The Prototypic Cyclotide Kalata B1 Has a Unique Mechanism of Entering Cells
Sonia Troeira Henriques, Yen-Hua Huang, Stephanie Chaousis, Marc-Antoine Sani, Aaron G Poth, Frances Separovic, David J Craik
Cell Chemical Biology | CELL PRESS | Published : 2015
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 inte..View full abstract
Awarded by Australian Research Council
Awarded by National Health and Medical Research Council
Awarded by NHMRC
S.T.H. is supported by a Discovery Early Career Research Award (grant ID DE120103152) from the Australian Research Council. D.J.C. is a National Health and Medical Research Council Professorial Fellow (grant ID APP1026501). Dr. Oleksiy Kovtun (IMB, UQ) is acknowledged for the help in the preparation of the GVs. Confocal microscopy imaging was performed at the Australian Cancer Research Foundation (ACRF)/IMB Dynamic Imaging Facility for Cancer Biology established with support of ACRF. We thank John Griffin (IMB, UQ) for technical assistance with confocal microscopy imaging. We thank Olivier Cheneval (IMB, UQ) and Phillip Walsh (IMB, UQ) for assistance in peptide synthesis and purification, and Dr. Nicole Lawrence (IMB, UQ) for assistance with cell culture and bioassays. NHMRC is acknowledged for funding this project (grant ID APP1084965).