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Publication Abstract from PubMed

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.

High Affinity Peptide Inhibitors of the Hepatitis C Virus NS3-4A Protease Refractory to Common Resistant Mutants.,Kugler J, Schmelz S, Gentzsch J, Haid S, Pollmann E, van den Heuvel J, Franke R, Pietschmann T, Heinz DW, Collins J J Biol Chem. 2012 Nov 9;287(46):39224-32. doi: 10.1074/jbc.M112.393843. Epub 2012, Sep 10. PMID:22965230^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.