Infection with Hepatitis C virus (HCV) affects over 150 million people and is a major cause of acute hepatitis and chronic liver disease. It affects more than 170 million people globally and is the leading cause of mortality due to an infectious agent. In this work,we describe recent advances in the development of inhibitors to HCV that could be used as part of an interferon-free combination therapy.
The non-structural protein 5A (NS5A) essential for HCV replicatation. However, no specific enzyme activity has been attributed to it and this has made the identification of inhibitors difficult. Two highly potent compounds BMS-790052 (Daclatasvir, Bristol-Myers Squibb) and AZD7295( Astrea Zenica), currently in clinic, are believed to target NS5A based on resistance mutations from viral replicon assays and pull-down experiments. No direct assay is available to measure NS5A binding and using conventional biophysical methods such as surface plasmon resonance have so far failed.
Our group has developed a novel biophysical assay that allows for the direct measurement of compound to NS5A and plan to use this to understand the effect that drug resistance mutations and genotype variation have on NS5A function. We report the binding studies of 31 compounds identifided from a virtual screen targetting NS5A and discuss their potential as potent inhibitors that could be used as part of an interferon free treatment option.