Biophysical Society Thematic Meeting | Ascona, Switzerland

Liposomes, Exosomes, and Virosomes: From Modeling Complex Membrane Processes to Medical Diagnostics and Drug Delivery

Wednesday Speaker Abstracts

Cyclotides, Stable Drug Scaffolds Use Phosphatidylethanolamine Lipids as a Switch to Internalize Inside Cells Sonia Troeira Henriques 1 , Yen-Hua Huang 1 , Stephanie Chaousis 1 , Marc-Antoine Sani 2 , Aaron G. Poth 1 , Frances Separovic 2 , David J. Craik 1 . 1 The University of Queensland, Brisbane, Queensland, Australia, 2 University of Melbourne, Melbourne, Victoria, Australia. Cyclotides, a large family of peptides from plants, are exceptionally stable and characterized by a cyclic structure and three disulfide-bonds arranged in a cystine knot. Recently we have found that cyclotides can be internalized into human cells at non-toxic concentrations. Their exceptional stability, bioactivities and cell-penetrating properties make cyclotides exciting templates in drug design and delivery. Using surface plasmon resonance, nuclear magnetic resonance spectroscopy, mass spectrometry, confocal microscopy and flow cytometry, we have shown that the prototypic cyclotide, kalata B1, can enter cells via both endocytosis and by direct membrane translocation. Both pathways are initiated through binding to the cell membrane by targeting phosphatidylethanolamine-phospholipids at the cell surface and inducing membrane curvature. This unusual approach to initiate internalization might be employed to deliver drugs into cells and, in particular, into cancer cells with a higher proportion of surface-exposed phosphatidylethanolamine-phospholipids. Our findings highlight the potential of using cyclotides in the development of stable delivery systems for the manipulation of traditionally ‘undruggable’ targets, such as intracellular protein-protein interactions in cancer pathways.

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