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<p>SARS-CoV-2 variants resistant to current antivirals remain a significant threat, particularly in high-risk patients. Although nirmatrelvir and ensitrelvir both target the viral 3CL protease (M<sup>pro</sup>), their distinct susceptibility profiles may allow alternative therapeutic approaches. Here, we identify a deletion mutation at glycine 23 (Δ23G) in M<sup>pro</sup> that conferred high-level resistance to ensitrelvir ( ~ 35-fold) while paradoxically increasing susceptibility to nirmatrelvir ( ~ 8-fold). This opposite susceptibility pattern is confirmed both in vitro and in a male hamster infection model. Recombinant viruses carrying M<sup>pro</sup>-Δ23G exhibit impaired replication, pathogenicity, and transmissibility compared to wild-type, though the co-occurring mutation T45I partially restore viral fitness. Structural analyses reveal critical conformational changes in the catalytic loop (Ile136–Val148) and β-hairpin loop (Cys22–Thr26), directly influencing inhibitor binding selectivity. These results highlight differential resistance profiles of M<sup>pro</sup> inhibitors, supporting potential sequential or alternative use of nirmatrelvir and ensitrelvir in patients requiring prolonged antiviral treatment.</p>

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A SARS-CoV-2 Mpro mutation conferring ensitrelvir resistance paradoxically increases nirmatrelvir susceptibility

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月22日

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  • Seong Cheol Min,
  • Jin-Ju Seo,
  • Ju Hwan Jeong,
  • Beom Kyu Kim,
  • Ji-Hyun Park,
  • Ju Ryeong Lee,
  • Dong Gyu Lee,
  • Gi Chan Lee,
  • Se Hee An,
  • Yun Hee Baek,
  • Young Ki Choi,
  • Hyunah Choo,
  • Hyo Yong Park,
  • Gyeongmin Kim,
  • Byungsun Jeon,
  • Sang Chul Shin,
  • Min-Suk Song

摘要

SARS-CoV-2 variants resistant to current antivirals remain a significant threat, particularly in high-risk patients. Although nirmatrelvir and ensitrelvir both target the viral 3CL protease (Mpro), their distinct susceptibility profiles may allow alternative therapeutic approaches. Here, we identify a deletion mutation at glycine 23 (Δ23G) in Mpro that conferred high-level resistance to ensitrelvir ( ~ 35-fold) while paradoxically increasing susceptibility to nirmatrelvir ( ~ 8-fold). This opposite susceptibility pattern is confirmed both in vitro and in a male hamster infection model. Recombinant viruses carrying Mpro-Δ23G exhibit impaired replication, pathogenicity, and transmissibility compared to wild-type, though the co-occurring mutation T45I partially restore viral fitness. Structural analyses reveal critical conformational changes in the catalytic loop (Ile136–Val148) and β-hairpin loop (Cys22–Thr26), directly influencing inhibitor binding selectivity. These results highlight differential resistance profiles of Mpro inhibitors, supporting potential sequential or alternative use of nirmatrelvir and ensitrelvir in patients requiring prolonged antiviral treatment.