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Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication.
Vuong, Wayne; Khan, Muhammad Bashir; Fischer, Conrad; Arutyunova, Elena; Lamer, Tess; Shields, Justin; Saffran, Holly A; McKay, Ryan T; van Belkum, Marco J; Joyce, Michael A; Young, Howard S; Tyrrell, D Lorne; Vederas, John C; Lemieux, M Joanne.
  • Vuong W; Department of Chemistry, University of Alberta, Edmonton, T6G 2G2, AB, Canada.
  • Khan MB; Department of Biochemistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton, T6G 2R3, AB, Canada.
  • Fischer C; Department of Chemistry, University of Alberta, Edmonton, T6G 2G2, AB, Canada.
  • Arutyunova E; Department of Biochemistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton, T6G 2R3, AB, Canada.
  • Lamer T; Department of Chemistry, University of Alberta, Edmonton, T6G 2G2, AB, Canada.
  • Shields J; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, T6G 2R3, AB, Canada.
  • Saffran HA; Li Ka Shing Institute of Virology, University of Alberta, Edmonton, T6G 2E1, AB, Canada.
  • McKay RT; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, T6G 2R3, AB, Canada.
  • van Belkum MJ; Li Ka Shing Institute of Virology, University of Alberta, Edmonton, T6G 2E1, AB, Canada.
  • Joyce MA; Department of Chemistry, University of Alberta, Edmonton, T6G 2G2, AB, Canada.
  • Young HS; Department of Chemistry, University of Alberta, Edmonton, T6G 2G2, AB, Canada.
  • Tyrrell DL; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, T6G 2R3, AB, Canada.
  • Vederas JC; Li Ka Shing Institute of Virology, University of Alberta, Edmonton, T6G 2E1, AB, Canada.
  • Lemieux MJ; Department of Biochemistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton, T6G 2R3, AB, Canada.
Nat Commun ; 11(1): 4282, 2020 08 27.
Article in English | MEDLINE | ID: covidwho-733525
Preprint
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ABSTRACT
The main protease, Mpro (or 3CLpro) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide. Feline infectious peritonitis, a fatal coronavirus infection in cats, was successfully treated previously with a prodrug GC376, a dipeptide-based protease inhibitor. Here, we show the prodrug and its parent GC373, are effective inhibitors of the Mpro from both SARS-CoV and SARS-CoV-2 with IC50 values in the nanomolar range. Crystal structures of SARS-CoV-2 Mpro with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 replication in cell culture. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals. The work here lays the framework for their use in human trials for the treatment of COVID-19.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Protease Inhibitors / Viral Nonstructural Proteins / Coronavirus, Feline / Betacoronavirus Limits: Animals / Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2020 Document Type: Article Affiliation country: S41467-020-18096-2

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Protease Inhibitors / Viral Nonstructural Proteins / Coronavirus, Feline / Betacoronavirus Limits: Animals / Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2020 Document Type: Article Affiliation country: S41467-020-18096-2