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

  1. Wayne Vuong
  2. Muhammad Bashir Khan
  3. Conrad Fischer
  4. Elena Arutyunova
  5. Tess Lamer
  6. Justin Shields
  7. Holly A. Saffran
  8. Ryan T. McKay
  9. Marco J. van Belkum
  10. Michael A. Joyce
  11. Howard S. Young
  12. D. Lorne Tyrrell
  13. John C. Vederas
  14. M. Joanne Lemieux

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Abstract

The main protease, M pro (or 3CL pro ) 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 M pro from both SARS-CoV and SARS-CoV-2 with IC 50 values in the nanomolar range. Crystal structures of SARS-CoV-2 M pro 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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  1. Version published to 10.1038/s41467-020-18096-2
  2. ScreenIT

    SciScore for 10.1101/2020.05.03.073080: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

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  3. Version published to 10.1101/2020.05.03.073080v2 on bioRxiv
  4. Version published to 10.1101/2020.05.03.073080v1 on bioRxiv