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Discovery of SARS-CoV-2-E channel inhibitors as antiviral candidates.
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.
  • Wang Y; CAS Key Laboratory of Receptor Research, Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Fang S; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • Wu Y; CAS Key Laboratory of Receptor Research, Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Cheng X; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.
  • Zhang LK; CAS Key Laboratory of Receptor Research, Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Shen XR; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • Li SQ; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.
  • Xu JR; CAS Key Laboratory of Receptor Research, Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Shang WJ; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • Gao ZB; CAS Key Laboratory of Receptor Research, Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Xia BQ; University of Chinese Academy of Sciences, Beijing, 100049, China.
Acta Pharmacol Sin ; 43(4): 781-787, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1387237
ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / COVID-19 Limits: Humans Language: English Journal: Acta Pharmacol Sin Journal subject: Pharmacology Year: 2022 Document Type: Article Affiliation country: S41401-021-00732-2

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / COVID-19 Limits: Humans Language: English Journal: Acta Pharmacol Sin Journal subject: Pharmacology Year: 2022 Document Type: Article Affiliation country: S41401-021-00732-2