A cinnamon-derived procyanidin type A compound inhibits hepatitis C virus cell entry
Background and aims
Chronic hepatitis C virus (HCV) infection is a major cause of liver disease worldwide. Although direct-acting antivirals can cure the large majority of treated patients, important limitations remain, including treatment failure and high costs precluding access to therapy in resource-limited settings. We report herein the anti-HCV effects of IND02, a procyanidin type A molecule, isolated and characterized from cinnamon.
Methods and results
Using cellculture-derived HCV (HCVcc), HCV pseudoparticles (HCVpp), and subgenomic replicons, we demonstrated that IND02 markedly and dose-dependently inhibited HCV cell entry. Kinetic assays demonstrated that IND02 inhibits HCV entry most likely at a postbinding step. Experiments performed using primary human hepatocytes confirmed inhibition of HCV entry by IND02, demonstrating the functional impact in the most physiological cell-based system for studying HCV–host interactions.
The natural compound IND02 exhibits potent HCV cell entry inhibition and provides a novel perspective for development of a low-cost antiviral for treatment of HCV infection.
KeywordsAntiviral IND02 Hepatitis C Infection Liver
Hepatitis C virus
Vesicular stomatitis virus
50 % tissue culture infective dose
Primary human hepatocytes
50 % effective concentration
The authors thank F. Chisari (The Scripps Research Institute, La Jolla, CA) for the gift of Huh7.5.1 cells, T. Wakita (Department of Virology II, National Institutes of Health, Tokyo, Japan), C. M. Rice (Rockefeller University, New York, NY) for providing HCV strain JFH1, and R. Bartenschlager (University of Heidelberg, Heidelberg, Germany) for HCV strain Luc-Jc1 and VL:JFH1. The authors thank P. Pessaux (Strasbourg University Hospitals) for liver resection to isolate PHH. The authors thank Eric Soulier for technical assistance in PHH experiments and HCV RT-PCR, and Dr. Luzia Mayr and Dr. Mirjam Zeisel for helpful discussions and support in manuscript editing.
M.L., C.F., C.M., and T.F.B. wrote the manuscript. M.L., C.F., E.P., C.M., and T.F.B. designed experiments. M.L., C.F., and L.H. performed experiments. M.L., C.F., L.H., C.M., and T.F.B. analyzed data. E.P. and B.S. provided reagents. M.V. isolated and purified IND02. C.M. and T.F.B. directed the project.
Compliance with ethical standards
Conflict of interest
The authors disclose the following: E. Prakash, S. Bhaskaran, and M. Vishwaraman are employed by Indus Biotech. Authors C. Fauvelle, M. Lambotin, L. Heydmann, T. F. Baumert, and C. Moog declare no conflicts. Part of the research was funded by Indus Biotech Pvt Ltd, but this sponsor had no impact on experimental design or data analyses.
Liver tissue from patients undergoing surgical resection for isolation of human hepatocytes was obtained with informed consent from all patients. The protocol was approved by the Ethics Committee of the University of Strasbourg Hospitals (CPP 10-17).
This work was supported by Dormeur Investment Service Ltd. and Indus Biotech Pvt ltd. M.L. was supported by the European Community’s Seventh Framework Programme (FP7/2007-2013; EuroNeut41).
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