文献类型：期刊文献

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

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

机构：[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

年份：2020

卷号：11

期号：10

起止页码：723

中文期刊名：Protein & Cell

外文期刊名：蛋白质与细胞（英文版）

收录：CSTPCD;;Scopus;CSCD:【CSCD2019_2020】；PubMed;

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.

语种：英文

中文关键词：de novo pyrimidine biosynthesis;DHODH inhibitors;SARS-CoV-2;influenza viruses;virus replication;immuno-regulation

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.