文献类型：期刊文献

英文题名：Design, Synthesis, and Biological Evaluation of Peptidomimetic Aldehydes as Broad-Spectrum Inhibitors against Enterovirus and SARS-CoV-2

作者：Dai, Wenhao[1,2];Jochmans, Dirk[3];Xie, Hang[1];Yang, Hang[4];Li, Jian[1,5];Su, Haixia[1,2];Chang, Di[6];Wang, Jiang[1,2,7];Peng, Jingjing[1,2];Zhu, Lili[6];Nian, Yong[1,5];Hilgenfeld, Rolf[8,9];Jiang, Hualiang[1,2,7];Chen, Kaixian[1,2];Zhang, Leike[4];Xu, Yechun[1,2,7];Neyts, Johan[3];Liu, Hong[1,2,5,7]

机构：[1]Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China;[2]Univ Chinese Acad Sci, Beijing 100049, Peoples R China;[3]Katholieke Univ Leuven, Dept Microbiol & Immunol, Lab Virol & Chemotherapy, Rega Inst Med Res, B-3000 Leuven, Belgium;[4]Chinese Acad Sci, Ctr Biosafety Megasci, Wuhan Inst Virol, State Key Lab Virol, Wuhan 430071, Hubei, Peoples R China;[5]Nanjing Univ Chinese Med, Coll Pharm, Nanjing 210023, Peoples R China;[6]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[7]Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Beijing 100049, Peoples R China;[8]Univ Lubeck, Inst Mol Med, D-23562 Lubeck, Germany;[9]Univ Lubeck, German Ctr Infect Res DZIF, D-23562 Lubeck, Germany

年份：2022

卷号：65

期号：4

起止页码：2794

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000797940600005)】；

基金：We are grateful to the National Natural Science Foundation of China (21632008, 21672231, 21877122, 21877118, and 81620108027), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12040107 and XDA12040201), and the Youth Innovation Promotion Association CAS (grants 2018367 to L.-K.Z.) for financial support

语种：英文

摘要：A novel series of peptidomimetic aldehydes was designed and synthesized to target 3C protease (3C(pro)) of enterovirus 71 (EV71). Most of the compounds exhibited high antiviral activity, and among them, compound 18p demonstrated potent enzyme inhibitory activity and broad-spectrum antiviral activity on a panel of enteroviruses and rhinoviruses. The crystal structure of EV71 3C(pro) in complex with 18p determined at a resolution of 1.2 angstrom revealed that 18p covalently linked to the catalytic Cys147 with an aldehyde group. In addition, these compounds also exhibited good inhibitory activity against the 3CL(pro) and the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially compound 18p (IC50 = 0.034 mu M, EC50 = 0.29 mu M). According to our previous work, these compounds have no reasons for concern regarding acute toxicity. Compared with AG7088, compound 18p also exhibited good pharmacokinetic properties and more potent anticoronavirus activity, making it an excellent lead for further development.