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

When we prepared the manuscript, a severe outbreak of SARS-CoV-2 occurred in Wuhan in December 2019, we responded quickly to examine the antiviral activity of DHODHi against this new coronavirus. The data in Fig. 2C showed that all the DHODHi tested is low toxic to SARS-CoV-2 susceptible Vero E6 cells. Teriflunomide had a solid antiviral efficacy of EC50=26.06uM (at MOI=0.05, ~2.4-fold stronger than Favipiravir [EC50=61.88μM] 29 ) (Fig. 2C upper right) , whereas its pro-drug Leflunomide showed less inhibition of EC50=63.56uM (data not shown). We therefore further did immuno-florescent assay to visualize the drug efficacy. To determine more carefully the efficacy of Teriflunomide, which can be transferred to clinical treatment of SARS-CoV-2 immediately as an approved drug, a bit low MOI of 0.03 (Fig. 2C upper left) were applied. In this condition, the EC50 of Teriflunomide could reach 6μM with SI>33, indicating that Teriflunomide with effective EC50 and SI values have all the potentials to treat SARS-CoV-2-induced COVID-19 disease as an 'old drug in new use' option.