SCHEDULED MAINTENANCE
A chameleonic macrocyclic peptide with drug delivery applications†
a
Bastian
Franke,
a
Mark F.
Fisher,
b
Fatemeh
Hajiaghaalipour,
a
Courtney E.
McAleese,
a
Angela
Song,
a
Grishma
Vadlamani,
b
Richard J.
Clark,
a
Rodney F.
Minchin,
a
Joshua S.
Mylne
b
and
K. Johan
Rosengren
*a
Abstract
Head-to-tail cyclized peptides are intriguing natural products with unusual properties. The PawS-Derived Peptides (PDPs) are ribosomally synthesized as part of precursors for seed storage albumins in species of the daisy family, and are post-translationally excised and cyclized during proteolytic processing. Here we report a PDP twice the typical size and 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 β-hairpins cross-clasp and enclose a hydrophobic core, creating a square prism. This dimer can be split by addition of micelles or organic solvent and in monomeric form PDP-23 adopts open or closed V-shapes, exposing different levels of hydrophobicity dependent on conditions. This chameleonic character is unusual for disulfide-rich peptides and engenders PDP-23 with potential for cell delivery and accessing novel targets. We demonstrate this by conjugating a rhodamine dye to PDP-23, creating a stable, cell-penetrating inhibitor of the P-glycoprotein drug efflux pump.
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