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

导出学术成果认领

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 broadspectrum 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 EC50 of 17 nmol/L and an Sl value of 10,505.88 in infected 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/Terifiunomide) 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.

作者 Rui Xiong ^[1] Leike Zhang ^[2] Shiliang Li ^[1] Yuan Sun ^[2] Minyi Ding ^[1] Yong Wang ^[3] Yongliang Zhao ^[3] Yan Wu ^[2] Weijuan Shang ^[2] Xiaming Jiang ^[2] Jiwei Shan ^[1] Zihao Shen ^[1] Yi Tong ^[1] Liuxin Xu ^[1] Yu Chen ^[3] Yingle Liu ^[3] Gang Zou ^[4] Dimitri Lavillete ^[4] Zhenjiang Zhao ^[1] Rui Wang ^[1] Lili Zhu ^[1] Gengfu Xiao ^[2] Ke Lan ^[3] Honglin Li ^[1] Ke Xu ^[5] 学术成果认领

作者单位 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 ^[1] State Key Laboratory of Virology,Wuhan Institute of Virology,Center for Biosafety Mega-Science,Chinese Academy of Sciences,Wuhan 430071,China ^[2] State Key Laboratory of Virology,College of Life Sciences,Wuhan University,Wuhan 430072,China ^[3] 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 ^[4] State Key Laboratory of Virology,College of Life Sciences,Wuhan University,Wuhan 430072,China;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 ^[5]

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

栏目名称 RESEARCH ARTICLES

发布时间 2020-11-23

基金项目

This work was supported in part by the National Key Research and Development Program Grants the National Natural Science Foundation of China the National Science &Technology Major Project "Key New Drug Creation and Manufacturing Program" of China Application & Frontier Research Program of Wuhan Government 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 thank Dr Zhengli Shi for reviewing and Dr Andy T Lau for English proofreading of this manuscript We also thank our group members of the SARS-CoV-2 working group in State Key Laboratory of Virology,Wuhan University,who work tightly together during this new virus outbreak inside and outside of Wuhan city for their research spirits and courage,especially to Fang Liu,Qi Zhang,Ming Guo,Yuan Liu,Yan We are grateful to Taikang Insurance Group Co.,L td,Beijing Taikang Yicai Foundation,and Special Fund for COVID-19 Research of Wuhan University for their great supports to this work

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