Discovery of Nirmatrelvir Resistance Mutations in SARS-CoV-2 3CLpro: A Computational-Experimental Approach.

ABSTRACT: The COVID-19 pandemic has emphasized the urgency for effective antiviral therapies against SARS-CoV-2. Targeting the main protease (3CLpro) of the virus has emerged as a promising approach, and nirmatrelvir (PF-07321332), the active component of Pfizer's oral drug Paxlovid, has demonstrated remarkable clinical efficacy. However, the emergence of resistance mutations poses a challenge to its continued success. In this study, we employed alchemical free energy perturbation (FEP) alanine scanning to identify nirmatrelvir-resistance mutations within SARS-CoV-2 3CLpro. FEP identified several mutations, which were validated through in vitro IC₅₀ experiments and found to result in 8- and 72-fold increases in nirmatrelvir IC₅₀ values. Additionally, we constructed SARS-CoV-2 o

SUBMITTER: Havranek B 

PROVIDER: S-EPMC10976418 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature