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Discovery and Mechanism Study of SARS-CoV-2 3C-like Protease Inhibitors with a New Reactive Group

文献类型：期刊论文

作者Ren, Pengxuan1,2; Li, Hui3,4; Nie, Tianqing4; Jian, Xiaoqin5; Yu, Changyue4; Li, Jian4; Su, Haixia4; Zhang, Xianglei1,2; Li, Shiwei1,2; Yang, Xin1,2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-08-18
页码18
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c00818
通讯作者Zhang, Leike(zhangleike@wh.iov.cn) ; Xu, Yechun(ycxu@simm.ac.cn) ; Liu, Hong(hliu@simm.ac.cn) ; Bai, Fang(baifang@shanghaitech.edu.cn)
英文摘要3CL(pro) is an attractive target for the treatmentofCOVID-19. Using the scaffold hopping strategy, we identified a potentinhibitor of 3CL(pro) (3a) that contains a thiocyanatemoiety as a novel warhead that can form a covalent bond with Cys145of the protein. Tandem mass spectrometry (MS/MS) and X-ray crystallographyconfirmed the mechanism of covalent formation between 3a and the protein in its catalytic pocket. Moreover, several analoguesof compound 3a were designed and synthesized. Among them,compound 3h shows the best inhibition of 3CL(pro) with an IC50 of 0.322 & mu;M and a k (inact)/K (i) value of 1669.34M(-1) s(-1), and it exhibits goodtarget selectivity for 3CL(pro) against host proteases. Compound 3c inhibits SARS-CoV-2 in Vero E6 cells (EC50 =2.499 & mu;M) with low cytotoxicity (CC50 > 200 & mu;M).These studies provide ideas and insights to explore and develop new3CL(pro) inhibitors in the future.
WOS关键词ARYLOXYETHYL THIOCYANATE DERIVATIVES ; MOLECULAR-ORBITAL THEORY ; MAIN PROTEASE ; COVALENT INHIBITORS ; DESIGN ; PENICILLAMINE ; PHARMACOLOGY ; CLOPIDOGREL ; TARGET ; MODEL
资助项目Science and Technology Commission of Shanghai Municipality grants[20QA1406400] ; Science and Technology Commission of Shanghai Municipality grants[20430780300] ; Science and Technology Commission of Shanghai Municipality grants[22YF1457300] ; National Key Ramp;D Program of China[2022YFC3400501] ; Lingang Laboratory[LG202102-01-03] ; Lingang Laboratory[LG202103-04-03] ; Lingang Laboratory[LG-QS-202205-02] ; National Natural Science Foundation of China[82003654] ; ShanghaiTech University ; Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine at ShanghaiTech University
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001051340300001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/306953]  
专题新药研究国家重点实验室
通讯作者Zhang, Leike; Xu, Yechun; Liu, Hong; Bai, Fang
作者单位1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
2.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Chinese Acad Sci, Wuhan Inst Virol, Ctr Biosafety Mega Sci, State Key Lab Virol, Wuhan 430071, Peoples R China
6.Chinese Acad Sci, Shanghai Adv Res Inst, Natl Facil Prot Sci Shanghai, Shanghai 201210, Peoples R China
7.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
8.ShanghaiTech Univ, Sch Informat Sci & Technol, Shanghai 201210, Peoples R China
9.Shanghai Clin Res & Trial Ctr, Shanghai 201210, Peoples R China
推荐引用方式
GB/T 7714		 Ren, Pengxuan,Li, Hui,Nie, Tianqing,et al. Discovery and Mechanism Study of SARS-CoV-2 3C-like Protease Inhibitors with a New Reactive Group[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023:18.
APA Ren, Pengxuan.,Li, Hui.,Nie, Tianqing.,Jian, Xiaoqin.,Yu, Changyue.,...&Bai, Fang.(2023).Discovery and Mechanism Study of SARS-CoV-2 3C-like Protease Inhibitors with a New Reactive Group.JOURNAL OF MEDICINAL CHEMISTRY,18.
MLA Ren, Pengxuan,et al."Discovery and Mechanism Study of SARS-CoV-2 3C-like Protease Inhibitors with a New Reactive Group".JOURNAL OF MEDICINAL CHEMISTRY (2023):18.

入库方式： OAI收割

来源：上海药物研究所

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