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High affinity peptide inhibitors of the hepatitis C virus NS3-4A protease refractory to common resistant mutants.Kügler, Jonas; Schmelz, Stefan; Gentzsch, Juliane; Haid, Sibylle; Pollmann, Erik; van den Heuvel, Joop; Franke, Raimo; Pietschmann, Thomas; Heinz, Dirk W; Collins, John; et al. (2012-11-09)Hepatitis C virus (HCV) NS3-4A protease is essential for viral replication. All current small molecular weight drugs against NS3-4A are substrate peptidomimetics that have a similar binding and resistance profile. We developed inhibitory peptides (IPs) capping the active site and binding via a novel "tyrosine" finger at an alternative NS3-4A site that is of particular interest for further HCV drug development. The peptides are not cleaved due to a combination of geometrical constraints and impairment of the oxyanion hole function. Selection and optimization through combinatorial phagemid display, protein crystallography, and further modifications resulted in a 32-amino acid peptide with a K(i) of 0.53 nm. Inhibition of viral replication in cell culture was demonstrated by fusion to a cell-penetrating peptide. Negligible susceptibility to known (A156V and R155K) resistance mutations of the NS3-4A protease was observed. This work shows for the first time that antiviral peptides can target an intracellular site and reveals a novel druggable site on the HCV protease.