Antiviral activity and resistance of HCV NS5A replication complex inhibitors

•HCV NS5A replication complex inhibitors.•Exceptional potency with broad genotype coverage translated in clinical studies.•Important component for HCV combination therapy.•Potential mode of inhibition.

Treatment of Hepatitis C Virus (HCV) infection is rapidly evolving with the introduction of direct acting antiviral agents (DAA). HCV NS5A replication complex inhibitors, exemplified by Daclatasvir (BMS-790052), represent a new class of DAA. The exceptional in vitro potency (EC50 values at pM to low nM range) and broad genotype coverage of NS5A inhibitors have translated to robust anti-HCV effects in infected patients, making NS5A inhibitors an essential component of effective HCV DAA combination therapies. On the basis of drug-induced resistance substitutions and computer modeling, NS5A inhibitors most likely act at the N-terminus of NS5A (domain I). Mechanism of inhibition studies to elucidate the exquisite potency of these inhibitors have generated several working models.