Discovery of SARS-CoV-2-E channel inhibitors as antiviral candidates  

作　　者：Yi Wang Sui Fang Yan Wu Xi Cheng Lei-ke Zhang Xu-rui Shen Shuang-qu Li Jian-rong Xu Wei-juan Shang Zhao-bing Gao Bing-qing Xia 

机构地区：[1]CAS Key Laboratory of Receptor Research,Stake Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [2]University of Chinese Academy of Sciences,Beijing,100049,China [3]State Key Laboratory of Virology,Wuhan Institute of Virology,Center for Biosafety Mega-Science,Chinese Academy of Sciences,Wuhan,430071,China [4]Academy of Integrative Medicine,Shanghai University of Traditional Chinese Medicine,Shanghai,201203,China [5]Department of Pharmacology and Chemical Biology,Shanghai Jiao Tong University School of Medicine,Shanghai,200025,China [6]Zhongshan Institute of Drug Discovery,Institution for Drug Discovery Innovation,Chinese Academy of Science,Zhongshan,528400,China

出　　处：《Acta Pharmacologica Sinica》2022年第4期781-787,共7页中国药理学报（英文版）

基　　金：We are grateful to the National Science Fund of Distinguished Young Scholars(81825021);Fund of Youth Innovation Promotion Association(2019285);the National Natural Science Foundation of China(81773707,31700732);Fund of Shanghai Science and Technology Innovation Action Plan(20ZR1474200);the National Key Research and Development Program of China(2020YFC0842000);the Strategic Leading Science and Technology Projects of Chinese Academy of Sciences(XDA12050308);Fund of National Science and Technology Major Project(2018ZX09711002-002-006);the Hubei Science and Technology Project(2020FCA003)for financial support.

摘　　要：Lack of efficiency has been a major problem shared by all currently developed anti-SARS-CoV-2 therapies. Our previous study shows that SARS-CoV-2 structural envelope (2-E) protein forms a type of cation channel, and heterogeneously expression of 2-E channels causes host cell death. In this study we developed a cell-based high throughput screening (HTS) assay and used it to discover inhibitors against 2-E channels. Among 4376 compounds tested, 34 hits with cell protection activity were found. Followed by an anti-viral analysis, 15 compounds which could inhibit SARS-CoV-2 replication were identified. In electrophysiological experiments, three representatives showing inhibitory effect on 2-E channels were chosen for further characterization. Among them, proanthocyanidins directly bound to 2-E channel with binding affinity (KD) of 22.14 μM in surface plasmon resonance assay. Molecular modeling and docking analysis revealed that proanthocyanidins inserted into the pore of 2-E N-terminal vestibule acting as a channel blocker. Consistently, mutations of Glu 8 and Asn 15, two residues lining the proposed binding pocket, abolished the inhibitory effects of proanthocyanidins. The natural product proanthocyanidins are widely used as cosmetic, suggesting a potential of proanthocyanidins as disinfectant for external use. This study further demonstrates that 2-E channel is an effective antiviral drug target and provides a potential antiviral candidate against SARS-CoV-2.

关 键 词：SARS-CoV-2 envelope protein(2-E) cation channel high-throughput screening(HTS) ANTI-VIRUS 

分 类 号：R965[医药卫生—药理学] R51[医药卫生—药学]