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Author Notes:

Correspondence: Raymond F Schinazi Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, Health Sciences Research Building, Room e-418, 1760 Haygood Drive, Atlanta, GA 30322, USA Tel +1 404 727 1414 Fax +1 404 727 1330 email rschina@emory.edu

The authors thank Judy Matthew for her careful editing of the manuscript.

The authors report no conflicts of interest in this work.

Subjects:

Research Funding:

This work was supported in part by National Institutes of Health grant 5P30-AI-50409 (Centers for AIDS Research) and by the Department of Veterans Affairs.

Keywords:

  • HCV replication complex
  • direct acting antivirals (DAAs)
  • clinical trials

Approaches to hepatitis C treatment and cure using NS5A inhibitors

Tools:

Journal Title:

Infection and Drug Resistance

Volume:

Volume 7

Publisher:

, Pages 41-56

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2014 Kohler et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/).

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