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

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

To identify potent and low-toxicity DHODH inhibitors (DHODHi), we previously conducted a hierarchal structure-based virtual screening (Fig. 1A) against ~280,000 compounds library towards the ubiquinone-binding site of DHODH 26 . We finally obtained two highly potent DHODHi S312 and S416 with IC50s of 29.2 nM and 7.5 nM through structural optimization 27, 28 , which are > 10-folds potent than the FDA approved DHODHi Teriflunomide (IC50 of 307.1 nM). By using these two potent inhibitors, we could fully evaluate DHODH as a valuable host target both in infected cells and in vivo in infected animals. We identified that targeting DHODH offers broad-spectrum antiviral efficacies against various RNA viruses, including the DAA-resistant influenza virus and the newly emerged coronavirus SARS-CoV-2. Especially, our potent DHODHi can protect 100% mice from lethal influenza challenge, which is as good as the DAA drugs, and is even effective in the late phase of infection when DAA drug is no longer responding.