Charge delocalisation and the design of novel mastoparan analogues: enhanced cytotoxicity and secretory efficacy of [Lys5, Lys8, Aib10]MP.

2.50
Hdl Handle:
http://hdl.handle.net/2436/15857
Title:
Charge delocalisation and the design of novel mastoparan analogues: enhanced cytotoxicity and secretory efficacy of [Lys5, Lys8, Aib10]MP.
Authors:
Jones, Sarah; Howl, John D.
Abstract:
The formation of an amphipathic helix is a major determinant of the biological activity of the tetradecapeptide mastoparan (MP). To address the functional significance of lysyl residues at positions 4, 11 and 12 of MP, we synthesised five novel analogues using sequence permutation and arginine-substitution to delocalise cationic charge. Comparative bioassays determined cytotoxicity, beta-hexoseaminidase secretory efficacy and peptide-activated extracellular receptor-stimulated kinase (ERK)1/2 phosphorylation. The monosubstitution of individual lysine residues with arginine produced differential changes to the indices of cytotoxicity and secretion indicating that these conservative substitutions are compatible with membrane translocation and the selective binding and activation of intracellular proteins. More profound changes to the predicted hydrophilic face of MP, resulting from the relocation or substitution of additional lysyl residues, enhanced both the cytotoxicity and secretory efficacy of novel peptides. Significantly, the more amphipathic peptide [Lys5, Lys8, Aib10]MP was identified to be both the most cytotoxic and the most potent secretagogue of all the peptides compared here. Charge delocalisation within the hydrophilic face of MP analogues was also compatible with peptide-induced activation of ERK1/2 phosphorylation. Our data indicate that charge delocalisation is a suitable strategy to engineer more potent analogues of MP that differentially target intracellular proteins.
Citation:
Regulatory Peptides, 121(1-3): 121-128
Publisher:
Elsevier BV
Issue Date:
2004
URI:
http://hdl.handle.net/2436/15857
DOI:
10.1016/j.regpep.2004.04.015
PubMed ID:
15256282
Additional Links:
http://dx.doi.org/10.1016/j.regpep.2004.04.015
Type:
Article
Language:
en
Description:
Metadata only
ISSN:
0167-0115
Appears in Collections:
Molecular Pharmacology Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorJones, Sarah-
dc.contributor.authorHowl, John D.-
dc.date.accessioned2008-01-09T10:23:41Z-
dc.date.available2008-01-09T10:23:41Z-
dc.date.issued2004-
dc.identifier.citationRegulatory Peptides, 121(1-3): 121-128en
dc.identifier.issn0167-0115-
dc.identifier.pmid15256282-
dc.identifier.doi10.1016/j.regpep.2004.04.015-
dc.identifier.urihttp://hdl.handle.net/2436/15857-
dc.descriptionMetadata onlyen
dc.description.abstractThe formation of an amphipathic helix is a major determinant of the biological activity of the tetradecapeptide mastoparan (MP). To address the functional significance of lysyl residues at positions 4, 11 and 12 of MP, we synthesised five novel analogues using sequence permutation and arginine-substitution to delocalise cationic charge. Comparative bioassays determined cytotoxicity, beta-hexoseaminidase secretory efficacy and peptide-activated extracellular receptor-stimulated kinase (ERK)1/2 phosphorylation. The monosubstitution of individual lysine residues with arginine produced differential changes to the indices of cytotoxicity and secretion indicating that these conservative substitutions are compatible with membrane translocation and the selective binding and activation of intracellular proteins. More profound changes to the predicted hydrophilic face of MP, resulting from the relocation or substitution of additional lysyl residues, enhanced both the cytotoxicity and secretory efficacy of novel peptides. Significantly, the more amphipathic peptide [Lys5, Lys8, Aib10]MP was identified to be both the most cytotoxic and the most potent secretagogue of all the peptides compared here. Charge delocalisation within the hydrophilic face of MP analogues was also compatible with peptide-induced activation of ERK1/2 phosphorylation. Our data indicate that charge delocalisation is a suitable strategy to engineer more potent analogues of MP that differentially target intracellular proteins.en
dc.language.isoenen
dc.publisherElsevier BVen
dc.relation.urlhttp://dx.doi.org/10.1016/j.regpep.2004.04.015en
dc.subjectCharge delocalisationen
dc.subjectNovel mastoparan analoguesen
dc.subjectCytotoxicityen
dc.subjectSecretory efficacyen
dc.subjectLys5, Lys8, Aib10]MPen
dc.subjectDesignen
dc.titleCharge delocalisation and the design of novel mastoparan analogues: enhanced cytotoxicity and secretory efficacy of [Lys5, Lys8, Aib10]MP.en
dc.typeArticleen
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