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Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization
In this work, the relationship between cyclophilin A (CypA) and HCV prompted us to screen a series of small molecule CypA inhibitors which were previously reported by our group. Among them, compound 1, discovered as a non-immunosuppressive anti-HCV agent with an EC(50) value of 0.67 μM in a virus as...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272715/ https://www.ncbi.nlm.nih.gov/pubmed/26053489 http://dx.doi.org/10.3390/molecules200610342 |
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author | Yan, Wenzhong Qing, Jie Mei, Hanbing Mao, Fei Huang, Jin Zhu, Jin Jiang, Hualiang Liu, Lei Zhang, Linqi Li, Jian |
author_facet | Yan, Wenzhong Qing, Jie Mei, Hanbing Mao, Fei Huang, Jin Zhu, Jin Jiang, Hualiang Liu, Lei Zhang, Linqi Li, Jian |
author_sort | Yan, Wenzhong |
collection | PubMed |
description | In this work, the relationship between cyclophilin A (CypA) and HCV prompted us to screen a series of small molecule CypA inhibitors which were previously reported by our group. Among them, compound 1, discovered as a non-immunosuppressive anti-HCV agent with an EC(50) value of 0.67 μM in a virus assay, was selected for further study. Subsequent chemical modification by O-acylation led to a novel class of molecules, among which compound 25 demonstrated the most potent anti-HCV activity in the virus assay (EC(50) = 0.19 μM), but low cytotoxicity and hERG cardiac toxicity. The following studies (a solution stability assay and a simple pharmacokinetic test together with a CypA enzyme inhibition assay) preliminarily indicated that 25 was a prodrug of 1. To the best of our knowledge, 25 is probably the most potent currently reported small molecule anti-HCV agent acting via the CypA inhibitory mechanism. Consequently, our study has provided a new potential small molecule for curing HCV infection. |
format | Online Article Text |
id | pubmed-6272715 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-62727152018-12-31 Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization Yan, Wenzhong Qing, Jie Mei, Hanbing Mao, Fei Huang, Jin Zhu, Jin Jiang, Hualiang Liu, Lei Zhang, Linqi Li, Jian Molecules Article In this work, the relationship between cyclophilin A (CypA) and HCV prompted us to screen a series of small molecule CypA inhibitors which were previously reported by our group. Among them, compound 1, discovered as a non-immunosuppressive anti-HCV agent with an EC(50) value of 0.67 μM in a virus assay, was selected for further study. Subsequent chemical modification by O-acylation led to a novel class of molecules, among which compound 25 demonstrated the most potent anti-HCV activity in the virus assay (EC(50) = 0.19 μM), but low cytotoxicity and hERG cardiac toxicity. The following studies (a solution stability assay and a simple pharmacokinetic test together with a CypA enzyme inhibition assay) preliminarily indicated that 25 was a prodrug of 1. To the best of our knowledge, 25 is probably the most potent currently reported small molecule anti-HCV agent acting via the CypA inhibitory mechanism. Consequently, our study has provided a new potential small molecule for curing HCV infection. MDPI 2015-06-04 /pmc/articles/PMC6272715/ /pubmed/26053489 http://dx.doi.org/10.3390/molecules200610342 Text en © 2015 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 license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Yan, Wenzhong Qing, Jie Mei, Hanbing Mao, Fei Huang, Jin Zhu, Jin Jiang, Hualiang Liu, Lei Zhang, Linqi Li, Jian Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization |
title | Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization |
title_full | Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization |
title_fullStr | Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization |
title_full_unstemmed | Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization |
title_short | Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization |
title_sort | discovery of novel small molecule anti-hcv agents via the cypa inhibitory mechanism using o-acylation-directed lead optimization |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272715/ https://www.ncbi.nlm.nih.gov/pubmed/26053489 http://dx.doi.org/10.3390/molecules200610342 |
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