A SARS-CoV-2 Mpro mutation conferring ensitrelvir resistance paradoxically increases nirmatrelvir susceptibility DOI
Min‐Suk Song, Seong Cheol Min,

Jin-Ju Seo

и другие.

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Апрель 21, 2025

Abstract 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 identified novel deletion mutation at glycine 23 (Δ23G) Mpro that conferred substantial resistance (~ 35-fold) while paradoxically increasing 8-fold). This opposite pattern was confirmed vitro hamster infection model. Recombinant viruses carrying Mpro-Δ23G exhibited impaired replication, pathogenicity, transmissibility compared wild-type, though co-occurring T45I partially restored fitness. Structural analyses revealed critical conformational changes catalytic loop (Ile136–Val148) β-hairpin (Cys22–Thr26), directly influencing inhibitor binding selectivity. These results highlight differential of inhibitors, supporting potential sequential or use patients requiring prolonged antiviral treatment.

Язык: Английский

A SARS-CoV-2 Mpro mutation conferring ensitrelvir resistance paradoxically increases nirmatrelvir susceptibility DOI
Min‐Suk Song, Seong Cheol Min,

Jin-Ju Seo

и другие.

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Апрель 21, 2025

Abstract 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 identified novel deletion mutation at glycine 23 (Δ23G) Mpro that conferred substantial resistance (~ 35-fold) while paradoxically increasing 8-fold). This opposite pattern was confirmed vitro hamster infection model. Recombinant viruses carrying Mpro-Δ23G exhibited impaired replication, pathogenicity, transmissibility compared wild-type, though co-occurring T45I partially restored fitness. Structural analyses revealed critical conformational changes catalytic loop (Ile136–Val148) β-hairpin (Cys22–Thr26), directly influencing inhibitor binding selectivity. These results highlight differential of inhibitors, supporting potential sequential or use patients requiring prolonged antiviral treatment.

Язык: Английский

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