UMMS Affiliation

Department of Biochemistry and Molecular Biotechnology; Schiffer Lab; Graduate School of Biomedical Sciences

Publication Date

2022-06-21

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Biochemistry | Enzymes and Coenzymes | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry | Molecular Biology | Structural Biology | Virology

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 (M(pro)) of SARS-CoV-2, an essential enzyme that promotes viral maturation. We solved nine high-resolution cocrystal structures of SARS-CoV-2 M(pro) bound to substrate peptides and six structures with cleavage products. These structures enabled us to define the substrate envelope of M(pro), 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 M(pro) inhibitors. Our results suggest strategies for developing robust inhibitors against SARS-CoV-2 that will retain longer-lasting efficacy against this evolving viral pathogen.

Keywords

Proteases, Viral infection, Viral proteins, X-ray crystallography, SARS-CoV-2

Rights and Permissions

Copyright © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

DOI of Published Version

10.1038/s41467-022-31210-w

Source

Shaqra AM, Zvornicanin SN, Huang QYJ, Lockbaum GJ, Knapp M, Tandeske L, Bakan DT, Flynn J, Bolon DNA, Moquin S, Dovala D, Kurt Yilmaz N, Schiffer CA. Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance. Nat Commun. 2022 Jun 21;13(1):3556. doi: 10.1038/s41467-022-31210-w. PMID: 35729165; PMCID: PMC9211792. Link to article on publisher's site

Journal/Book/Conference Title

Nature communications

Related Resources

Link to Article in PubMed

PubMed ID

35729165

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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