Targeting the NS5A protein of HCV: An emerging option

Hepatitis C virus (HCV) infects more than 3% of the world's population, leading to an increased risk of cirrhosis and hepatocellular carcinoma. The current standard of care, a combination of pegylated interferon alfa and ribavirin, is poorly tolerated and often ineffective against the most prevalent genotype of the virus, genotype 1. The very recent approval of boceprevir and telaprevir, two HCV protease inhibitors, promises to significantly improve treatment options and outcomes. In addition to the viral protease NS3 and the viral polymerase NS5B, direct-acting antivirals are now in development against NS5A. A multifunctional phosphoprotein, NS5A is essential to HCV genome replication, but has no known enzymatic function. Here we report how the design of small-molecule inhibitors against NS5A has evolved from promising monomers to highly potent dimeric compounds effective against many HCV genotypes. We also highlight recent clinical data and how the inhibitors may bind to NS5A, itself capable of forming dimers.