A Chameleonic Macrocyclic Peptide with Drug Delivery Applications
Payne, C. D.; Franke, B.; Fisher, M. F.; Hajiaghaalipour, F.; McAleese, C. E.; Song, A.; Eliasson, C.; Zhang, J.; Jayasena, A.; Vadlamani, G.; Clark, R. J.; Minchin, R. F.; Mylne, J. S.; Rosengren, K. J.
Show abstract
Head-to-tail cyclized peptides are intriguing natural products with unique properties. The PawS-Derived Peptides (PDPs) are produced from precursors of seed storage albumins in species of the daisy family. Here we report an unusually large PDP with two disulfide bonds, identified from seeds of Zinnia elegans. In water, synthetic PDP-23 forms a unique dimeric structure in which two monomers containing two {beta}-hairpins cross-clasp and enclose a hydrophobic core, creating a square prism. This stable dimer can be split and each monomer unfolds to a V-shape in micelles or organic solvents. This chameleonic character is unusual for disulfide-rich peptides and engenders PDP-23 with potential for cell delivery and accessing novel targets. We demonstrated this by conjugating a rhodamine dye to the PDP-23 scaffold, creating a stable, cell-penetrating inhibitor of the P-glycoprotein drug efflux pump.
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