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Discovery of SARS-CoV-2-E channel inhibitors as antiviral candidates
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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Singapore
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295639/ https://www.ncbi.nlm.nih.gov/pubmed/34294887 http://dx.doi.org/10.1038/s41401-021-00732-2 |
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author | 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 |
author_facet | 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 |
author_sort | Wang, Yi |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8295639 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer Singapore |
record_format | MEDLINE/PubMed |
spelling | pubmed-82956392021-07-22 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 Acta Pharmacol Sin Article 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. Springer Singapore 2021-07-22 2022-04 /pmc/articles/PMC8295639/ /pubmed/34294887 http://dx.doi.org/10.1038/s41401-021-00732-2 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article 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 Discovery of SARS-CoV-2-E channel inhibitors as antiviral candidates |
title | Discovery of SARS-CoV-2-E channel inhibitors as antiviral candidates |
title_full | Discovery of SARS-CoV-2-E channel inhibitors as antiviral candidates |
title_fullStr | Discovery of SARS-CoV-2-E channel inhibitors as antiviral candidates |
title_full_unstemmed | Discovery of SARS-CoV-2-E channel inhibitors as antiviral candidates |
title_short | Discovery of SARS-CoV-2-E channel inhibitors as antiviral candidates |
title_sort | discovery of sars-cov-2-e channel inhibitors as antiviral candidates |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295639/ https://www.ncbi.nlm.nih.gov/pubmed/34294887 http://dx.doi.org/10.1038/s41401-021-00732-2 |
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