High affinity peptide inhibitors of the hepatitis C virus NS3-4A protease refractory to common resistant mutants.

2.50
Hdl Handle:
http://hdl.handle.net/10033/266634
Title:
High affinity peptide inhibitors of the hepatitis C virus NS3-4A protease refractory to common resistant mutants.
Authors:
Kügler, Jonas; Schmelz, Stefan; Gentzsch, Juliane; Haid, Sibylle; Pollmann, Erik; van den Heuvel, Joop; Franke, Raimo; Pietschmann, Thomas; Heinz, Dirk W; Collins, John
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.
Affiliation:
Research Group Directed Evolution, Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany.
Citation:
High affinity peptide inhibitors of the hepatitis C virus NS3-4A protease refractory to common resistant mutants. 2012, 287 (46):39224-32 J. Biol. Chem.
Journal:
The Journal of biological chemistry
Issue Date:
9-Nov-2012
URI:
http://hdl.handle.net/10033/266634
DOI:
10.1074/jbc.M112.393843
PubMed ID:
22965230
Type:
Article
Language:
en
ISSN:
1083-351X
Appears in Collections:
Publications of RG Directed Evolution (DirEv)

Full metadata record

DC FieldValue Language
dc.contributor.authorKügler, Jonasen_GB
dc.contributor.authorSchmelz, Stefanen_GB
dc.contributor.authorGentzsch, Julianeen_GB
dc.contributor.authorHaid, Sibylleen_GB
dc.contributor.authorPollmann, Eriken_GB
dc.contributor.authorvan den Heuvel, Joopen_GB
dc.contributor.authorFranke, Raimoen_GB
dc.contributor.authorPietschmann, Thomasen_GB
dc.contributor.authorHeinz, Dirk Wen_GB
dc.contributor.authorCollins, Johnen_GB
dc.date.accessioned2013-01-23T10:44:47Z-
dc.date.available2013-01-23T10:44:47Z-
dc.date.issued2012-11-09-
dc.identifier.citationHigh affinity peptide inhibitors of the hepatitis C virus NS3-4A protease refractory to common resistant mutants. 2012, 287 (46):39224-32 J. Biol. Chem.en_GB
dc.identifier.issn1083-351X-
dc.identifier.pmid22965230-
dc.identifier.doi10.1074/jbc.M112.393843-
dc.identifier.urihttp://hdl.handle.net/10033/266634-
dc.description.abstractHepatitis 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.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to The Journal of biological chemistryen_GB
dc.titleHigh affinity peptide inhibitors of the hepatitis C virus NS3-4A protease refractory to common resistant mutants.en
dc.typeArticleen
dc.contributor.departmentResearch Group Directed Evolution, Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany.en_GB
dc.identifier.journalThe Journal of biological chemistryen_GB
This item is licensed under a Creative Commons License
Creative Commons
All Items in HZI are protected by copyright, with all rights reserved, unless otherwise indicated.