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

It is known that severe acute infections including influenza and COVID-19 always induce pathogenic immunity as cytokine/chemokine storms. Leflunomide and Teriflunomide are already clinically used in autoimmune disease to inhibit pathogenic cytokines and chemokines. We, therefore, suspect that DHODHi should also be anticytokine-storm in viral infectious disease. BALF from either Osel-or 'S312+Osel'treated mice were collected at D14 in an independently repeated experiment with a . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . lower infection dose. A parallel body weights excluded differences in virus load (Supplementary Fig. 4A) . The data in Supplementary Fig. 4B showed that the pathogenic inflammatory cytokines in 'S312+Osel'-treated group was largely reduced as compared to Osel-treated mouse in the levels of IL6, MCP-1, IL5, KC/GRO(CXCL1), IL2, IFN-γ, IP-10, IL9, TNF-α, GM-CSF, EPO, IL12p70, MIP3α and IL17A/F (listed in the order of reduce significance).