RT Journal Article SR Electronic T1 Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2 JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.03.11.983056 DO 10.1101/2020.03.11.983056 A1 Rui Xiong A1 Leike Zhang A1 Shiliang Li A1 Yuan Sun A1 Minyi Ding A1 Yong Wang A1 Yongliang Zhao A1 Yan Wu A1 Weijuan Shang A1 Xiaming Jiang A1 Jiwei Shan A1 Zihao Shen A1 Yi Tong A1 Liuxin Xu A1 Chen Yu A1 Yingle Liu A1 Gang Zou A1 Dimitri Lavillete A1 Zhenjiang Zhao A1 Rui Wang A1 Lili Zhu A1 Gengfu Xiao A1 Ke Lan A1 Honglin Li A1 Ke Xu YR 2020 UL http://biorxiv.org/content/early/2020/03/12/2020.03.11.983056.abstract AB Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of coronavirus SARS-CoV-2. Existing direct-acting antiviral (DAA) drugs cannot be applied immediately to new viruses because of virus-specificity, and the development of new DAA drugs from the beginning is not timely for outbreaks. Thus, host-targeting antiviral (HTA) drugs have many advantages to fight against a broad spectrum of viruses, by blocking the viral replication and overcoming the potential viral mutagenesis simultaneously. Herein, we identified two potent inhibitors of DHODH, S312 and S416, with favorable drug-like and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus (H1N1, H3N2, H9N2), Zika virus, Ebola virus, and particularly against the recent novel coronavirus SARS-CoV-2. 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 knocking-out cells. We also proposed the drug combination of DAA and HTA was a promising strategy for anti-virus treatment and proved that S312 showed more advantageous than Oseltamivir to treat advanced influenza diseases in severely infected animals. Notably, S416 is reported to be the most potent inhibitor with an EC50 of 17nM and SI value >5882 in SARS-CoV-2-infected cells so far. This work demonstrates that both our self-designed candidates and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-repression may have clinical potentials not only to influenza but also to COVID-19 circulating worldwide, no matter such viruses mutate or not.