Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

查看全文 作　　者：Rui [2]Xiong;Leike [3]Zhang;Shiliang [2]Li;Yuan [3]Sun;Minyi [2]Ding;Yong [1]Wang;Yongliang [1]Zhao;Yan [3]Wu;Weijuan [3]Shang;Xiaming [3]Jiang;Jiwei [2]Shan;Zihao [2]Shen;Yi [2]Tong;Liuxin [2]Xu;Yu [1]Chen;Yingle [1]Liu;Gang [4]Zou;Dimitri [4]Lavillete;Zhenjiang [2]Zhao;Rui [2]Wang;Lili [2]Zhu;Gengfu [3]Xiao;Ke [1]Lan;Honglin [2]Li;Ke [1,4]Xu

机构地区：[1]State Key Laboratory of Virology,College of Life Sciences,Wuhan University,Wuhan 430072,China;[2]Shanghai Key Laboratory of New Drug Design,State Key Laboratory of Bioreactor Engineering,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China;[3]State Key Laboratory of Virology,Wuhan Institute of Virology,Center for Biosafety Mega-Science,Chinese Academy of Sciences,Wuhan 430071,China;[4]CAS Key Laboratory of Molecular Virology and Immunology,Institut Pasteur of Shanghai,University of Chinese Academy of Sciences,Chinese Academy of Sciences,Shanghai 200031,China

出　　处：《Protein & Cell》索引2020年第11卷第10期,共17页

基　　金：This work was supported in part by the National Key Research and Development Program Grants(2018FYA0900801 and 2018ZX10101004003001 to K.X.2016YFA0502304 to H.L.);the National Natural Science Foundation of China(Grants 31922004 and 81772202 to K.X.,81825020 to H.L.);the National Science&Technology Major Project'Key New Drug Creation and Manufac-turing Program'of China(Grant 2018ZX09711002 to H.L.);Appli-cation&Frontier Research Program of Wuhan Govemment(2019020701011463 to K.X.).Honglin Li is also sponsored by the National Program for Special Supports of Eminent Professionals and National Program for Support of Top-Notch Young Professionals;We are grateful to Taikang Insurance Group Co,Ltd,Beiing Taikang Yicai Foundation,and Special Fund for COVID-19 Research of Wuhan University for their great supports to this work. 摘　　要：Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide,such as the on-going outbreak of the novel coronavirus SARS-CoV-2.Herein,we identified two potent inhibitors of human DHODH,S312 and S416,with favorable drug-likeness and pharmacokinetic profiles,which all showed broad-spectrum antiviral effects against various RNA viruses,including influenza A virus,Zika virus,Ebola virus,and particularly against SARS-CoV-2.Notably,S416 is reported to be the most potent inhibitor so far with an EC5o of 17 nmol/L and an SI value of 10,505.88 in infec-ted cells.Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells.This work demonstrates that both S312/S416 and old drugs(Leflunomide/Teriflunomide)with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide,no matter such viruses are mutated or not. 关键词：de novo pyrimidine biosynthesis DHODH inhibitors SARS-CoV-2 influenza viruses virus replication immuno-regulation

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Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

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