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Structure-Based Development of Ultra-Broad-Spectrum 3C-Like Protease Inhibitors

文献类型：期刊论文

作者Su, Haixia1,6; Nie, Tianqing1,3,5; Chen, Guofeng1,8; Xiong, Muya1,8; Zhang, Yumin7; Wu, Guoqing1,8; You, Mengyuan1; Xie, Hang1; He, Jian1,6; Xiong, Yanchao1,6
刊名ADVANCED SCIENCE
出版日期2025-12-12
页码17
关键词3C-like protease conservation analysis of the binding pocket co-crystal structure structure-based drug design ultra-broad-spectrum inhibitors
DOI10.1002/advs.202512342
英文摘要Recurrence of coronavirus outbreaks and zoonotic origins of human coronaviruses underscore the importance of developing pan-coronavirus antivirals. The highly conserved 3C-like protease (3CLpro) in coronaviruses, together with the well-established druggability, makes it an ideal target for broad-spectrum antiviral therapeutics. Here, the inhibitory activity of approved 3CLpro inhibitors, including nirmatrelvir, ensitrelvir, and simnotrelvir, against fifteen 3CLpros is first reported by enzymatic assays. Despite their potent inhibition toward 3CLpros of beta-CoVs, these inhibitors show reduced potency against 3CLpros from the other three genera, particularly against two newly identified human coronaviruses (alpha-CCoV-HuPn-2018 and delta-PDCoV). In this context, continued efforts in structure-based optimization of nirmatrelvir lead to the identification of compound 8 that potently inhibits a panel of 32 3CLpros across all subgenera (IC50s: 19-146 nm), with an IC50 value of 61 and 81 nm against alpha-CCoV-HuPn-2018 and delta-PDCoV 3CLpros, respectively. Moreover, it effectively inhibits nirmatrelvir-resistant 3CLpro mutants and demonstrates broad-spectrum antiviral efficacy in cells. These findings suggest an important rule that a small, non-cyclic P2 segment and a P4 segment with a suitable size are preferred by the design of ultra-broad-spectrum 3CLpro inhibitors, and provide a proof-of-concept guide for developing broad-spectrum antivirals as potential pan-CoV therapeutics.
资助项目Strategic Priority Research Program of the Chinese Academy of Sciences[XDB0830000] ; National Natural Science Foundation of China[22277130] ; National Natural Science Foundation of China[22307133] ; National Natural Science Foundation of China[32301050] ; Research Program of Shanghai Institute of Materia Medica, the Chinese Academy of Sciences[SIMM0320231006] ; Research Program of Shanghai Institute of Materia Medica, the Chinese Academy of Sciences[SKLDR-2024-TT-03] ; National Key Research and Development Plan of China[2024YFC2607300] ; Hubei Natural Science Foundation for Distinguished Young Scholars[2022CFA099]
WOS研究方向Chemistry ; Science & Technology - Other Topics ; Materials Science
语种英语
WOS记录号WOS:001637226600001
出版者WILEY
源URL[http://119.78.100.183/handle/2S10ELR8/322390]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Su, Haixia; Zhang, Leike; Xu, Yechun
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Adv Res Inst, Shanghai Synchrotron Radiat Facil, Shanghai 201204, Peoples R China
3.ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai 201210, Peoples R China
4.Hubei Jiangxia Lab, Wuhan 430200, Peoples R China
5.Lingang Lab, Shanghai 200031, Peoples R China
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
7.Chinese Acad Sci, Wuhan Inst Virol, Ctr Biosafety Megasci, State Key Lab Virol, Wuhan 430071, Hubei, Peoples R China
8.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 Su, Haixia,Nie, Tianqing,Chen, Guofeng,et al. Structure-Based Development of Ultra-Broad-Spectrum 3C-Like Protease Inhibitors[J]. ADVANCED SCIENCE,2025:17.
APA Su, Haixia.,Nie, Tianqing.,Chen, Guofeng.,Xiong, Muya.,Zhang, Yumin.,...&Xu, Yechun.(2025).Structure-Based Development of Ultra-Broad-Spectrum 3C-Like Protease Inhibitors.ADVANCED SCIENCE,17.
MLA Su, Haixia,et al."Structure-Based Development of Ultra-Broad-Spectrum 3C-Like Protease Inhibitors".ADVANCED SCIENCE (2025):17.

入库方式： OAI收割

来源：上海药物研究所

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