TY - JOUR AU - Wang Yi AU - Fang Sui AU - Wu Yan AU - Cheng Xi AU - Zhang Lei-ke AU - Shen Xu-rui AU - Li Shuang-qu AU - Xu Jian-rong AU - Shang Wei-juan AU - Gao Zhao-bing AU - Xia Bing-qing PY - 2022 TI - Discovery of SARS-CoV-2-E channel inhibitors as antiviral candidates JF - Acta Pharmacologica Sinica; Vol 43, No 4 (April 2022): Acta Pharmacologica Sinica Y2 - 2022 KW - N2 - 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 ( K D ) 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. UR - http://www.chinaphar.com/article/view/10519