Structural insights into the nirmatrelvir-resistant SARS-CoV-2 M^pro L50F/E166A/L167F triple mutant-inhibitor-complex reveal strategies for next generation coronaviral inhibitor design.

ABSTRACT: Drug-resistance is an eminent threat in antiviral therapy, and is currently a concern in nirmatrelvir-based therapy of SARS-CoV-2. Nirmatrelvir (antiviral component in Paxlovid) binds covalently to the active site cysteine of the main protease of SARS-CoV-2 (M^pro), thereby blocking enzyme activity and halting viral replication. In vitro passage experiments mimicking a multi-dosage nirmatrelvir treatment regime, identified M^pro variants with mutations in the active site and near the C-terminal dimerization interface with variable levels of nirmatrelvir resistance. One such variant harbors a triple mutation in M^pro, L50F/E166A/L167F, that displays decreased potency for nirmatrelvir (IC₅₀ ∼ 850-1600 nM) and ibuzatrelvir while viral replicatio

SUBMITTER: Fischer C 

PROVIDER: S-EPMC12356143 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature