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Molecules 2015, 20(6), 10342-10359;

Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization

Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China
School of Medicine, Tsinghua University, Beijing 100084, China
Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
These authors contributed equally to this work.
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 6 May 2015 / Revised: 28 May 2015 / Accepted: 29 May 2015 / Published: 4 June 2015
(This article belongs to the Section Medicinal Chemistry)
Full-Text   |   PDF [871 KB, uploaded 4 June 2015]   |  


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 EC50 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 (EC50 = 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. View Full-Text
Keywords: CypA; small molecule inhibitor; anti-HCV; O-acylation CypA; small molecule inhibitor; anti-HCV; O-acylation

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Yan, W.; Qing, J.; Mei, H.; Mao, F.; Huang, J.; Zhu, J.; Jiang, H.; Liu, L.; Zhang, L.; Li, J. Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization. Molecules 2015, 20, 10342-10359.

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