Predicting Antiviral Resistance Mutations in SARS-CoV-2 Main Protease with Computational and Experimental Screening

Vishnu M. Sasi, Sven Ullrich, Jennifer Ton, Sarah E. Fry, Jason Johansen-Leete, Richard J. Payne, Christoph Nitsche*, Colin J. Jackson*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    27 Citations (Scopus)

    Abstract

    The main protease (Mpro) of SARS-CoV-2 is essential for viral replication and has been the focus of many drug discovery efforts since the start of the COVID-19 pandemic. Nirmatrelvir (NTV) is an inhibitor of SARS-CoV-2 Mprothat is used in the combination drug Paxlovid for the treatment of mild to moderate COVID-19. However, with increased use of NTV across the globe, there is a possibility that future SARS-CoV-2 lineages will evolve resistance to NTV. Early prediction and monitoring of resistance mutations could allow for measures to slow the spread of resistance and for the development of new compounds with activity against resistant strains. In this work, we have used in silico mutational scanning and inhibitor docking of Mproto identify potential resistance mutations. Subsequent in vitro experiments revealed five mutations (N142L, E166M, Q189E, Q189I, and Q192T) that reduce the potency of NTV and of a previously identified non-covalent cyclic peptide inhibitor of Mpro. The E166M mutation reduced the half-maximal inhibitory concentration (IC50) of NTV 24-fold and 118-fold for the non-covalent peptide inhibitor. Our findings inform the ongoing genomic surveillance of emerging SARS-CoV-2 lineages.

    Original languageEnglish
    Pages (from-to)2495-2505
    Number of pages11
    JournalBiochemistry
    Volume61
    Issue number22
    DOIs
    Publication statusPublished - 15 Nov 2022

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