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 documented elsewhere that DAA drugs such as Osel is only completely effective in the early phase of infection, optimally within 48 hours of symptom onset 31 . And till now, there is no approved drug to treat advanced influenza disease at the late phase specifically. We suppose that S312 could be effective in the middle or late phase of disease because it targets a host pro-viral factor of DHODH not affected by viral replication cycle. To test this, we compared the therapeutic windows of S312 and Osel in early (D3-D7), middle & late (D5-D9)，severe late (D7-D11 or D6-D14) phases (workflow shown in Fig. 5A ). When drugs were given in the early phase, both Oseltreatment and 'Osel+S312'-combination-treatment conferred 100% protection (Fig. 5B ). When drugs were given at the middle & late phase (Fig. 5C) , single Osel-treatment wholly lost its antiviral effect with no surviving. However, S312-treatment could provide 50% protection, and drug combination reached to 100% protection. When drugs were given at severe late phase of disease that mice were starting dying (Fig. 5D) , neither single treatment of Osel nor S312 can rescue the mice from death but combined treatment still conferred to 25% survival. To really show the advantage of S312 in treating severe disease, we additionally treated the mice a bit early before dying around 80% of initial weights (D6-D14) with a more optimal dose of S312 (5mg/kg). The data in Fig. 5E showed that S312 rescued 50% of mice from severe body-weight losses, and combined treatment coffered additional 25% survival. These results once again highlight that S312 has remarkable advantages over Osel to treat severe diseases at the late phase, and its therapeutic effectiveness could even be improved when S312 was combined with DAA drug.