; Lessells, Richard J.; Bhiman, Jinal N.; Williamson, Carolyn; de Oliveira, Tulio

    Nature (London, United Kingdom) (2021), 592 (7854), 438-443CODEN: NATUAS; ISSN:0028-0836. (Nature Portfolio)

    Continued uncontrolled transmission of SARS-CoV-2 in many parts of the world is creating conditions for substantial evolutionary changes to the virus. We describe a newly arisen lineage of SARS-CoV-2 (designated 501Y.V2; also known as B.1.351 or 20H) that is defined by 8 mutations in the spike protein, including 3 substitutions (K417N, E484K, and N501Y) at residues in its receptor-binding domain that may have functional importance. This lineage was identified in South Africa after the 1st wave of the epidemic in a severely affected metropolitan area (Nelson Mandela Bay) that is located on the coast of the Eastern Cape province. This lineage spread rapidly, and became dominant in Eastern Cape, Western Cape, and KwaZulu-Natal provinces within weeks. Although the full import of the mutations is yet to be detd., the genomic data, which show rapid expansion and displacement of other lineages in several regions, suggest that this lineage is assocd. with a selection advantage that most plausibly results from increased transmissibility or immune escape.
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    Wakshlag, J. J.; Schwark, W. S.; Deabold, K. A.; Talsma, B. N.; Cital, S.; Lyubimov, A.; Iqbal, A.; Zakharov, A. Front. Vet. Sci. 2020, 7, 505,  DOI: 10.3389/fvets.2020.00505

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    Pharmacokinetics of Cannabidiol, Cannabidiolic Acid, Δ9-Tetrahydrocannabinol, Tetrahydrocannabinolic Acid and Related Metabolites in Canine Serum After Dosing With Three Oral Forms of Hemp Extract

    Wakshlag Joseph J; Schwark Wayne S; Deabold Kelly A; Talsma Bryce N; Cital Stephen; Lyubimov Alex; Iqbal Asif; Zakharov Alexander

    Frontiers in veterinary science (2020), 7 (), 505 ISSN:2297-1769.

    Cannabidiol (CBD)-rich hemp extract use is increasing in veterinary medicine with little examination of serum cannabinoids. Many products contain small amounts of Δ9-tetrahydrocannabinol (THC), and precursor carboxylic acid forms of CBD and THC known as cannabidiolic acid (CBDA) and tetrahydrocannabinolic acid (THCA). Examination of the pharmacokinetics of CBD, CBDA, THC, and THCA on three oral forms of CBD-rich hemp extract that contained near equal amounts of CBD and CBDA, and minor amounts (<0.3% by weight) of THC and THCA in dogs was performed. In addition, we assess the metabolized psychoactive component of THC, 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and CBD metabolites 7-hydroxycannabidiol (7-OH-CBD) and 7-nor-7-carboxycannabidiol (7-COOH-CBD) to better understand the pharmacokinetic differences between three formulations regarding THC and CBD, and their metabolism. Six purpose-bred female beagles were utilized for study purposes, each having an initial 7-point, 24-h pharmacokinetic study performed using a dose of 2 mg/kg body weight of CBD/CBDA (~1 mg/kg CBD and ~1 mg/kg CBDA). Dogs were then dosed every 12 h for 2 weeks and had further serum analyses at weeks 1 and 2, 6 h after the morning dose to assess serum cannabinoids. Serum was analyzed for each cannabinoid or cannabinoid metabolite using liquid chromatography and tandem mass spectroscopy (LC-MS/MS). Regardless of the form provided (1, 2, or 3) the 24-h pharmacokinetics for CBD, CBDA, and THCA were similar, with only Form 2 generating enough data above the lower limit of quantitation to assess pharmacokinetics of THC. CBDA and THCA concentrations were 2- to 3-fold higher than CBD and THC concentrations, respectively. The 1- and 2-week steady-state concentrations were not significantly different between the two oils or the soft chew forms. CBDA concentrations were statistically higher with Form 2 than the other forms, showing superior absorption/retention of CBDA. Furthermore, Form 1 showed less THCA retention than either the soft chew Form 3 or Form 2 at weeks 1 and 2. THC was below the quantitation limit of the assay for nearly all samples. Overall, these findings suggest CBDA and THCA are absorbed or eliminated differently than CBD or THC, respectively, and that a partial lecithin base provides superior absorption and/or retention of CBDA and THCA.
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    Nguyen, L. C.; Yang, D.; Nicolaescu, V.; Best, T. J.; Ohtsuki, T.; Chen, S.-N.; Friesen, J. B.; Drayman, N.; Mohamed, A.; Dann, C.; Silva, D.; Gula, H.; Jones, K. A.; Millis, J. M.; Dickinson, B. C.; Tay, S.; Oakes, S. A.; Pauli, G. F.; Meltzer, D. O.; Randall, G.; Rosner, M. R. bioRxiv 2021, 2021.03.10.432967.

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    Tautenhahn, R.; Patti, G. J.; Rinehart, D.; Siuzdak, G. Anal. Chem. 2012, 84, 5035– 5039,  DOI: 10.1021/ac300698c

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    XCMS Online: A Web-Based Platform to Process Untargeted Metabolomic Data

    Tautenhahn, Ralf; Patti, Gary J.; Rinehart, Duane; Siuzdak, Gary

    Analytical Chemistry (Washington, DC, United States) (2012), 84 (11), 5035-5039CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)

    Recently, interest in untargeted metabolomics has become prevalent in the general scientific community among an increasing no. of investigators. The majority of these investigators, however, do not have the bioinformatic expertise that has been required to process metabolomic data by using command-line driven software programs. Here, we introduce a novel platform to process untargeted metabolomic data that uses an intuitive graphical interface and does not require installation or tech. expertise. This platform, called XCMS Online, is a web-based version of the widely used XCMS software that allows users to easily upload and process liq. chromatog./mass spectrometry data with only a few mouse clicks. XCMS Online provides a soln. for the complete untargeted metabolomic workflow including feature detection, retention time correction, alignment, annotation, statistical anal., and data visualization. Results can be browsed online in an interactive, customizable table showing statistics, chromatograms, and putative METLIN identities for each metabolite. Addnl., all results and images can be downloaded as zip files for offline anal. and publication. XCMS Online is available at https://xcmsonline.scripps.edu.
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    Trott, O.; Olson, A. J. J. Comput. Chem. 2009, 31, 455– 461,  DOI: 10.1002/jcc.21334

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    Berman, H. M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T. N.; Weissig, H.; Shindyalov, I. N.; Bourne, P. E. Nucleic Acids Res. 2000, 28, 235– 242,  DOI: 10.1093/nar/28.1.235

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    The Protein Data Bank

    Berman, Helen M.; Westbrook, John; Feng, Zukang; Gilliland, Gary; Bhat, T. N.; Weissig, Helge; Shindyalov, Ilya N.; Bourne, Philip E.

    Nucleic Acids Research (2000), 28 (1), 235-242CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)

    The Protein Data Bank (PDB; http://www.rcsb.org/pdb/)is the single worldwide archive of structural data of biol. macromols. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.
46. 46

    Bates, T. A.; Weinstein, J. B.; Farley, S.; Leier, H. C.; Messer, W. B.; Tafesse, F. G. Cell Reports 2021, 34 (7), 108737,  DOI: 10.1016/j.celrep.2021.108737

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    Cross-reactivity of SARS-CoV structural protein antibodies against SARS-CoV-2

    Bates, Timothy A.; Weinstein, Jules B.; Farley, Scotland; Leier, Hans C.; Messer, William B.; Tafesse, Fikadu G.

    Cell Reports (2021), 34 (7), 108737CODEN: CREED8; ISSN:2211-1247. (Cell Press)

    In the ongoing coronavirus disease 2019 (COVID-19) pandemic, there remain unanswered questions regarding the nature and significance of the humoral immune response toward other coronavirus infections. Here, we investigate the cross-reactivity of antibodies raised against the first severe acute respiratory syndrome coronavirus (SARS-CoV) for their reactivity toward SARS-CoV-2. We extensively characterize a selection of 10 antibodies covering all of the SARS-CoV structural proteins: spike, membrane, nucleocapsid, and envelope. Although nearly all of the examd. SARS-CoV antibodies display some level of reactivity to SARS-CoV-2, we find only partial cross-neutralization for the spike antibodies. The implications of our work are two-fold. First, we establish a set of antibodies with known reactivity to both SARS-CoV and SARS-CoV-2, which will allow further study of both viruses. Second, we provide empirical evidence of the high propensity for antibody cross-reactivity between distinct strains of human coronaviruses, which is crit. information for designing diagnostic and vaccine strategies for COVID-19.
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    Crawford, K. H. D.; Eguia, R.; Dingens, A. S.; Loes, A. N.; Malone, K. D.; Wolf, C. R.; Chu, H. Y.; Tortorici, M. A.; Veesler, D.; Murphy, M.; Pettie, D.; King, N. P.; Balazs, A. B.; Bloom, J. D. Viruses 2020, 12, 513,  DOI: 10.3390/v12050513

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    Protocol and reagents for pseudotyping lentiviral particles with SARS-CoV-2 spike protein for neutralization assays

    Crawford, Katharine H. D.; Eguia, Rachel; Dingens, Adam S.; Loes, Andrea N.; Malone, Keara D.; Wolf, Caitlin R.; Chu, Helen Y.; Tortorici, M. Alejandra; Veesler, David; Murphy, Michael; Pettie, Deleah; King, Neil P.; Balazs, Alejandro B.; Bloom, Jesse D.

    Viruses (2020), 12 (5), 513CODEN: VIRUBR; ISSN:1999-4915. (MDPI AG)

    SARS-CoV-2 enters cells using its Spike protein, which is also the main target of neutralizing antibodies. Therefore, assays to measure how antibodies and sera affect Spike-mediated viral infection are important for studying immunity. Because SARS-CoV-2 is a biosafety-level-3 virus, one way to simplify such assays is to pseudotype biosafety-level-2 viral particles with Spike. Such pseudotyping has now been described for single-cycle lentiviral, retroviral, and vesicular stomatitis virus (VSV) particles, but the reagents and protocols are not widely available. Here, we detailed how to effectively pseudotype lentiviral particles with SARS-CoV-2 Spike and infect 293T cells engineered to express the SARS-CoV-2 receptor, ACE2. We also made all the key exptl. reagents available in the BEI Resources repository of ATCC and the NIH. Furthermore, we demonstrated how these pseudotyped lentiviral particles could be used to measure the neutralizing activity of human sera or plasma against SARS-CoV-2 in convenient luciferase-based assays, thereby providing a valuable complement to ELISA-based methods that measure antibody binding rather than neutralization.
48. 48

    Case, J. B.; Bailey, A. L.; Kim, A. S.; Chen, R. E.; Diamond, M. S. Virology 2020, 548, 39– 48,  DOI: 10.1016/j.virol.2020.05.015

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    Growth, detection, quantification, and inactivation of SARS-CoV-2

    Case, James Brett; Bailey, Adam L.; Kim, Arthur S.; Chen, Rita E.; Diamond, Michael S.

    Virology (2020), 548 (), 39-48CODEN: VIRLAX; ISSN:0042-6822. (Elsevier B.V.)

    Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 is the agent responsible for the coronavirus disease 2019 (COVID-19) global pandemic. SARS-CoV-2 is closely related to SARS-CoV, which caused the 2003 SARS outbreak. Although numerous reagents were developed to study SARS-CoV infections, few have been applicable to evaluating SARS-CoV-2 infection and immunity. Current limitations in studying SARS-CoV-2 include few validated assays with fully replication-competent wild-type virus. We have developed protocols to propagate, quantify, and work with infectious SARS-CoV-2. Here, we describe: (1) virus stock generation, (2) RT-qPCR quantification of SARS-CoV-2 RNA; (3) detection of SARS-CoV-2 antigen by flow cytometry, (4) quantification of infectious SARS-CoV-2 by focus-forming and plaque assays; and (5) validated protocols for virus inactivation. Collectively, these methods can be adapted to a variety of exptl. designs, which should accelerate our understanding of SARS-CoV-2 biol. and the development of effective countermeasures against COVID-19.
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    Katzelnick, L. C.; Coello Escoto, A.; McElvany, B. D.; Chávez, C.; Salje, H.; Luo, W.; Rodriguez-Barraquer, I.; Jarman, R.; Durbin, A. P.; Diehl, S. A.; Smith, D. J.; Whitehead, S. S.; Cummings, D. A. T. PLOS Neglect. Trop. Dis. 2018, 12, e0006862,  DOI: 10.1371/journal.pntd.0006862

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