Predicting Antiviral Resistance Mutations in SARS-CoV-2 Main Protease with Computational and Experimental Screening
Date
2022-11-03
Authors
Mini Sasi, Vishnu
Ullrich, Sven
Ton, Jennifer
Fry, Sarah E.
Johansen-Leete, Jason
Payne, Richard J.
Nitsche, Christoph
Jackson, Colin
Journal Title
Journal ISSN
Volume Title
Publisher
American Chemical Society
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 Mpro that 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 Mpro to 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.
Description
Keywords
Antivirals, COVID-19, mutations, nirmatrelvir, resistance
Citation
Collections
Source
Biochemistry
Type
Journal article
Book Title
Entity type
Access Statement
Open Access