Approaches to hepatitis C treatment and cure using NS5A inhibitors

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 maj...

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Bibliographic Details
Published in:Infection and drug resistance 2014-01, Vol.7 (default), p.41-56
Main Authors: Kohler, James J, Nettles, James H, Amblard, Franck, Hurwitz, Selwyn J, Bassit, Leda, Stanton, Richard A, Ehteshami, Maryam, Schinazi, Raymond F
Format: Article
Language:English
Subjects:
Analysis
Antiviral agents
Care and treatment
Clinical trials
Drug dosages
Drug resistance
Genotype & phenotype
Hepatitis
Hepatitis C
Hepatitis C virus
Infections
Internet
Laboratories
Liver diseases
NMR
Nuclear magnetic resonance
Protein interaction
Proteinase inhibitors
Proteins
Replication
Review
RNA polymerase
RNA-directed RNA polymerase
Synergism
Virus research
Viruses
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Summary: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.
ISSN:1178-6973
1178-6973
DOI:10.2147/idr.s36247