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

There are only a few inhibitors against pyrimidine synthesis that can be carried forward to animal studies, however, their antiviral efficacies were unsatisfactory or even ineffective at all 12, 16, 17, 21, [23] [24] [25] . For example, a pyrimidine synthesis inhibitor FA-613 without a specific target protected only 30.7% of mice from lethal influenza A virus infection when compared to the DAA drug Zanamivir (100%) in parallel 23 . Another two compounds, Cmp1 24 and FK778 25 , which target DHODH, a rate-limiting enzyme in the fourth step of the de novo pyrimidine synthesis pathway, could only inhibit the DNA virus (CMV) replication in RAG -/mice, but their therapeutic effects on the upcoming diseases were unexplored. Therefore, more potent pyrimidine synthesis inhibitors, especially ones with the specific drug target, are urgent to be developed to prove whether such an HTA drug is valuable towards clinical use or has any advantages over DAA drugs in antiviral treatment.