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

Yi Wang1,2, Sui Fang1, Yan Wu3, Xi Cheng1,2, Lei-ke Zhang3, Xu-rui Shen1,2, Shuang-qu Li1,2, Jian-rong Xu4,5, Wei-juan Shang3, Zhao-bing Gao1,2,6, Bing-qing Xia1,2
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
Correspondence to: Wei-juan Shang:, Zhao-bing Gao:, Bing-qing Xia:,
DOI: 10.1038/s41401-021-00732-2
Received: 23 February 2021
Accepted: 29 June 2021
Advance online: 22 July 2021


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.
Keywords: SARS-CoV-2; envelope protein (2-E); cation channel; high-throughput screening (HTS); anti-virus

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