Evolutionary and Structural Insights about Potential SARS-CoV-2 Evasion of Nirmatrelvir. Academic Article uri icon


  • 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 (MPro) 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 MPro 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.

published proceedings

  • J Med Chem

altmetric score

  • 20

author list (cited authors)

  • Yang, K. S., Leeuwon, S. Z., Xu, S., & Liu, W. R.

citation count

  • 41

complete list of authors

  • Yang, Kai S||Leeuwon, Sunshine Z||Xu, Shiqing||Liu, Wenshe Ray

publication date

  • January 2022