By Bouzidi HS, Driouich J-S, Klitting R, Bernadin O, Piorkowski G, Amaral R, Fraisse L, Mowbray CE, Scandale I, Escudié F, Chatelain E, de Lamballerie X, Nougairède A, Touret F. Antiviral Research 2024, 222: 105814. doi: 10.1016/j.antiviral.2024.105814
Summary: To date, the protease inhibitor nirmatrelvir has shown the best results in clinical trials of treatments for SARS-CoV-2 and the greatest robustness against variants. A second protease inhibitor, ensitrelvir, was approved in Japan under the emergency regulatory approval procedure in November 2022 and is currently in Phase 3 trials. In this study, the authors experimentally generated mutants resistant to nirmatrelvir and ensitrelvir in vitro and showed that the ensitrelvir M49L mutation confers a high level of resistance in vivo. A recent increase in the prevalence of M49L-carrying sequences, which appears to be associated with multiple repeated emergence events in Japan, may be related to the use of ensitrelvir. These results highlight the importance of genetic monitoring of circulating SARS-CoV-2 strains.