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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 , 2022. "Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31210-w
    DOI: 10.1038/s41467-022-31210-w
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    References listed on IDEAS

    as
    1. Zhenming Jin & Xiaoyu Du & Yechun Xu & Yongqiang Deng & Meiqin Liu & Yao Zhao & Bing Zhang & Xiaofeng Li & Leike Zhang & Chao Peng & Yinkai Duan & Jing Yu & Lin Wang & Kailin Yang & Fengjiang Liu & Re, 2020. "Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors," Nature, Nature, vol. 582(7811), pages 289-293, June.
    2. Bjoern Meyer & Jeanne Chiaravalli & Stacy Gellenoncourt & Philip Brownridge & Dominic P. Bryne & Leonard A. Daly & Arturas Grauslys & Marius Walter & Fabrice Agou & Lisa A. Chakrabarti & Charles S. Cr, 2021. "Characterising proteolysis during SARS-CoV-2 infection identifies viral cleavage sites and cellular targets with therapeutic potential," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    3. Daniel W. Kneller & Gwyndalyn Phillips & Hugh M. O’Neill & Robert Jedrzejczak & Lucy Stols & Paul Langan & Andrzej Joachimiak & Leighton Coates & Andrey Kovalevsky, 2020. "Structural plasticity of SARS-CoV-2 3CL Mpro active site cavity revealed by room temperature X-ray crystallography," Nature Communications, Nature, vol. 11(1), pages 1-6, December.
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