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== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
The SARS-CoV-2 main protease (M (pro) ) is a major therapeutic target. The M (pro) inhibitor, nirmatrelvir, is the antiviral component of Paxlovid, an orally available treatment for COVID-19. As M (pro) inhibitor use increases, drug resistant mutations will likely emerge. We have established a non-pathogenic system, in which yeast growth serves as a proxy for M (pro) 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 showed that an E166R substitution conferred strong nirmatrelvir resistance while an E166N mutation compromised activity. On the other hand, N142A and P132H mutations caused little to no change in drug response and activity. Standard enzymatic assays confirmed the yeast results. In turn, we solved the structures of M (pro) E166R, and M (pro) 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 M (pro) that may arise as M (pro) antivirals become more widely used.
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.


A yeast-based system to study SARS-CoV-2 M (pro) structure and to identify nirmatrelvir resistant mutations.,Ou J, Lewandowski EM, Hu Y, Lipinski AA, Morgan RT, Jacobs LMC, Zhang X, Bikowitz MJ, Langlais P, Tan H, Wang J, Chen Y, Choy JS bioRxiv. 2022 Aug 8. doi: 10.1101/2022.08.06.503039. PMID:35982672<ref>PMID:35982672</ref>
A yeast-based system to study SARS-CoV-2 Mpro structure and to identify nirmatrelvir resistant mutations.,Ou J, Lewandowski EM, Hu Y, Lipinski AA, Aljasser A, Colon-Ascanio M, Morgan RT, Jacobs LMC, Zhang X, Bikowitz MJ, Langlais PR, Tan H, Wang J, Chen Y, Choy JS PLoS Pathog. 2023 Aug 31;19(8):e1011592. doi: 10.1371/journal.ppat.1011592. , eCollection 2023 Aug. PMID:37651467<ref>PMID:37651467</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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