Identification of a resveratrol tetramer as a potent inhibitor of hepatitis C virus helicase

Abstract

BACKGROUND AND PURPOSEHepatitis C virus (HCV) infection is responsible for various chronic inflammatory liver diseases. Here, we have identified a naturally occurring compound with anti-HCV activity and have elucidated its mode of antiviral action. EXPERIMENTAL APPROACHLuciferase reporter and real-time RT-PCR assays were used to measure HCV replication. Western blot, fluorescence-labelled HCV replicons and infectious clones were employed to quantitate expression levels of viral proteins. Resistant HCV mutant mapping, in vitro NS3 protease, helicase, NS5B polymerase and drug affinity responsive target stability assays were also used to study the antiviral mechanism. KEY RESULTSA resveratrol tetramer, vitisin B from grapevine root extract showed high potency against HCV replication (EC 50 = 6 nM) with relatively low cytotoxicity (EC 50 >10 μM). Combined treatment of vitisin B with an NS5B polymerase inhibitor (sofosbuvir) exhibited a synergistic or at least additive antiviral activity. Analysis of a number of vitisin B-resistant HCV variants suggested an NS3 helicase as its potential target. We confirmed a direct binding between vitisin B and a purified NS3 helicase in vitro. Vitisin B was a potent inhibitor of a HCV NS3 helicase (IC 50 = 3 nM). In vivo, Finally, we observed a preferred tissue distribution of vitisin B in the liver after i.p. injection in rats, at clinically attainable concentrations. CONCLUSION AND IMPLICATIONSVitisin B is one of the most potent HCV helicase inhibitors identified so far. Vitisin B is thus a prime candidate to be developed as the first HCV drug derived from natural products.

Gnetin‐C and other resveratrol oligomers with cancer chemopreventive potential

“…The discovery that some resveratrol oligomers possess biological properties, including antifungal, antioxidant, antibacterial, antiviral, anti‐inflammatory, and antitumor properties (with some resveratrol oligomers reported to be superior to resveratrol), has continued to generate scientific interest in these derivatives. With the broad range of biological activities of resveratrol oligomers and their pharmacological potential for drug development, several research groups have successfully generated synthetic versions of these compounds with variable molecular complexity, mainly using biomimetic synthesis or de novo synthetic approaches …”

Update on Phytochemistry and Pharmacology of Naturally Occurring Resveratrol Oligomers

“…The resveratrol tetramer vitisin B exhibited a strong inhibition of HCV replication with an EC 50 value of 6 nM and showed remarkably low cytotoxicity (EC 50 >10 μmol/L). The mechanisms of action of vitisin B were related to the potent inhibition of a HCV NS3 helicase with IC 50 3 nM [ 82 ].…”

Resveratrol: Is It Really Good for Liver Health?

“…However, RES on the other side prevented formation of hepatic steatosis in C57BL/6 mice infected with HCV core recombinant adenoviruses by inhibiting expression of SIRT1 and PPAR-α (41). In addition, highly beneficial effects of vitisin B (a RES tetramer) had high potency against HCV replication and exhibited synergistic antiviral effects with the established NS5B polymerase inhibitor sofosbuvir (42). In hepatitis B virus (HBV) X protein (HBx) transgenic mice, RES at 30 mg/kg/day had pleiotropic beneficial effects on intracellular reactive oxygen species, hepatocyte proliferation, and lipogenic genes resulting in a delayed HBx-mediated hepatocarcinogenesis and significantly reduced HCC incidence (43).…”