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      Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.

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          Abstract

          The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.

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          A pneumonia outbreak associated with a new coronavirus of probable bat origin

          Peng Zhou, Xing-Lou Yang, Xian-Guang Wang … (2020)
          Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.
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            A new coronavirus associated with human respiratory disease in China

            Fan Wu, Su Zhao, Bin Yu … (2020)
            Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health 1–3 . 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 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. Epidemiological investigations have suggested that the outbreak was associated 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 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing 4 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 analysis 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 5 . This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.
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              Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR

              Victor M Corman, Olfert Landt, Marco Kaiser … (2020)
              Background The ongoing outbreak of the recently emerged novel coronavirus (2019-nCoV) poses a challenge for public health laboratories as virus isolates are unavailable while there is growing evidence that the outbreak is more widespread than initially thought, and international spread through travellers does already occur. Aim We aimed to develop and deploy robust diagnostic methodology for use in public health laboratory settings without having virus material available. Methods Here we present a validated diagnostic workflow for 2019-nCoV, its design relying on close genetic relatedness of 2019-nCoV with SARS coronavirus, making use of synthetic nucleic acid technology. Results The workflow reliably detects 2019-nCoV, and further discriminates 2019-nCoV from SARS-CoV. Through coordination between academic and public laboratories, we confirmed assay exclusivity based on 297 original clinical specimens containing a full spectrum of human respiratory viruses. Control material is made available through European Virus Archive – Global (EVAg), a European Union infrastructure project. Conclusion The present study demonstrates the enormous response capacity achieved through coordination of academic and public laboratories in national and European research networks.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Science
                Title: Science (New York, N.Y.)
                Publisher: American Association for the Advancement of Science (AAAS)
                ISSN (Electronic): 1095-9203
                ISSN (Print): 0036-8075
                Publication date (Electronic): April 24 2020
                Volume: 368
                Issue: 6489
                Affiliations
                [1 ] Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany.
                [2 ] German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Site, University of Lübeck, 23562 Lübeck, Germany.
                [3 ] Changchun Discovery Sciences Ltd., 789 Shunda Road, Changchun, Jilin 130012, China.
                [4 ] Institute for Biophysical Chemistry, Hannover Medical School, 30625 Hannover, Germany.
                [5 ] Institute of Virology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.
                [6 ] Institute of Virology, University of Marburg, 35043 Marburg, Germany.
                [7 ] German Center for Infection Research (DZIF), Marburg-Gießen-Langen Site, University of Marburg, 35043 Marburg, Germany.
                [8 ] Department of Chemical Biology, Helmholtz Center for Infection Research (HZI), 38124 Braunschweig, Germany.
                [9 ] German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Helmholtz Center for Infection Research, 38124 Braunschweig, Germany.
                [10 ] Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany. rolf.hilgenfeld@uni-luebeck.de.
                Article
                Publisher Item ID: science.abb3405
                DOI: 10.1126/science.abb3405
                PMC ID: 7164518
                PubMed ID: 32198291
                SO-VID: 2cfae919-d215-488e-bc36-d42000d7c747
                Copyright © Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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