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Inhibitor Development against p7 Channel in Hepatitis C Virus

Hepatitis C Virus (HCV) is the key cause of chronic and severe liver diseases. The recent direct-acting antiviral agents have shown the clinical success on HCV-related diseases, but the rapid HCV mutations of the virus highlight the sustaining necessity to develop new drugs. p7, the viroporin protei...

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Autores principales: Wei, Shukun, Hu, Xiaoyou, Du, Lingyu, Zhao, Linlin, Xue, Hongjuan, Liu, Chaolun, Chou, James J., Zhong, Jin, Tong, Yimin, Wang, Shuqing, OuYang, Bo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961618/
https://www.ncbi.nlm.nih.gov/pubmed/33802584
http://dx.doi.org/10.3390/molecules26051350
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author Wei, Shukun
Hu, Xiaoyou
Du, Lingyu
Zhao, Linlin
Xue, Hongjuan
Liu, Chaolun
Chou, James J.
Zhong, Jin
Tong, Yimin
Wang, Shuqing
OuYang, Bo
author_facet Wei, Shukun
Hu, Xiaoyou
Du, Lingyu
Zhao, Linlin
Xue, Hongjuan
Liu, Chaolun
Chou, James J.
Zhong, Jin
Tong, Yimin
Wang, Shuqing
OuYang, Bo
author_sort Wei, Shukun
collection PubMed
description Hepatitis C Virus (HCV) is the key cause of chronic and severe liver diseases. The recent direct-acting antiviral agents have shown the clinical success on HCV-related diseases, but the rapid HCV mutations of the virus highlight the sustaining necessity to develop new drugs. p7, the viroporin protein from HCV, has been sought after as a potential anti-HCV drug target. Several classes of compounds, such as amantadine and rimantadine have been testified for p7 inhibition. However, the efficacies of these compounds are not high. Here, we screened some novel p7 inhibitors with amantadine scaffold for the inhibitor development. The dissociation constant (Kd) of 42 ARD-series compounds were determined by nuclear magnetic resonance (NMR) titrations. The efficacies of the two best inhibitors, ARD87 and ARD112, were further confirmed using viral production assay. The binding mode analysis and binding stability for the strongest inhibitor were deciphered by molecular dynamics (MD) simulation. These ARD-series compounds together with 49 previously published compounds were further analyzed by molecular docking. Key pharmacophores were identified among the structure-similar compounds. Our studies suggest that different functional groups are highly correlated with the efficacy for inhibiting p7 of HCV, in which hydrophobic interactions are the dominant forces for the inhibition potency. Our findings provide guiding principles for designing higher affinity inhibitors of p7 as potential anti-HCV drug candidates.
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spelling pubmed-79616182021-03-17 Inhibitor Development against p7 Channel in Hepatitis C Virus Wei, Shukun Hu, Xiaoyou Du, Lingyu Zhao, Linlin Xue, Hongjuan Liu, Chaolun Chou, James J. Zhong, Jin Tong, Yimin Wang, Shuqing OuYang, Bo Molecules Article Hepatitis C Virus (HCV) is the key cause of chronic and severe liver diseases. The recent direct-acting antiviral agents have shown the clinical success on HCV-related diseases, but the rapid HCV mutations of the virus highlight the sustaining necessity to develop new drugs. p7, the viroporin protein from HCV, has been sought after as a potential anti-HCV drug target. Several classes of compounds, such as amantadine and rimantadine have been testified for p7 inhibition. However, the efficacies of these compounds are not high. Here, we screened some novel p7 inhibitors with amantadine scaffold for the inhibitor development. The dissociation constant (Kd) of 42 ARD-series compounds were determined by nuclear magnetic resonance (NMR) titrations. The efficacies of the two best inhibitors, ARD87 and ARD112, were further confirmed using viral production assay. The binding mode analysis and binding stability for the strongest inhibitor were deciphered by molecular dynamics (MD) simulation. These ARD-series compounds together with 49 previously published compounds were further analyzed by molecular docking. Key pharmacophores were identified among the structure-similar compounds. Our studies suggest that different functional groups are highly correlated with the efficacy for inhibiting p7 of HCV, in which hydrophobic interactions are the dominant forces for the inhibition potency. Our findings provide guiding principles for designing higher affinity inhibitors of p7 as potential anti-HCV drug candidates. MDPI 2021-03-03 /pmc/articles/PMC7961618/ /pubmed/33802584 http://dx.doi.org/10.3390/molecules26051350 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wei, Shukun
Hu, Xiaoyou
Du, Lingyu
Zhao, Linlin
Xue, Hongjuan
Liu, Chaolun
Chou, James J.
Zhong, Jin
Tong, Yimin
Wang, Shuqing
OuYang, Bo
Inhibitor Development against p7 Channel in Hepatitis C Virus
title Inhibitor Development against p7 Channel in Hepatitis C Virus
title_full Inhibitor Development against p7 Channel in Hepatitis C Virus
title_fullStr Inhibitor Development against p7 Channel in Hepatitis C Virus
title_full_unstemmed Inhibitor Development against p7 Channel in Hepatitis C Virus
title_short Inhibitor Development against p7 Channel in Hepatitis C Virus
title_sort inhibitor development against p7 channel in hepatitis c virus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961618/
https://www.ncbi.nlm.nih.gov/pubmed/33802584
http://dx.doi.org/10.3390/molecules26051350
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