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

• Published in: Acta pharmacologica Sinica Vol. 43; no. 4; pp. 781 - 787
• Main Authors: Wang, Yi, Fang, Sui, Wu, Yan, Cheng, Xi, Zhang, Lei-ke, Shen, Xu-rui, Li, Shuang-qu, Xu, Jian-rong, Shang, Wei-juan, Gao, Zhao-bing, Xia, Bing-qing
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.04.2022; Nature Publishing Group
• Subjects: Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antiviral drugs; Biomedical and Life Sciences; Biomedicine; Cell death; COVID-19; Disinfectants; High-throughput screening; High-Throughput Screening Assays; Humans; Immunology; Internal Medicine; Medical Microbiology; Molecular Docking Simulation; Molecular modelling; Natural products; Pharmacology/Toxicology; Proanthocyanidins; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Surface plasmon resonance; Therapeutic targets; Vaccine; SARS-CoV-2; cation channel; envelope protein (2-E); high-throughput screening (HTS); anti-virus
• ISSN: 1671-4083; 1745-7254; 1745-7254
• DOI: 10.1038/s41401-021-00732-2

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.