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High affinity peptide inhibitors of the hepatitis C virus NS3-4A protease refractory to common resistant mutants.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2012 Nov 09; Vol. 287 (46), pp. 39224-32. Date of Electronic Publication: 2012 Sep 10. - Publication Year :
- 2012
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 287
- Issue :
- 46
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22965230
- Full Text :
- https://doi.org/10.1074/jbc.M112.393843