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

Although several DHODHi have been documented to be antiviral by high-throughput screening [34] [35] [36] [37] . Most of these compounds are still at cell culture level with unknown in vivo efficacy. Therefore, the development of broad-spectrum antiviral agents targeting DHODH is still an exciting avenue in antiviral research. S312 and S416 present more potent inhibition and favorable pharmacokinetic profiles, moreover, the half-lives of S312 and S416 (8.20 and 9.12 h, respectively) are much shorter and more appropriate than that of Teriflunomide, indicating that they may have less possibility to bring toxic side effects from drug accumulation in the body. Strikingly, S312 showed active effects in vivo in lethal dose infection of influenza A viruses not only when used from the beginning of infection but also in the late phase when DAA drug is not responding anymore. Another surprise is the high SI value of S416 to against Zika (SI=1087.62), Ebola (SI=4746.11), and the current SARS-CoV-2 (SI>5882). These data interpreted that S416 is highly promising to develop further as it should be to S312. The extremely high SI of S416 may be due to its high binding affinity and favorable occupation of the ubiquinone-binding site of DHODH with faster-associating characteristics (kon = 1.76×10 6 M -1 s -1 ) and slower dissociating binding characteristic (koff=2.97×10 -3 s -1 ), which will reduce the possibility of off-target in vivo.