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

J Med Chem. 2022 Jul 14;65(13):8686-8698. doi: 10.1021/acs.jmedchem.2c00404. Epub 2022 Jun 22.


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.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • COVID-19 Drug Treatment*
  • Coronavirus 3C Proteases
  • Humans
  • Pandemics
  • SARS-CoV-2* / genetics
  • Viral Nonstructural Proteins / chemistry


  • Viral Nonstructural Proteins
  • Coronavirus 3C Proteases

Supplementary concepts

  • SARS-CoV-2 variants