1. High affinity peptide inhibitors of the hepatitis C virus NS3-4A protease refractory to common resistant mutants.
- Author
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Kügler J, Schmelz S, Gentzsch J, Haid S, Pollmann E, van den Heuvel J, Franke R, Pietschmann T, Heinz DW, and Collins J
- Subjects
- Antiviral Agents pharmacology, Binding Sites, Cell-Penetrating Peptides chemistry, Crystallography methods, Drug Design, Drug Resistance, Viral drug effects, Drug Resistance, Viral genetics, Humans, Inhibitory Concentration 50, Intracellular Signaling Peptides and Proteins, Kinetics, Models, Molecular, Molecular Conformation, Peptide Library, Peptides chemistry, Solvents chemistry, Carrier Proteins chemistry, Mutation, Viral Nonstructural Proteins chemistry
- Abstract
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.
- Published
- 2012
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