Abstract
The medium-length fungal peptaibol SPF-5506-A4 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-A4'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-A4 is the first peptaibol to be shown to facilitate leakage of large (4.6nm diameter) fluorescence-labeled dextran from vesicles while leaving the vesicles intact. We conclude that SPF-5506-A4 follows the toroidal pore model in its mode of action.
Original language | English |
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Journal | B B A - Proteins and Proteomics |
Volume | 1854 |
Issue | 8 |
Pages (from-to) | 882-889 |
Number of pages | 8 |
ISSN | 1570-9639 |
DOIs | |
Publication status | Published - Aug 2015 |