@article{fdi:010093041,
  title = {{G}eneration and evaluation of protease inhibitor-resistant {SARS}-{C}o{V}-2 strains},
  author = {{B}ouzidi, {H}.{S}. and {D}riouich, {J}.{S}. and {K}litting, {R}. and {B}ernadin, {O}. and {P}iorkowski, {G}. and {A}maral, {R}. and {F}raisse, {L}. and {M}owbray, {C}.{E}. and {S}candale, {I}. and {E}scudi{\'e}, {F}. and {C}hatelain, {E}. and {D}e {L}amballerie, {X}. and {N}ougair{\`e}de, {A}. and {T}ouret, {F}ranck},
  editor = {},
  language = {{ENG}},
  abstract = {{S}ince the start of the {SARS}-{C}o{V}-2 pandemic, the search for antiviral therapies has been at the forefront of medical research. {T}o date, the 3{CL}pro inhibitor nirmatrelvir ({P}axlovid®) has shown the best results in clinical trials and the greatest robustness against variants. {A} second {SARS}-{C}o{V}-2 protease inhibitor, ensitrelvir ({X}ocova®), has been developed. {E}nsitrelvir, currently in {P}hase 3, was approved in {J}apan under the emergency regulatory approval procedure in {N}ovember 2022,


and is available since {M}arch 31, 2023. {O}ne of the limitations for the use of antiviral monotherapies is the emergence of resistance mutations. {H}ere, we experimentally generated mutants resistant to nirmatrelvir and ensitrelvir in vitro following repeating passages of {SARS}-{C}o{V}-2 in the presence of both antivirals. {F}or both molecules, we demonstrated a loss of sensitivity for resistance mutants in vitro. {U}sing a {S}yrian golden hamster infection model, we showed that the ensitrelvir


{M}49{L} mutation, in the multi-passage strain, confers a high level of in vivo resistance. {F}inally, we identified a recent increase in the prevalence of {M}49{L}-carrying sequences, which appears to be associated with multiple repeated emergence events in {J}apan and may be related to the use of {X}ocova® in the country since {N}ovember 2022. {T}hese results highlight the strategic importance of genetic monitoring of circulating {SARS}-{C}o{V}-2 strains to ensure that treatments administered retain


their full effectiveness.},
  keywords = {},
  booktitle = {},
  journal = {{A}ntiviral {R}esearch},
  volume = {222},
  numero = {},
  pages = {105814 [13 ]},
  ISSN = {0166-3542},
  year = {2024},
  DOI = {10.1016/j.antiviral.2024.105814},
  URL = {https://www.documentation.ird.fr/hor/fdi:010093041},
}