title: Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization.
abstract: 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.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China. 15901872753@163.com.
authors.forename: Wenzhong
authors.initials: W
authors.lastname: Yan
authors.affiliation: 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. qing282420@163.com.|School of Medicine, Tsinghua University, Beijing 100084, China. qing282420@163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Qing
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China. xiuzhifumhb@126.com.
authors.forename: Hanbing
authors.initials: H
authors.lastname: Mei
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China. maofei@ecust.edu.cn.
authors.forename: Fei
authors.initials: F
authors.lastname: Mao
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China. huangjin@ecust.edu.cn.
authors.forename: Jin
authors.initials: J
authors.lastname: Huang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China. jinz@ecust.edu.cn.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China. hljiang@ecust.edu.cn.|Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China. hljiang@ecust.edu.cn.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: 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. lliu@mail.tsinghua.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: School of Medicine, Tsinghua University, Beijing 100084, China. zhanglinqi@biomed.tsinghua.edu.cn.
authors.forename: Linqi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China. jianli@ecust.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000215:Acylation; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D021984:Cyclophilin A / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D054852:Small Molecule Libraries; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D054852:Small Molecule Libraries; D021984:Cyclophilin A
keywords: CypA; O-acylation; anti-HCV; small molecule inhibitor