Naturally Occurring Mutations of SARS-CoV-2 Main Protease Confer Drug Resistance to Nirmatrelvir

The SARS-CoV-2 main protease (Mpro) is the drug target of Pfizer’s oral drug nirmatrelvir. The emergence of SARS-CoV-2 variants with mutations in Mpro raised the alarm of potential drug resistance. To identify potential clinically relevant drug-resistant mutants, we systematically characterized 102 naturally occurring Mpro mutants located at 12 residues at the nirmatrelvir-binding site, among which 22 mutations in 5 residues, including S144M/F/A/G/Y, M165T, E166 V/G/A, H172Q/F, and Q192T/S/L/A/I/P/H/V/W/C/F, showed comparable enzymatic activity to the wild-type (kcat/Km 10-fold increase). X-ray crystal structures were determined for six representative mutants with and/or without GC-376/nirmatrelvir. Using…

• OS
  Oklahoma State University
• NI
  National Institutes of Health

  Awards: S10_RR028976, AI157046, S10_OD027000, AI147325, AI158775, 5P20GM103648, S10_RR25528
• NI
  National Institute of General Medical Sciences

  Award: 5P20GM103648
• NI
  National Institute of Allergy and Infectious Diseases

  Awards: AI158775, S10_RR25528, S10_RR028976, AI147325, AI157046