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

Acute viral infections usually cause severe complications associated with hyper induction of pro-inflammatory cytokines, which is also known as "cytokine storm" firstly named in severe influenza disease 38, 39 . Several studies showed that lethal SARS patients expressed high serum levels of pro-inflammatory cytokines (IFN-γ, IL-1, IL-6, IL-12, and TGFβ) and chemokines (CCL2, CXCL10, CXCL9, and IL-8) compared to uncomplicated SARS patients [40] [41] [42] [43] . Similarly, in severe COVID-19 cases, ICU patients had higher plasma levels of IL-2, IL-7, IL-10, GSCF, MCP1, MIP1A, and TNFα compared to non-ICU patients 44 . Moreover, A clinical study of 123 patients with . 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 It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.11.983056 doi: bioRxiv preprint COVID-19 showed that the percentage of patients with IL-6 above normal is higher in severe group 45 . In terms of treatment, immunomodulatory agents can reduce mortality and organ injury of severe influenza. However, these immunomodulatory are mostly non-specific to viral infection but rather a systemic regulation, such as corticosteroid, intravenous immunoglobulin (IVIG) or angiotensin receptor blockers [46] [47] [48] [49] . Leflunomide and its active metabolite Teriflunomide have been approved for clinical treatment for excessive inflammatory diseases such as rheumatoid arthritis and multiple sclerosis 50 .