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

Molecules

Wenzhong Yan³  Jie Qing¹  Hanbing Mei³  Fei Mao³  Jin Huang³  Jin Zhu³  Hualiang Jiang³  Lei Liu¹  Linqi Zhang²  Jian Li³ 

[1] 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; E-Mail:;School of Medicine, Tsinghua University, Beijing 100084, China;Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China; E-Mails:

关键词: CypA;    small molecule inhibitor;    anti-HCV;    O-acylation;   

DOI  :  10.3390/molecules200610342

来源: mdpi

【 摘 要 】

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.

【 授权许可】

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© 2015 by the authors; licensee MDPI, Basel, Switzerland.