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Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.
Zhang, Linlin; Lin, Daizong; Sun, Xinyuanyuan; Curth, Ute; Drosten, Christian; Sauerhering, Lucie; Becker, Stephan; Rox, Katharina; Hilgenfeld, Rolf.
  • Zhang L; Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany.
  • Lin D; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Site, University of Lübeck, 23562 Lübeck, Germany.
  • Sun X; Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany.
  • Curth U; Changchun Discovery Sciences Ltd., 789 Shunda Road, Changchun, Jilin 130012, China.
  • Drosten C; Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany.
  • Sauerhering L; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Site, University of Lübeck, 23562 Lübeck, Germany.
  • Becker S; Institute for Biophysical Chemistry, Hannover Medical School, 30625 Hannover, Germany.
  • Rox K; Institute of Virology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.
  • Hilgenfeld R; Institute of Virology, University of Marburg, 35043 Marburg, Germany.
Science ; 368(6489): 409-412, 2020 04 24.
Article in English | MEDLINE | ID: covidwho-164984
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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Full text: Available Collection: International databases Database: MEDLINE Main subject: Protease Inhibitors / Cysteine Endopeptidases / Viral Nonstructural Proteins / Betacoronavirus / Amides Limits: Animals / Humans Language: English Journal: Science Year: 2020 Document Type: Article Affiliation country: Science.abb3405

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Protease Inhibitors / Cysteine Endopeptidases / Viral Nonstructural Proteins / Betacoronavirus / Amides Limits: Animals / Humans Language: English Journal: Science Year: 2020 Document Type: Article Affiliation country: Science.abb3405