Hepatitis C virus (HCV) NS3-4A is a protease and helicase/ATPase. All three activities can be targeted, but only protease inhibitors are clinically used as HCV drugs. We have developed a helicase inhibitor scaffold (HI-1) which molecular modeling suggests may interact with both the helicase and protease active sites. We combined HI-1 and protease inhibitors to test their ability to jointly inhibit NS3-4A. Low concentrations of HI-1 and protease inhibitors were applied to Huh 7.5 cells harboring a HCV 1b subgenomic replicon with a Renilla luciferase reporter. Significantly greater inhibition was observed than would be expected from additive inhibition alone.  This synergistic inhibition was not reproduced in a commercial (Anaspec) protease assay.  The results suggest there is some synergistic interaction between HI-1 and protease inhibitors but it may not be specific to the protease domain.

Effect of combining helicase and protease inhibitors on hepatitis C NS3-4A

247th National Meeting (2014)

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