Epoxide based inhibitors of the hepatitis C virus non-structural 2 autoprotease

•Epoxide-containing small molecules inhibit hepatitis C virus NS2 autoprotease in vitro.•These molecules also show specific inhibition of NS2-NS3 autocleavage dependent HCV genome replication in a cell based assay.•NS2 protease is a valid target for further drug development.

Hepatitis C virus (HCV) non-structural 2 (NS2) encodes an essential protease activity responsible for processing at the NS2-NS3 junction which represents an attractive antiviral target. Attempts to inhibit the NS2 autoprotease with mechanism-based protease inhibitors and substrate peptides have had limited success. We report a series of epoxide-containing small molecules capable of blocking NS2-NS3 proteolysis in vitro and demonstrate the potential for selectivity towards the NS2 autoprotease. A compound within this series was able to perturb HCV genome replication in a subgenomic replicon system only when polyprotein processing was dependent on NS2 autoprotease activity, in addition it inhibited replication of full length HCV. These findings suggest blocking HCV polyprotein processing through inhibition of the NS2 autoprotease represents a viable route to exert an antiviral effect.