Generation and evaluation of protease inhibitor-resistant SARS-CoV-2 strains

• DOI: 10.1016/j.antiviral.2024.105814
• Publication Date: 2024-01-24T02:42:50Z
• Authors: Hawa Sophia Bouzidi; Jean-Sélim Driouich; Raphaëlle Klitting; Ornéllie Bernadin; Géraldine Piorkowski; Rayane Amaral; Laurent Fraisse; Charles E. Mowbray; Ivan Scandale; Fanny Escudié; Eric Chatelain; Xavier de Lamball...; Antoine Nougairède; Franck Touret
• Keywords: Protease inhibitor (pharmacology); Pandemic; 2019-20 coronavirus outbreak

Since the start of SARS-CoV-2 pandemic, search for antiviral therapies has been at forefront medical research. To date, 3CLpro inhibitor nirmatrelvir (Paxlovid®) shown best results in clinical trials and greatest robustness against variants. A second protease inhibitor, ensitrelvir (Xocova®), developed. Ensitrelvir, currently Phase 3, was approved Japan under emergency regulatory approval procedure November 2022, is available since March 31, 2023. One limitations use monotherapies emergence resistance mutations. Here, we experimentally generated mutants resistant to vitro following repeating passages presence both antivirals. For molecules, demonstrated a loss sensitivity vitro. Using Syrian golden hamster infection model, showed that M49L mutation, multi-passage strain, confers high level vivo resistance. Finally, identified recent increase prevalence M49L-carrying sequences, which appears be associated with multiple repeated events may related Xocova® country 2022. These highlight strategic importance genetic monitoring circulating strains ensure treatments administered retain their full effectiveness.