title: 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.
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.
authors: 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.
authors: Heidi F
authors: HF
authors: Christoffersen
authors: 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.
authors: Sara K
authors: SK
authors: Hansen
authors: 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.
authors: Brian S
authors: BS
authors: Vad
authors: 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.
authors: Erik H
authors: EH
authors: Nielsen
authors: 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.
authors: Jakob T
authors: JT
authors: Nielsen
authors: 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.
authors: Thomas
authors: T
authors: Vosegaard
authors: 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.
authors: Troels
authors: T
authors: Skrydstrup
authors: 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.
authors: Daniel E
authors: DE
authors: Otzen
mesh_terms: D002463:Cell Membrane Permeability; D004910:Erythrocyte Membrane / Q000737:chemistry*; D004926:Escherichia coli / Q000737:chemistry; D006094:Gram-Positive Bacteria / Q000737:chemistry; D006461:Hemolysis; D006801:Humans; D008956:Models, Chemical; D009842:Oligopeptides / Q000737:chemistry*; D017433:Protein Structure, Secondary
chemical_list: D009842:Oligopeptides; C520915:SPF-5506-A4
keywords: Membrane activity; Peptaibol; Peptide synthesis; α-Aminoisobutyric acid