Next Article in Journal
Biological Activity and Molecular Structures of Bis(benzimidazole) and Trithiocyanurate Complexes
Previous Article in Journal
Overview of Methods for the Direct Molar Mass Determination of Cellulose
Article Menu

Export Article

Open AccessArticle
Molecules 2015, 20(6), 10342-10359; doi:10.3390/molecules200610342

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

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
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)
View Full-Text   |   Download PDF [871 KB, uploaded 4 June 2015]   |  

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

Figure 1

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).

Supplementary material

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

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.

Show more citation formats Show less citations formats

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]

Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top