Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic liver diseases that often requires liver transplantation. The standard therapies are limited by severe side effects, resistance development, high expense and in a substantial proportion of cases, fail to clear the infection which bespeak the need for development of well-tolerated antivirals. Since most of the drug development strategies target the replication stage of viral lifecycle, the identification of entry inhibitors might be crucial especially in case of liver-transplant recipients. In the present study we have evaluated fruits which are known for their hepatoprotective effects in order to screen for entry inhibitors. We report the identification of a flavonoid, rutin, isolated from Prunus domestica as a new HCV entry inhibitor. Characterization and confirmation of the chemical structure was done by LC-ESI-MS, NMR and IR spectral analyses. Rutin significantly inhibited HCV-LP binding to hepatoma cells and inhibited cell-culture derived HCV (HCVcc) entry into hepatoma cells. Importantly, rutin was found to be non-toxic to hepatoma cells. Furthermore, rutin inhibits the early entry stage of HCV lifecycle possibly by directly acting on the viral particle. In conclusion, rutin is a promising candidate for development of anti-HCV therapeutics in the management of HCV infection.
Highlights
Hepatitis C virus (HCV) is a leading cause of chronic viral hepatitis that is estimated to infect ~160 million people globally[1]
Genotype 3a of HCV is most prevalent in India, we initiated our studies using hepatitis C virus-like particles (HCV-LPs) comprising of core-E1-E2 derived from genotype 3a
The study was carried out using HCV-LP based system since virus-like particles (VLPs) mimic the morphology of native virus and represent a well-established system for studies on viral binding and entry[9, 10]
Summary
Hepatitis C virus (HCV) is a leading cause of chronic viral hepatitis that is estimated to infect ~160 million people globally[1]. The standard treatment for HCV infection includes the administration of pegylated interferon alpha in combination with ribavirin[3]. Limitation to this therapy includes low sustained virological response (SVR). Despite the fact that most of the DAAs target the replication step of HCV lifecycle, recent studies have depicted that addition of entry inhibitors to the DAAs exert a synergistic effect on the efficiency of antiviral treatment[6]. Combination of inhibitors targeting different stages of the virus lifecycle including entry, replication and assembly/secretion might be a better therapeutic strategy to reduce the risk of viral escape mutants. Chronic infection is associated with end-stage liver disease which represents the major cause of liver transplantation[7]. Compounds from natural sources have been reported for their antiviral effect against various infections such as herpes simplex virus[11], influenza virus, human immunodeficiency virus (HIV)[12, 13] hepatitis B and even hepatitis C virus[14, 15]
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