Discovery and Clinical Validation of HCV Inhibitors Targeting the NS5A Protein
HCV non‐structural protein 5A (NS5A) is a multifunctional protein that plays a diverse set of roles in the replication cycle of the virus. Although a significant level of effort has been invested over the past decade at characterizing this protein, our understanding and appreciation of its full structure and function remain far from complete. Despite these drawbacks, however, great strides have been made towards discovering potent HCV NS5A inhibitors that have exhibited promising efficacy in early clinical trials, and these inhibitors have the potential to become an integral component of effective combination therapies that are expected to emerge in the near future. Highlights of the biochemical characterization of the HCV NS5A protein, aspects of the seminal drug discovery effort that culminated in the identification of daclatasvir with which clinical proof‐of‐concept was obtained for NS5A as a target and the follow‐up efforts that identified additional inhibitors, along with findings from mode‐of‐action studies, are discussed.