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

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    Authors
    Jones, Sarah
    Howl, John D.
    Issue Date
    2004
    
    Metadata
    Show full item record
    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
    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
    Journal article
    Language
    en
    Description
    Metadata only
    ISSN
    0167-0115
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.regpep.2004.04.015
    Scopus Count
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    Research Institute in Healthcare Science

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