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Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses

Sarah N. Zvornicanin, Ala M. Shaqra, View ORCID ProfileQiu Yu J. Huang, Elizabeth Ornelas, Mallika Moghe, Mark Knapp, Stephanie Moquin, Dustin Dovala, Celia A. Schiffer, View ORCID ProfileNese Kurt Yilmaz
doi: https://doi.org/10.1101/2023.02.01.526623
Sarah N. Zvornicanin
1Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605, USA
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Ala M. Shaqra
1Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605, USA
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Qiu Yu J. Huang
1Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605, USA
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Elizabeth Ornelas
2Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
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Mallika Moghe
3Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA
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Mark Knapp
2Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
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Stephanie Moquin
2Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
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Dustin Dovala
2Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
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Celia A. Schiffer
1Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605, USA
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Nese Kurt Yilmaz
1Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605, USA
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  • ORCID record for Nese Kurt Yilmaz
  • For correspondence: Nese.KurtYilmaz@umassmed.edu
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Abstract

With the spread of SARS-CoV-2 throughout the globe to cause the COVID-19 pandemic, the threat of zoonotic transmissions of coronaviruses (CoV) has become even more evident. As human infections have been caused by alpha- and beta-CoVs, structural characterization and inhibitor design mostly focused on these two genera. However, viruses from the delta and gamma genera also infect mammals and pose potential zoonotic transmission threat. Here, we determined the inhibitor-bound crystal structures of the main protease (Mpro) from the delta-CoV porcine HKU15 and gamma-CoV SW1 from beluga whale. Comparison with the apo structure of SW1 Mpro, which we also present here, enabled identifying structural arrangements upon inhibitor binding at the active site. The binding modes and interactions of two covalent inhibitors, PF-00835231 (lufotrelvir) bound to HKU15 and GC376 bound to SW1 Mpro, reveal features that may be leveraged to target diverse coronaviruses and toward structure-based design of pan-CoV inhibitors.

Competing Interest Statement

This research received no external funding. The research at CAS laboratory was funded by Novartis Institutes for Biomedical Research.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted February 02, 2023.
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Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses
Sarah N. Zvornicanin, Ala M. Shaqra, Qiu Yu J. Huang, Elizabeth Ornelas, Mallika Moghe, Mark Knapp, Stephanie Moquin, Dustin Dovala, Celia A. Schiffer, Nese Kurt Yilmaz
bioRxiv 2023.02.01.526623; doi: https://doi.org/10.1101/2023.02.01.526623
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Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses
Sarah N. Zvornicanin, Ala M. Shaqra, Qiu Yu J. Huang, Elizabeth Ornelas, Mallika Moghe, Mark Knapp, Stephanie Moquin, Dustin Dovala, Celia A. Schiffer, Nese Kurt Yilmaz
bioRxiv 2023.02.01.526623; doi: https://doi.org/10.1101/2023.02.01.526623

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