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

Acta Pharmacol Sin. 2022 Apr;43(4):781-787. doi: 10.1038/s41401-021-00732-2. Epub 2021 Jul 22.


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

MeSH terms

  • Antiviral Agents* / chemistry
  • Antiviral Agents* / pharmacology
  • COVID-19*
  • High-Throughput Screening Assays
  • Humans
  • Molecular Docking Simulation
  • SARS-CoV-2


  • Antiviral Agents