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.
Highlights
Infection with hepatitis C virus (HCV) is well recognized as a worldwide health issue that chronically affects more than 170 million people [1,2,3]
The two newly synthesized compounds 14, 15 with acetoxyl substituents demonstrated more potent activity than 1 (0.55 and 0.46 μM vs. 0.92 μM), which suggested the chemical modification to be performed as the step, viz. O-acylation of the hydroxyl groups on the benzene ring
Considering the important role of Cyclophilin A (CypA) for HCV proliferation, we were enlightened and prompted to screen a series of compounds previously reported as CypA inhibitors and their derivatives
Summary
Infection with hepatitis C virus (HCV) is well recognized as a worldwide health issue that chronically affects more than 170 million people [1,2,3]. There are more than 20 directly-acting antivirals (DAAs) targeting the HCV NS3 protease, NS5B polymerase and NS5A protein in advanced clinical trials [6] These DAAs have to be used in combination clinically to avoid resistance, because HCV, an RNA virus, possesses high replication and mutation rates [6]. A strategy targeting host factors essential for viral replication such as cyclophilins (Cyps) may create alternative kinds of anti-HCV agents for clinical application alone or in combination. Via its PPIase activity, Cyps play a crucial role in numerous cellular processes, including transcriptional regulation, immune response, protein secretion, and mitochondrial function [8,9]. Abundant research has shown that CypA is an important host factor for HCV proliferation as the PPIase activity of the hydrophobic gorge area in CypA plays a critical role in the HCV. A series of experiments reported in this article were performed aiming at discovering and developing a novel kind of anti-HCV agent
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