Hepatitis C virus infection remains a major medical problem with approximately 200 million people world wide living with the disease.The current standard of therapy is based on α-interferon (Peg-Intron(R) and Pegasys(R)) in combination with ribavirin.This existing therapy is only partially effective with ~50% of genotype 1 patients.Furthermore,the current therapy is very poorly tolerated with 75% of patients exhibiting systemic side-effects including flu-like symptoms.In recent years,direct anti-viral drugs targeting the inhibition of viral enzymes have shown great promise in human clinical trials.One of these viral targets is the protein product of the non structural gene 3 (NS3 protease).A novel class ofphosphonate derivatives was designed to mimic the interaction of product-like carboxylate based inhibitors of HCV NS3 protease.A phosphonic acid was demonstrated to be a potent HCV NS3 protease inhibitor,and a potential candidate for treating HCV infection.The syntheses and biological evaluation of this phosphonate class of inhibitor will be described.