Molecular mechanisms of drug resistance and compensation in SARS-CoV-2 main protease: the interplay between E166 and L50.

ABSTRACT: The SARS-CoV-2 main protease (M^pro) is essential for viral replication and is a primary target for COVID-19 antivirals. Direct-acting antivirals such as nirmatrelvir, the active component of Paxlovid, target the M^pro active site to block viral polyprotein cleavage and thus replication. However, drug resistance mutations at the active site residue Glu166 (E166) have emerged during in vitro selection studies, raising concerns about the durability of current antiviral strategies. Here, we investigate the molecular basis of drug resistance conferred by E166A and E166V mutations against nirmatrelvir and the related PF-00835231, individually and in combination with the distal mutation L50F. We found that E166 mutations reduce nirmatrelvir potency by up to 3,000-fold

SUBMITTER: Zvornicanin SN 

PROVIDER: S-EPMC12077200 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature