Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance

Ala M. Shaqra, Sarah N. Zvornicanin, Qiu Yu J. Huang, Gordon J. Lockbaum, Mark Knapp, Laura Tandeske, David T. Bakan, Julia Flynn, Daniel N. A. Bolon, Stephanie Moquin, Dustin Dovala, Nese Kurt Yilmaz () and Celia A. Schiffer ()
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Ala M. Shaqra: University of Massachusetts Chan Medical School
Sarah N. Zvornicanin: University of Massachusetts Chan Medical School
Qiu Yu J. Huang: University of Massachusetts Chan Medical School
Gordon J. Lockbaum: University of Massachusetts Chan Medical School
Mark Knapp: Novartis Institutes for Biomedical Research
Laura Tandeske: Novartis Institutes for Biomedical Research
David T. Bakan: Novartis Institutes for Biomedical Research
Julia Flynn: University of Massachusetts Chan Medical School
Daniel N. A. Bolon: University of Massachusetts Chan Medical School
Stephanie Moquin: Novartis Institutes for Biomedical Research
Dustin Dovala: Novartis Institutes for Biomedical Research
Nese Kurt Yilmaz: University of Massachusetts Chan Medical School
Celia A. Schiffer: University of Massachusetts Chan Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Coronaviruses can evolve and spread rapidly to cause severe disease morbidity and mortality, as exemplified by SARS-CoV-2 variants of the COVID-19 pandemic. Although currently available vaccines remain mostly effective against SARS-CoV-2 variants, additional treatment strategies are needed. Inhibitors that target essential viral enzymes, such as proteases and polymerases, represent key classes of antivirals. However, clinical use of antiviral therapies inevitably leads to emergence of drug resistance. In this study we implemented a strategy to pre-emptively address drug resistance to protease inhibitors targeting the main protease (Mpro) of SARS-CoV-2, an essential enzyme that promotes viral maturation. We solved nine high-resolution cocrystal structures of SARS-CoV-2 Mpro bound to substrate peptides and six structures with cleavage products. These structures enabled us to define the substrate envelope of Mpro, map the critical recognition elements, and identify evolutionarily vulnerable sites that may be susceptible to resistance mutations that would compromise binding of the newly developed Mpro inhibitors. Our results suggest strategies for developing robust inhibitors against SARS-CoV-2 that will retain longer-lasting efficacy against this evolving viral pathogen.

Date: 2022
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DOI: 10.1038/s41467-022-31210-w

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