文献类型：期刊文献

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

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

机构：[1]Wuhan Univ, Coll Life Sci, State Key Lab Virol, Wuhan 430072, Peoples R China;[2]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[3]Chinese Acad Sci, Ctr Biosafety Megasci, Wuhan Inst Virol, State Key Lab Virol, Wuhan 430071, Peoples R China;[4]Univ Chinese Acad Sci, Chinese Acad Sci, Inst Pasteur Shanghai, CAS Key Lab Mol Virol & Immunol, Shanghai 200031, Peoples R China

年份：2020

卷号：11

期号：10

起止页码：723

外文期刊名：PROTEIN & CELL

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000555738000001)】；

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 Manufacturing Program" of China (Grant 2018ZX09711002 to H.L.), Application & Frontier Research Program of Wuhan Government (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 thank Dr. Zhengli Shi for reviewing and Dr. Andy T. Y. 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 Zhang, and Ying Zhu for their efforts. We are grateful to Taikang Insurance Group Co., Ltd, Beijing Taikang Yicai Foundation, and Special Fund for COVID-19 Research of Wuhan University for their great supports to this work.

语种：英文

外文关键词：de novopyrimidine 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 EC(50)of 17 nmol/L and an SI 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 efficacyin vivoand 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.