Approaches to hepatitis C treatment and cure using NS5A inhibitors

Abstract

Recent progress in the understanding of hepatitis C virus (HCV) biology and the availability of in vitro models to study its replication have facilitated the development of direct-acting antiviral agents (DAAs) that target specific steps in the viral replication cycle. Currently, there are three major classes of DAA in clinical development: NS3/4A protease inhibitors, NS5B polymerase inhibitors, and NS5A directed inhibitors. Several compounds thought to bind directly with NS5A are now in various clinical trial phases, including the most advanced, daclatasvir (BMS-790052), ledipasvir (GS-5885), and ABT-267. While many NS5A-targeted compounds demonstrate picomolar potency, the exact mechanism(s) of their action is still unclear. In the clinic, NS5A HCV inhibitors show promise as important components in DAA regimens and have multifunctionality. In addition to inhibiting viral replication, they may synergize with other DAAs, possibly by modulating different viral proteins, to help suppress the emergence of resistant viruses. Structure-based models have identified target interaction domains and spatial interactions that explain drug resistance for mutations at specific positions (eg, residues 93 and 31) within NS5A and potential binding partners. This review provides, insights into the unique complexity of NS5A as a central platform for multiple viral/host protein interactions, and possible mechanism(s) for the NS5A inhibitors currently undergoing clinical trials that target this nonstructural viral protein.

Asymmetric Binding to NS5A by Daclatasvir (BMS-790052) and Analogs Suggests Two Novel Modes of HCV Inhibition

“…This family of compounds includes some of the most active antiviral compounds tested, with low picomolar median effective concentration (EC 50 ) in HCV replicon assays. 2 − 5 Three structurally related compounds currently in clinical trials, 1 , 2 (GSK-2336805), and 3 (GS-5885), are illustrated in Chart 1 . Because NS5A lacks known enzymatic activity, the specific mechanism(s) for the extraordinary potency of this class of antiviral drugs is not yet clear.…”

“… 4 In clinical trials, compound 1 caused a rapid drop in viremia in responders but selected for the same 31/93 mutations in subjects with persistent Gt1b-infections. 2 , 12 , 13 …”

TRIM14 inhibits hepatitis C virus infection by SPRY domain-dependent targeted degradation of the viral NS5A protein

“…D1 is mainly attached to the inner-surface of phospholipid membrane9. D1 dimer includes a putative RNA-binding domain located at interface of the dimer10 and it forms a protective replication compartment that anchors the HCV RNA on intracellular membranes11.…”

Resistance Patterns Associated with HCV NS5A Inhibitors Provide Limited Insight into Drug Binding

“…This pattern also leads to decreased susceptibility to DCV in the other HCV genotypes. Although these variants show cross-resistance to the other NS5A inhibitors, they remain fully sensitive to other DAA classes and host targeting antivirals [ 34 , 38 , 39 ], including CypA inhibitors Alisporivir and SCY-635 [ 40 , 41 ].…”