Distal protein-protein interactions contribute to nirmatrelvir resistance.

ABSTRACT: SARS-CoV-2 main protease, M^pro, is responsible for processing the viral polyproteins into individual proteins, including the protease itself. M^pro is a key target of anti-COVID-19 therapeutics such as nirmatrelvir (the active component of Paxlovid). Resistance mutants identified clinically and in viral passage assays contain a combination of active site mutations (e.g., E166V, E166A, L167F), which reduce inhibitor binding and enzymatic activity, and non-active site mutations (e.g., P252L, T21I, L50F), which restore the fitness of viral replication. To probe the role of the non-active site mutations in fitness rescue, here we use an M^pro triple mutant (L50F/E166A/L167F) that confers nirmatrelvir drug resistance with a viral fitness level similar to the wild-

SUBMITTER: Lewandowski EM 

PROVIDER: S-EPMC11787374 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature