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Biochim Biophys Acta. 2015 Aug;1854(8):882-9. doi: 10.1016/j.bbapap.2015.03.003. Epub 2015 Mar 18.

The natural, peptaibolic peptide SPF-5506-A4 adopts a β-bend spiral structure, shows low hemolytic activity and targets membranes through formation of large pores.

Author information

1
Center for Insoluble Protein Structures (inSPIN), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus, Denmark; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus, Denmark.
2
Center for Insoluble Protein Structures (inSPIN), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus, Denmark; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus, Denmark. Electronic address: tv@chem.au.dk.
3
Center for Insoluble Protein Structures (inSPIN), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus, Denmark; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus, Denmark. Electronic address: ts@inano.au.dk.
4
Center for Insoluble Protein Structures (inSPIN), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus, Denmark; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus, Denmark. Electronic address: dao@inano.au.dk.

Abstract

The medium-length fungal peptaibol SPF-5506-A(4) has been shown to inhibit formation of the Aβ peptide involved in Alzheimer''s disease. As Aβ is a cleavage-product from the membrane-bound APP protein, we hypothesized that SPF-5506-A(4)'s activity might be linked to membrane interactions in general. Here we describe the synthesis, structure and membrane interactions of SPF-5506-A4. The challenging synthesis was carried out on solid phase and a detailed conformational analysis in solution revealed a β-bend ribbon spiral core structure with flexible termini. Investigations of its membrane activity revealed low hemolytic activity, limited inhibition of both Gram-positive and Gram-negative cell growth and a preference for an overall negatively charged membrane surface mimicking the bacterial cell surface. SPF-5506-A(4) is the first peptaibol to be shown to facilitate leakage of large (4.6 nm diameter) fluorescence-labeled dextran from vesicles while leaving the vesicles intact. We conclude that SPF-5506-A(4) follows the toroidal pore model in its mode of action.

KEYWORDS:

Membrane activity; Peptaibol; Peptide synthesis; α-Aminoisobutyric acid

PMID:
25796141
DOI:
10.1016/j.bbapap.2015.03.003
[Indexed for MEDLINE]

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