ArticlePLoS pathogens2023
A yeast-based system to study SARS-CoV-2 Mpro structure and to identify nirmatrelvir resistant mutations.
Article in PLoS pathogens, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 27 citations in OpenAlex.
- Heat Shock Protein Inhibitor Tanespimycin (17AAG) Suppresses SARS-CoV-2 Main Protease Activity and Is More Potent Than Clinically Approved Antiviral Nirmatrelvir.Chembiochem : a European journal of chemical biology · 2026Article
- Inhibitory effects and structural analysis of drug candidate PF-07817883 against coronaviral main proteases (MJournal of structural biology: X · 2026Article
- SARS-CoV-2 3CLpro mutations T21I and E166A confer differential resistance to simnotrelvir, bofutrelvir, and ensitrelvir.Journal of virology · 2026Article
- A data-driven sliding-window pairwise comparative approach for the estimation of transmission fitness of SARS-CoV-2 variants and construction of the evolution fitness landscape.Quantitative biology (Beijing, China) · 2025Article
- The SARS-CoV-2 main protease causes mitochondrial dysfunction in a yeast model.Scientific reports · 2025Article
- Potent antiviral activity of simnotrelvir against key epidemic SARS-CoV-2 variants with a high resistance barrier.Antimicrobial agents and chemotherapy · 2025Article
- Inhibitory efficacy and structural insights of Bofutrelvir against SARS-CoV-2 MCommunications biology · 2025Article
- Exploring Possible Drug-Resistant Variants of SARS-CoV-2 Main Protease (MACS bio & med chem Au · 2025Article
- Unveiling the mechanism of action of a novel natural dual inhibitor of SARS-CoV-2 Mpro and PLpro with molecular dynamics simulations.Natural products and bioprospecting · 2025Article
- An Investigation of Nirmatrelvir (Paxlovid) Resistance in SARS-CoV-2 MACS bio & med chem Au · 2024Article
- Backstage Heroes-Yeast in COVID-19 Research.International journal of molecular sciences · 2024Review
- An automated positive selection screen in yeast provides support for boron-containing compounds as inhibitors of SARS-CoV-2 main protease.Microbiology spectrum · 2024Article
- A comprehensive study of SARS-CoV-2 main protease (Mpro) inhibitor-resistant mutants selected in a VSV-based system.PLoS pathogens · 2024Article
- SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs.Cell chemical biology · 2024Review
- Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04.Cell discovery · 2024Article
- A community effort in SARS-CoV-2 drug discovery.Molecular informatics · 2024Article
- A comprehensive study of SARS-CoV-2 main protease (MbioRxiv : the preprint server for biology · 2023Article
- Systematic Analyses of the Resistance Potential of Drugs Targeting SARS-CoV-2 Main Protease.ACS infectious diseases · 2023Article
- Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors.Science advances · 2023Article
- Sierra SARS-CoV-2 sequence and antiviral resistance analysis program.Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology · 2022Article
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
Abstract
The SARS-CoV-2 main protease (Mpro) is a major therapeutic target. The Mpro inhibitor, nirmatrelvir, is the antiviral component of Paxlovid, an orally available treatment for COVID-19. As Mpro inhibitor use increases, drug resistant mutations will likely emerge. We have established a non-pathogenic system, in which yeast growth serves as an approximation for Mpro activity, enabling rapid identification of mutants with altered enzymatic activity and drug sensitivity. The E166 residue is known to be a potential hot spot for drug resistance and yeast assays identified substitutions which conferred strong nirmatrelvir resistance and others that compromised activity. On the other hand, N142A and the P132H mutation, carried by the Omicron variant, caused little to no change in drug response and activity. Standard enzymatic assays confirmed the yeast results. In turn, we solved the structures of Mpro E166R, and Mpro E166N, providing insights into how arginine may drive drug resistance while asparagine leads to reduced activity. The work presented here will help characterize novel resistant variants of Mpro that may arise as Mpro antivirals become more widely used.
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