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

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

机构地区：[1]Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical School,Beijing 100050,China [2]Institute of Pathogen Biology,Chinese Academy of Medical Sciences and Peking Union Medical School,Beijing 100730,China [3]Institute of Infectious Disease,Beijing Ditan Hospital,Capital Medical University,Beijing 100015,China [4]Lady Davis Institute,Jewish General Hospital,Mc Gill University,Montreal,Quebec H3T 1E2,Canada [5]CAMS Key Laboratory of Antiviral Drug Research,Peking Union Medical College,Chinese Academy of Medical Sciences,Beijing 100730,China

出　　处：《Acta Pharmaceutica Sinica B》2021年第6期1555-1567,共13页药学学报（英文版）

基　　金：supported by the National MegaProject for Infectious Disease (2018ZX10301408, China);the National Mega-Project for Significant New Drug Discovery (2018ZX09711003-002-002, China);the National Natural Science Foundation of China (81802019 and 81902075);the Beijing Natural Science Foundation (7184228, China);CAMS Innovation Fund for Medical Sciences (2018-I2M-3-004 and 2020-I2M-2010, China);the Peking Union Medical College Youth Fund (3332016063 and 3332018096, China)。

摘　　要：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(EC50) 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 antiSARS-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.

关 键 词：SARS-CoV-2 RDRP Structure-based virtual screening Viral replication Non-nucleoside inhibitor Drug combinations CORILAGIN 

分 类 号：R563.1[医药卫生—呼吸系统]