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

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

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 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13238-020-00768-w) contains supplementary material, which is available to authorized users.