Journal
CHEMISTRY & BIOLOGY
Volume 22, Issue 8, Pages 1087-1097Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2015.07.012
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Funding
- Australian Research Council [DE120103152]
- National Health and Medical Research Council [APP1026501]
- NHMRC [APP1084965]
- Australian Research Council [DE120103152] Funding Source: Australian Research Council
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Cyclotides combine the stability of disulfide-rich peptides with the intracellular accessibility of cell-penetrating peptides, giving them outstanding potential as drug scaffolds with an ability to inhibit intracellular protein-protein interactions. To realize and optimize the application of cyclotides as a drug framework and delivery system, we studied the ability of the prototypic cyclotide, kalata B1, to enter mammalian cells. We show that kalata B1 can enter cells via both endocytosis and direct membrane translocation. Both pathways are initiated by targeting phosphatidylethanolamine phospholipids at the cell surface and inducing membrane curvature. This unusual approach to initiate internalization might be harnessed to deliver drugs into cells and, in particular, cancer cells, which present a higher proportion of surface-exposed phosphatidylethanolamine phospholipids. Our findings highlight the potential of these peptides as drug leads for the modulation of traditionally undruggable targets, such as intracellular protein-protein interactions.
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