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

Our data once again proved that DHODHi could further reduce cytokine storm than DAA drugs when using influenza-A-virus infected animal as a model. We believe that a similar immune-regulating role of DHODHi will exist in COVID-19 patients. Thus, by targeting DHODH, the single key enzyme in viral genome replication and immuneregulation, a dual-action of DHODH can be realized in fighting against a broad spectrum of viruses and the corresponding pathogenic-inflammation in severe infections. We hope our study may quickly and finally benefit the patients now suffering from severe COVID-19 and other infectious diseases caused by emerging and reemerging viruses. The copyright holder for this preprint (which was not peer-reviewed) is the . was kindly provided by Bo Zhang from Wuhan Virology Institute of CAS 52 . DHODH inhibitors S312 and S416 were synthesized using our previously reported synthetic routes 27, 53 . Leflunomide, Teriflunomide, Brequinar, Oseltamivir, Adenosine, Uridine, Cytidine, Guanosine, Orotic acid, Dihydroorotate were purchased from Sigma-Aldrich. The copyright holder for this preprint (which was not peer-reviewed) is the . DHODH in the cell was 20 µM, and the concentration of inhibitor in the syringe was 150 µM for S312 or 100 µM for S416. All titration experiments were performed by adding the inhibitor in steps of 2 µL. The data were analyzed using Microcal origin software by fitting to a one-site binding model.