Potent HCV NS3 Protease Inhibition by a Water-Soluble Phyllanthin Congener.

NS3/4A protease of hepatitis C virus (HCV) plays an important role in viral RNA replication. A 1,4-diphenylbutanedicarboxylic acid derivative, namely, phyllanthin, extracted from the leaf of a herbal plant, inhibits HCV NS3/4A protease and replication activities. However, the reduced aqueous solubility, high toxicity, and poor oral bioavailability are major impediments with phyllanthin. We herein present a design approach to generate phyllanthin congeners in order to potentiate inhibition activity against protease. The phyllanthin congeners were synthesized by chemical methods and subjected to systematic biological studies. One of the congeners, annotated as , is identified as a novel and potent inhibitor of the HCV-NS3/4Aprotease activity and the viral RNA replication in cell culture. Structural analysis using the computational-based docking approach demonstrated important noncovalent interactions between and the catalytic residues of the viral protease. Furthermore, was found to be significantly nontoxic in cell culture. More importantly, oral administration of in BALB/c mice proved its better tolerability and bioavailability, as compared to native phyllanthin. Taken together, this study reveals a promising candidate for developing anti-HCV therapeutics to control HCV-induced liver diseases.