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Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication

Author

Listed:
  • Wayne Vuong

    (University of Alberta)

  • Muhammad Bashir Khan

    (University of Alberta)

  • Conrad Fischer

    (University of Alberta)

  • Elena Arutyunova

    (University of Alberta)

  • Tess Lamer

    (University of Alberta)

  • Justin Shields

    (University of Alberta
    University of Alberta)

  • Holly A. Saffran

    (University of Alberta
    University of Alberta)

  • Ryan T. McKay

    (University of Alberta)

  • Marco J. Belkum

    (University of Alberta)

  • Michael A. Joyce

    (University of Alberta
    University of Alberta)

  • Howard S. Young

    (University of Alberta)

  • D. Lorne Tyrrell

    (University of Alberta
    University of Alberta)

  • John C. Vederas

    (University of Alberta)

  • M. Joanne Lemieux

    (University of Alberta)

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.

Suggested Citation

  • Wayne Vuong & Muhammad Bashir Khan & Conrad Fischer & Elena Arutyunova & Tess Lamer & Justin Shields & Holly A. Saffran & Ryan T. McKay & Marco J. Belkum & Michael A. Joyce & Howard S. Young & D. Lorn, 2020. "Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication," Nature Communications, Nature, vol. 11(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18096-2
    DOI: 10.1038/s41467-020-18096-2
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    Cited by:

    1. Jaeyong Lee & Calem Kenward & Liam J. Worrall & Marija Vuckovic & Francesco Gentile & Anh-Tien Ton & Myles Ng & Artem Cherkasov & Natalie C. J. Strynadka & Mark Paetzel, 2022. "X-ray crystallographic characterization of the SARS-CoV-2 main protease polyprotein cleavage sites essential for viral processing and maturation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Norman Tran & Sathish Dasari & Sarah A. E. Barwell & Matthew J. McLeod & Subha Kalyaanamoorthy & Todd Holyoak & Aravindhan Ganesan, 2023. "The H163A mutation unravels an oxidized conformation of the SARS-CoV-2 main protease," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Hengrui Liu & Sho Iketani & Arie Zask & Nisha Khanizeman & Eva Bednarova & Farhad Forouhar & Brandon Fowler & Seo Jung Hong & Hiroshi Mohri & Manoj S. Nair & Yaoxing Huang & Nicholas E. S. Tay & Sumin, 2022. "Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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