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Design, synthesis and biological evaluation of covalent peptidomimetic 3CL protease inhibitors containing nitrile moiety

文献类型：期刊论文

作者Zhu, Mengwei1,2,3; Fu, Tiantian1,2,3; You, Mengyuan4; Cao, Junyuan5,6; Yang, Hanxi7; Chen, Xinyao2,3,8; Zhang, Qiumeng9; Xu, Yechun4,9; Jiang, Xiangrui9; Zhang, Leike5,6
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2023-05-03
卷号87页码:12
关键词COVID-19 SARS-CoV-2 3CL protease Nirmatrelvir Peptidomimetic inhibitors
ISSN号0968-0896
DOI10.1016/j.bmc.2023.117316
通讯作者Zhang, Leike(zhangleike@wh.iov.cn) ; Su, Haixia(suhaixia1@simm.ac.cn) ; Zhang, Yan(zhang_yan@simm.ac.cn)
英文摘要In this paper, a series of peptidomimetic SARS-CoV-2 3CL protease inhibitors with new P2 and P4 positions were synthesized and evaluated. Among these compounds, 1a and 2b exhibited obvious 3CLpro inhibitory activities with IC50 of 18.06 nM and 22.42 nM, respectively. 1a and 2b also showed excellent antiviral activities against SARS-CoV-2 in vitro with EC50 of 313.0 nM and 170.2 nM, respectively, the antiviral activities of 1a and 2b were 2- and 4-fold better than that of nirmatrelvir, respectively. In vitro studies revealed that these two compounds had no significant cytotoxicity. Further metabolic stability tests and pharmacokinetic studies showed that the metabolic stability of 1a and 2b in liver microsomes was significantly improved, and 2b had similar pharmacokinetic parameters to that of nirmatrelvir in mice.
WOS关键词CORONAVIRUS ; 3CL(PRO) ; BINDING
资助项目National Key Research and Devel-opment Plan of China[2021YFC2300700] ; National Key Research and Devel-opment Plan of China[2022YFC2303300] ; Shanghai Institute of Materia Medica[SIMM010203] ; Strategic Priority Research Program of Chinese Academy of Sciences
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:001001290300001
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/306677]  
专题新药研究国家重点实验室
通讯作者Zhang, Leike; Su, Haixia; Zhang, Yan
作者单位1.Hui Univ Tradit Chinese Med, Coll Pharm, Hefei 230012, Peoples R China
2.Yangtze Delta Drug Adv Res Inst, Nantong 226133, Peoples R China
3.Yangtze Delta Pharmaceut Coll, Nantong 226133, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Chinese Acad Sci, Wuhan Inst Virol, Ctr Biosafety Mega Sci, State Key Lab Virol, Wuhan 430071, Hubei, Peoples R China
6.Hubei Jiangxia Lab, Wuhan 430200, Peoples R China
7.Zhengzhou Univ, Coll Chem, Zhengzhou 450001, Peoples R China
8.Shenyang Pharmaceut Univ, Wuya Coll Innovat, Shenyang 110016, Peoples R China
9.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zhu, Mengwei,Fu, Tiantian,You, Mengyuan,et al. Design, synthesis and biological evaluation of covalent peptidomimetic 3CL protease inhibitors containing nitrile moiety[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2023,87:12.
APA Zhu, Mengwei.,Fu, Tiantian.,You, Mengyuan.,Cao, Junyuan.,Yang, Hanxi.,...&Shen, Jingshan.(2023).Design, synthesis and biological evaluation of covalent peptidomimetic 3CL protease inhibitors containing nitrile moiety.BIOORGANIC & MEDICINAL CHEMISTRY,87,12.
MLA Zhu, Mengwei,et al."Design, synthesis and biological evaluation of covalent peptidomimetic 3CL protease inhibitors containing nitrile moiety".BIOORGANIC & MEDICINAL CHEMISTRY 87(2023):12.

入库方式： OAI收割

来源：上海药物研究所

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