High affinity peptide inhibitors of the hepatitis C virus NS3-4A protease refractory to common resistant mutants.
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Authors
Kügler, JonasSchmelz, Stefan
Gentzsch, Juliane
Haid, Sibylle
Pollmann, Erik
van den Heuvel, Joop
Franke, Raimo
Pietschmann, Thomas
Heinz, Dirk W
Collins, John
Issue Date
2012-11-09
Metadata
Show full item recordAbstract
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.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.Affiliation
Research Group Directed Evolution, Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany.PubMed ID
22965230Type
ArticleLanguage
enISSN
1083-351Xae974a485f413a2113503eed53cd6c53
10.1074/jbc.M112.393843
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