Evolutionary and Structural Insights about Potential SARS-CoV-2 Evasion of Nirmatrelvir

The U.S. FDA approval of PAXLOVID, a combination therapy of nirmatrelvir and ritonavir has significantly boosted our morale in fighting the COVID-19 pandemic. Nirmatrelvir is an inhibitor of the main protease (M Pro ) of SARS-CoV-2. Since many SARS-CoV-2 variants that resist vaccines and antibodies have emerged, a concern of acquired viral resistance to nirmatrelvir naturally arises. Here, possible mutations in M Pro to confer viral evasion of nirmatrelvir are analyzed and discussed from both evolutionary and structural standpoints. The analysis indicates that those mutations will likely reside in the whole aa45-51 helical region and residues including M165, L167, P168, R188, and Q189. Relevant mutations have also been observed in existing SARS-CoV-2 samples. Implications of this analysis to the fight against future drug-resistant viral variants and the development of broad-spectrum antivirals are discussed as well.