Generation and evaluation of protease inhibitor-resistant SARS-CoV-2 strains
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 Lamballerie, Antoine Nougairède, Franck Touret
Antiviral Research, doi:10.1016/j.antiviral.2024.105814
Since the start of the SARS-CoV-2 pandemic, the search for antiviral therapies has been at the forefront of medical research. To date, the 3CLpro inhibitor nirmatrelvir (Paxlovid®) has shown the best results in clinical trials and the greatest robustness against variants. A second SARS-CoV-2 protease inhibitor, ensitrelvir (Xocova®), has been developed. Ensitrelvir, currently in Phase 3, was approved in Japan under the emergency regulatory approval procedure in November 2022, and is available since March 31, 2023. One of the limitations for the use of antiviral monotherapies is the emergence of resistance mutations. Here, we experimentally generated mutants resistant to nirmatrelvir and ensitrelvir in vitro following repeating passages of SARS-CoV-2 in the presence of both antivirals. For both molecules, we demonstrated a loss of sensitivity for resistance mutants in vitro. Using a Syrian golden hamster infection model, we showed that the ensitrelvir M49L mutation, in the multipassage strain, confers a high level of in vivo resistance. Finally, we identified a recent increase in the prevalence of M49L-carrying sequences, which appears to be associated with multiple repeated emergence events in Japan and may be related to the use of Xocova® in the country since November 2022. These results highlight the strategic importance of genetic monitoring of circulating SARS-CoV-2 strains to ensure that treatments administered retain their full effectiveness.
continuous monitoring in countries where ensitrelvir is, or will soon be, approved for use. These findings argues in favor of genetic monitoring of circulating strains to ensure that the treatments administered retain their full effectiveness. In addition, the range of antiviral treatments available against SARS-CoV-2 has become worryingly limited, with most commercial monoclonal drugs losing their activity against the most recent variants. Obviously, there is still a need to develop other antivirals targeting other viral proteins to broaden the therapeutic armory, and possibly to develop dual therapies as has been done for other viral diseases.
CRediT authorship contribution statement
Hawa
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.antiviral.2024.105814 .
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