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Article

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

by
Wenzhong Yan
1,†,
Jie Qing
2,3,†,
Hanbing Mei
1,
Fei Mao
1,
Jin Huang
1,
Jin Zhu
1,
Hualiang Jiang
1,4,
Lei Liu
2,*,
Linqi Zhang
3,* and
Jian Li
1,*
1
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
2
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
3
School of Medicine, Tsinghua University, Beijing 100084, China
4
Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2015, 20(6), 10342-10359; https://doi.org/10.3390/molecules200610342
Submission received: 6 May 2015 / Revised: 28 May 2015 / Accepted: 29 May 2015 / Published: 4 June 2015
(This article belongs to the Section Medicinal Chemistry)
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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.
Keywords: CypA; small molecule inhibitor; anti-HCV; O-acylation CypA; small molecule inhibitor; anti-HCV; O-acylation

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MDPI and ACS Style

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. https://doi.org/10.3390/molecules200610342

AMA Style

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(6):10342-10359. https://doi.org/10.3390/molecules200610342

Chicago/Turabian Style

Yan, Wenzhong, Jie Qing, Hanbing Mei, Fei Mao, Jin Huang, Jin Zhu, Hualiang Jiang, Lei Liu, Linqi Zhang, and Jian Li. 2015. "Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization" Molecules 20, no. 6: 10342-10359. https://doi.org/10.3390/molecules200610342

APA Style

Yan, W., Qing, J., Mei, H., Mao, F., Huang, J., Zhu, J., Jiang, H., Liu, L., Zhang, L., & Li, J. (2015). Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization. Molecules, 20(6), 10342-10359. https://doi.org/10.3390/molecules200610342

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