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

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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.

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Shaw, J., Harris, M., & Fishwick, C. W. G. (2015). Identification of a lead like inhibitor of the hepatitis C virus non-structural NS2 autoprotease. Antiviral Research, 124, 54–60. https://doi.org/10.1016/j.antiviral.2015.10.001

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