NS5A as a Target for HCV Drug Discovery

Abstract

Discovery and development of HCV inhibitors is one of the most successful stories in the history of antiviral research. After more than 30 years of effort by academic and pharmaceutical researchers, HCV infection is a curable disease. In fact, HCV is the first chronic infectious disease to be cured with combinations of direct antiviral agents. Among these antiviral agents, NS5A inhibitors are the most potent. The unprecedented low pM potency, pan-genotype coverage, and well-tolerated clinical profile have made NS5A inhibitors an essential component of all interferon-/ribavirin-free regimens in currently approved HCV therapies. Since NS5A has no known enzymatic activity and is not a traditional antiviral target, this review focuses on the challenges and concerns that arose during the discovery of this class of inhibitor, the mode of action/inhibition, and the value of NS5A inhibitors in the treatment of HCV infection.