Corilagin inhibits SARS-CoV-2 replication by targeting viral RNA-dependent RNA polymerase

Li, Quanjie; Yi, Dongrong; Lei, Xiaobo; Zhao, Jianyuan; Zhang, Yongxin; Cui, Xiangling; Xiao, Xia; Jiao, Tao; Dong, Xiaojing; Zhao, Xuesen; Zeng, Hui; Liang, Chen; Ren, Lili; Guo, Fei; Li, Xiaoyu; Wang, Jianwei; Cen, Shan

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become one major threat to human population health. The RNA-dependent RNA polymerase (RdRp) presents an ideal target of antivirals, whereas nucleoside analogs inhibitor is hindered by the proofreading activity of coronavirus. Herein, we report that corilagin (RAI-S-37) as a non-nucleoside inhibitor of SARS-CoV-2 RdRp, binds directly to RdRp, effectively inhibits the polymerase activity in both cell-free and cell-based assays, fully resists the proofreading activity and potently inhibits SARS-CoV-2 infection with a low 50% effective concentration (EC(50)) value of 0.13 μmol/L. Computation modeling predicts that RAI-S-37 lands at the palm domain of RdRp and prevents conformational changes required for nucleotide incorporation by RdRp. In addition, combination of RAI-S-37 with remdesivir exhibits additive activity against anti-SARS-CoV-2 RdRp. Together with the current data available on the safety and pharmacokinetics of corilagin as a medicinal herbal agent, these results demonstrate the potential of being developed into one of the much-needed SARS-CoV-2 therapeutics.