Additionally, we showed that over time, the SARS-CoV-2 M pro enzyme remained under purifying selection and was highly conserved relative to the spike protein. Structural comparison of M pro also showed conservation of key nirmatrelvir contact residues across the extended Coronaviridae family (α-, β-, and γ-coronaviruses). Mutations at sites key to nirmatrelvir binding and protease functionality (e.g., dimerization sites) were still rare. Any mutations identified from comparison to the reference sequence (Wuhan-Hu-1) were catalogued and analyzed. To establish the baseline mutational landscape of M pro prior to the introduction of M pro inhibitors, M pro sequences and its cleavage junction regions were retrieved from ~4,892,000 high-quality SARS-CoV-2 genomes in the open-access Global Initiative on Sharing Avian Influenza Data (GISAID) database. The significant viral sequencing effort during the ongoing COVID-19 pandemic represented a unique opportunity to assess potential nirmatrelvir escape mutations from emerging variants of SARS-CoV-2. Nirmatrelvir is a potent M pro inhibitor and the antiviral component of Paxlovid. An important coronaviral drug target for treatment of COVID-19 is the conserved main protease (M pro). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to represent a global health emergency as a highly transmissible, airborne virus.
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