Abstract
BackgroundCurrent therapy of chronic hepatitis C virus (HCV) with direct-acting antivirals (DAAs) has dramatically improved the sustained virologic response (SVR) of affected patients; however, treatment with DAAs remains expensive, and drug-resistant HCV variants remain a threat. As a result, there is still a need to continue to develop affordable and effective drugs for the treatment of HCV. Previously, we have demonstrated that a crude extract from Artocarpus heterophyllus leaves is a potential anti-HCV candidate. In this study, we have further purified this crude extract, examined which sub-fraction possesses the highest antiviral activity, and then explored its efficacy at different HCV life cycle stages. We also assessed synergistic antiviral effects between the A. heterophyllus extract and commercially available anti-HCV drugs.MethodsWe used vacuum liquid chromatography (VLC) and high-performance liquid chromatography (HPLC) to fractionate a dichloromethane extract of A. heterophyllus leaves. We then examined the anti-HCV activity of the fractions using HCV genotype 2a, JFH1a; the antiviral mode of action was determined by exploring adding the treatments at different times. We examined the antiviral effects on the viral entry stage through a virucidal activity test, viral adsorption examination, and pretreatment of cells with the drug. The effects on the post-viral entry stage were determined by the levels of HCV protein expression and HCV RNA expression in infected cells.ResultsThrough activity guided purification, we identified the sub-fraction FR3T3 as possessing the most robust anti-HCV activity with an IC50 value of 4.7 ± 1.0 μg/mL. Mode-of-action analysis revealed that FR3T3 inhibited post-viral entry stages such as HCV NS3 protein expression and HCV RNA replication with marginal effects on the viral entry stage. Thin-layer Chromatography (TLC) indicated that FR3T3 contained terpenoids and chlorophyll-related compounds. We also found a synergistic antiviral activity when the DCM extract of A. heterohyllus was used in combination therapy with commercial anti-HCV drugs; Ribavirin, Simeprevir, Cyclosporin A.ConclusionsThe extract of A. heterophyllus and its sub-fraction, FR3T3, presented here have anti-HCV activities and could be candidate drugs for add-on-therapy for treatment of chronic HCV infections.
Highlights
Current therapy of chronic hepatitis C virus (HCV) with direct-acting antivirals (DAAs) has dramatically improved the sustained virologic response (SVR) of affected patients; treatment with DAAs remains expensive, and drug-resistant HCV variants remain a threat
Direct-acting antivirals (DAAs) are an effective therapy for HCV that target viral proteins such as NS3/NS4A protease, the NS5A protein, and NS5B polymerase, which are involved in viral replication
We found that A. heterophyllus leaves exhibit anti-HCV activity
Summary
Current therapy of chronic hepatitis C virus (HCV) with direct-acting antivirals (DAAs) has dramatically improved the sustained virologic response (SVR) of affected patients; treatment with DAAs remains expensive, and drug-resistant HCV variants remain a threat. We assessed synergistic antiviral effects between the A. heterophyllus extract and commercially available anti-HCV drugs. The non-structural proteins play an essential role in RNA replication, virus assembly, and virus release [2]. The HCV life cycle is mainly divided into seven steps: (1) virus attachment, (2) entry, (3) uncoating, (4) translation, (5) RNA genome replication, (6) assembly and maturation, and (7) virion release [3, 4]. Direct-acting antivirals (DAAs) are an effective therapy for HCV that target viral proteins such as NS3/NS4A protease, the NS5A protein, and NS5B polymerase, which are involved in viral replication. There are two groups of NS5B polymerase inhibitors, another class of DAAs: Nucleoside Polymerase Inhibitor’s (NPIs) such as Sofosbuvir, and Non-NPIs (NNPIs) such as Dasabuvir [8]
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