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

Biochimica Et Biophysica Acta
Heidi F ChristoffersenDaniel E Otzen

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.

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Citations

May 10, 2017·Biointerphases·Mikkel VestergaardBirgit Schiøtt
Jul 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Tianxi LiZeliang Chen

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