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Article

Next-generation inhibitors of SARS-CoV-2 Mpro overcome the deficiencies of Paxlovid.

Nature communications - 4 Apr 2026

Luo Gan, Wang Gang, Liao Chongbing, Zhong Baisen, Fan Lianfeng, Zhang Jue, Rao Jie, Zhang Junjie, Wang Ziqiao, Luo Man, Yan Yan, Lu Lu, Xu Wei, Wu Fan, Gao Xihui, Lu Wuyuan

Abstract excerpt

It remains elusive to design peptidomimetic inhibitors of SARS-CoV-2 main protease (Mpro) refractory to multiple deficiencies of Paxlovid (ritonavir-boosted nirmatrelvir), pertaining mainly to E166X mutations-conferred drug resistance and inherent pharmacokinetic limitations to nirmatrelvir. We identify via virtual screening an iso-quinoline P1 moiety in place of the traditional γ-lactam and design...

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Identifiers

PMID: 41935038
DOI: 10.1038/s41467-026-71436-6
PMCID: PMC13230851

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