A SARS-CoV-2 M^pro mutation conferring ensitrelvir resistance paradoxically increases nirmatrelvir susceptibility.

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 (M^pro), their distinct susceptibility profiles may allow alternative therapeutic approaches. Here, we identify a deletion mutation at glycine 23 (Δ23G) in M^pro 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^pro-Δ23G exhibit impaired replication, pathogenicity, and transmissibility compared to wild-type, though the co-occurring mutation T45I partiall

SUBMITTER: Min SC 

PROVIDER: S-EPMC12663368 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature