Identification of a lead like inhibitor of the hepatitis C virus non-structural NS2 autoprotease

Hepatitis C virus (HCV) non-structural protein 2 (NS2) encodes a 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, therefore in this independent study we applied a structure-guided virtual high-throughput screening approach to identify a lead-like small molecule inhibitor of the NS2 autoprotease. This screen identified a candidate lead-like small molecule that was able to inhibit both NS2-mediated proteolysis in vitro and NS2-dependent genome replication in a cell-based assay. Structure-activity relationship 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.