Department of Biochemistry and Molecular Biotechnology; Schiffer Lab; Graduate School of Biomedical Sciences
Amino Acids, Peptides, and Proteins | Biochemistry | Enzymes and Coenzymes | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry | Molecular Biology | Structural Biology | Virology
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.
Proteases, Viral infection, Viral proteins, X-ray crystallography, SARS-CoV-2
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DOI of Published Version
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
Shaqra AM, Zvornicanin SN, Huang QY, Lockbaum GJ, Knapp M, Tandeske L, Bakan DT, Flynn JM, Bolon DN, Moquin S, Dovala D, Yilmaz NK, Schiffer CA. (2022). Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance. Schiffer Lab Publications. https://doi.org/10.1038/s41467-022-31210-w. Retrieved from https://escholarship.umassmed.edu/schiffer/48
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