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

Wayne Vuong, View ORCID ProfileMuhammad Bashir Khan, View ORCID ProfileConrad Fischer, Elena Arutyunova, Tess Lamer, Justin Shields, Holly A. Saffran, View ORCID ProfileRyan T. McKay, Marco J. van Belkum, View ORCID ProfileMichael Joyce, View ORCID ProfileHoward S. Young, View ORCID ProfileD. Lorne Tyrrell, View ORCID ProfileJohn C. Vederas, View ORCID ProfileM. Joanne Lemieux
doi: https://doi.org/10.1101/2020.05.03.073080
Wayne Vuong
1Department of Chemistry, Faculty of Science, University of Alberta, Edmonton T6G 2G2, Alberta, Canada
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Muhammad Bashir Khan
2Department of Biochemistry, Faculty of Medicine and Dentistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
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Conrad Fischer
1Department of Chemistry, Faculty of Science, University of Alberta, Edmonton T6G 2G2, Alberta, Canada
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Elena Arutyunova
2Department of Biochemistry, Faculty of Medicine and Dentistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
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Tess Lamer
1Department of Chemistry, Faculty of Science, University of Alberta, Edmonton T6G 2G2, Alberta, Canada
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Justin Shields
3Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
4Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G 2E1, Alberta, Canada
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Holly A. Saffran
3Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
4Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G 2E1, Alberta, Canada
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Ryan T. McKay
1Department of Chemistry, Faculty of Science, University of Alberta, Edmonton T6G 2G2, Alberta, Canada
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  • ORCID record for Ryan T. McKay
Marco J. van Belkum
1Department of Chemistry, Faculty of Science, University of Alberta, Edmonton T6G 2G2, Alberta, Canada
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Michael Joyce
3Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
4Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G 2E1, Alberta, Canada
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Howard S. Young
2Department of Biochemistry, Faculty of Medicine and Dentistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
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D. Lorne Tyrrell
3Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
4Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G 2E1, Alberta, Canada
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  • For correspondence: lorne.tyrrell@ualberta.ca john.vederas@ualberta.ca mlemieux@ualberta.ca
John C. Vederas
1Department of Chemistry, Faculty of Science, University of Alberta, Edmonton T6G 2G2, Alberta, Canada
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  • For correspondence: lorne.tyrrell@ualberta.ca john.vederas@ualberta.ca mlemieux@ualberta.ca
M. Joanne Lemieux
2Department of Biochemistry, Faculty of Medicine and Dentistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
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  • For correspondence: lorne.tyrrell@ualberta.ca john.vederas@ualberta.ca mlemieux@ualberta.ca
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Abstract

The COVID-19 pandemic, attributed to the SARS-CoV-2 coronavirus infection, resulted in millions infected worldwide and an immediate need for antiviral treatments. The main protease (Mpro) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide and subsequent viral replication. Feline infectious peritonitis, a fatal infection in cats caused by a coronavirus, was successfully treated previously with a dipeptide-based protease inhibitor. Here we show this drug, GC376, and its analog 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 the SARS-CoV and 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 in cell culture, with EC50 values near one micromolar and little to no toxicity. These protease inhibitors are soluble, non-toxic, and bind reversibly. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals (cats). The work here lays the framework for their use in human trials for the treatment of COVID-19.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Correction in Author name (corrected misspelling)

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 05, 2020.
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Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication
Wayne Vuong, Muhammad Bashir Khan, Conrad Fischer, Elena Arutyunova, Tess Lamer, Justin Shields, Holly A. Saffran, Ryan T. McKay, Marco J. van Belkum, Michael Joyce, Howard S. Young, D. Lorne Tyrrell, John C. Vederas, M. Joanne Lemieux
bioRxiv 2020.05.03.073080; doi: https://doi.org/10.1101/2020.05.03.073080
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Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication
Wayne Vuong, Muhammad Bashir Khan, Conrad Fischer, Elena Arutyunova, Tess Lamer, Justin Shields, Holly A. Saffran, Ryan T. McKay, Marco J. van Belkum, Michael Joyce, Howard S. Young, D. Lorne Tyrrell, John C. Vederas, M. Joanne Lemieux
bioRxiv 2020.05.03.073080; doi: https://doi.org/10.1101/2020.05.03.073080

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