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Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease

文献类型：期刊论文

作者Su, Haixia1,2,3; Yao, Sheng3,4,5; Zhao, Wenfeng1,2; Zhang, Yumin6; Liu, Jia3,4,5; Shao, Qiang1,2; Wang, Qingxing3,6; Li, Minjun7; Xie, Hang1,2; Shang, Weijuan6
刊名NATURE COMMUNICATIONS
出版日期2021-06-15
卷号12期号:1页码:12
ISSN号2041-1723
DOI10.1038/s41467-021-23751-3
通讯作者Zhang, Leike(zhangleike@wh.iov.cn) ; Ye, Yang(yye@simm.ac.cn) ; Xu, Yechun(ycxu@simm.ac.cn)
英文摘要The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CL(pro)) is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CL(pro). Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CL(pro)s, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands. SARS-CoV-2 3CL protease (3CL(pro)) is essential for coronavirus replication and of great interest as an antiviral drug target. Here, the authors show that the naturally occurring flavonoid myricetin is a non-peptidomimetic and covalent inhibitor of 3CL(pro), and they solve crystal structures of 3CL(pro) with myricetin and derivatives, which reveal that the pyrogallol group covalently modifies the catalytic cysteine.
WOS关键词ACCELERATED MOLECULAR-DYNAMICS ; DRUG DISCOVERY ; CORONAVIRUS ; SARS ; MYRICETIN ; KINETICS ; CYSTEINE ; VIRUS ; PERSPECTIVE ; INTEGRATION
资助项目National Key R&D Program of China[2016YFA0502301] ; National Key R&D Program of China[2017YFB0202604] ; National Natural Science Foundation of China[21877122] ; National Natural Science Foundation of China[91953000] ; National Natural Science Foundation of China[32071248] ; National Natural Science Foundation of China[21920102003] ; Science and Technology Commission of Shanghai Municipality[20430780300] ; Science and Technology Commission of Shanghai Municipality[18430712500] ; International Partnership Program of Chinese Academy of Sciences[153631KYSB20160004] ; International Partnership Program of Chinese Academy of Sciences[153631KYSB20170043]
WOS研究方向Science & Technology - Other Topics
语种英语
出版者NATURE RESEARCH
WOS记录号WOS:000665021800005
源URL[http://119.78.100.183/handle/2S10ELR8/296826]  
专题新药研究国家重点实验室
通讯作者Zhang, Leike; Ye, Yang; Xu, Yechun
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai, Peoples R China
3.Univ Chinese Acad Sci, Beijing, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Nat Prod Chem Dept, Shanghai, Peoples R China
6.Chinese Acad Sci, Ctr Biosafety Mega Sci, Wuhan Inst Virol, State Key Lab Virol, Wuhan, Peoples R China
7.Chinese Acad Sci, Shanghai Adv Res Inst, Shanghai Synchrotron Radiat Facil, Shanghai, Peoples R China
8.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai, Peoples R China
9.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
10.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Peoples R China
推荐引用方式
GB/T 7714		 Su, Haixia,Yao, Sheng,Zhao, Wenfeng,et al. Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease[J]. NATURE COMMUNICATIONS,2021,12(1):12.
APA Su, Haixia.,Yao, Sheng.,Zhao, Wenfeng.,Zhang, Yumin.,Liu, Jia.,...&Xu, Yechun.(2021).Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease.NATURE COMMUNICATIONS,12(1),12.
MLA Su, Haixia,et al."Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease".NATURE COMMUNICATIONS 12.1(2021):12.

入库方式： OAI收割

来源：上海药物研究所

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