Abstract
Hepatitis C virus (HCV) non-structural protein 2 (NS2) encodes an autoprotease activity that is essential for virus replication and thus represents an attractive anti-viral target. Recently, we demonstrated that a series of epoxide-based compounds, previously identified as potent inhibitors of the clotting factor, FXIII, also inhibited NS2-mediated proteolysis in vitro and possessed anti-viral activity in cell culture models. This suggested that a selective small molecule inhibitor of the NS2 autoprotease represents a viable prospect. In this independent study, we applied a structure-guided virtual high-throughput screening approach in order to identify a lead-like small molecule inhibitor of the NS2 autoprotease. This screen identified a molecule that was able to inhibit both NS2-mediated proteolysis in vitro and NS2-dependent genome replication in a cell-based assay. A subsequent preliminary structure–activity relationship (SAR) analysis shed light on the nature of the active pharmacophore in this compound and may inform further development into a more potent inhibitor of NS2 mediated proteolysis.
Highlights
Hepatitis C virus (HCV) infects 2.8% of the worldwide population, with 85% of cases progressing to chronic infection (Webster et al, 2015), associated with both liver cirrhosis and hepatocellular carcinoma
Recent advances in all-oral, interferon-free HCV therapeutic regimes have involved the use of direct acting antiviral (DAA) targeting HCV-encoded enzyme activities; namely inhibitors targeting NS3/4A protease and NS5B RNA polymerase
The only HCV-encoded enzyme activity which has not been targeted with DAAs is the protease activity encoded within the Cterminus of non-structural protein 2 (NS2)
Summary
Hepatitis C virus (HCV) infects 2.8% of the worldwide population, with 85% of cases progressing to chronic infection (Webster et al, 2015), associated with both liver cirrhosis and hepatocellular carcinoma. Due to its essential nature in the HCV lifecycle, the NS2 autoprotease represents an attractive therapeutic target (Lorenz, 2010; Rice, 2011) In this regard, we recently reported that a series of epoxide-containing small molecule inhibitors of the transglutaminase FXIII-A (Avery et al, 2015) were able to inhibit NS2 mediated proteolysis both in vitro and in cell-based systems (Shaw et al, 2015). To further explore the potential to inhibit the HCV NS2 autoprotease a structure-guided virtual high-throughput screening approach was employed to identify a lead-like small molecule inhibitor This molecule represents a first-in-class anti-viral agent with activity against infectious HCV in cell culture and provides evidence that inhibitors of virally encoded auto-proteases are a viable prospect
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