A chameleonic macrocyclic peptide with drug delivery applications

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...

Solution NMR and racemic crystallography provide insights into a novel structural class of cyclic plant peptides

“…Small disulfide-rich peptides can be difficult to study by crystallography, but racemic crystallography in which a mixture of chemically synthesised peptides assembled with all l or all d amino acids improves crystallisation by allowing access to more favoured space groups. 35,36 Thus, to independently determine the tertiary and quaternary structure of PDP-23 for comparison with the water-based solution NMR spectroscopy, 9 we attempted racemic X-ray crystallography. Both PDP-23 and its mirror image, d -PDP-23, were synthesised as described previously using (Fmoc)-based solid phase peptide synthesis.…”

“…However, a new member of the PDP family was discovered that contains 28 amino acids and two disulfide bonds in a I–II/III–IV ladder-like configuration. 9 NMR spectroscopy showed that this peptide, PDP-23, adopts a unique tertiary structure wherein two loops, each containing a β-sheet bridged by a single disulfide bond, fold together into a V-shaped tertiary structure enclosing a hydrophobic core, more akin to the structures of larger proteins. 9 Additionally, in water PDP-23 self-associates and forms a square prism-shaped symmetrical homodimer quaternary structure by increasing the distance between the loop regions and merging the hydrophobic cores of the two monomers.…”

“… 9 NMR spectroscopy showed that this peptide, PDP-23, adopts a unique tertiary structure wherein two loops, each containing a β-sheet bridged by a single disulfide bond, fold together into a V-shaped tertiary structure enclosing a hydrophobic core, more akin to the structures of larger proteins. 9 Additionally, in water PDP-23 self-associates and forms a square prism-shaped symmetrical homodimer quaternary structure by increasing the distance between the loop regions and merging the hydrophobic cores of the two monomers. 9 The PDP-23 symmetrical homodimer disassociates into two well-defined monomers in less polar environments like 20% acetonitrile or membrane-mimicking micelles.…”

“… 9 Additionally, in water PDP-23 self-associates and forms a square prism-shaped symmetrical homodimer quaternary structure by increasing the distance between the loop regions and merging the hydrophobic cores of the two monomers. 9 The PDP-23 symmetrical homodimer disassociates into two well-defined monomers in less polar environments like 20% acetonitrile or membrane-mimicking micelles. In each case the β-sheet structure is retained but the hinges allow opening and closing of the ‘V’.…”

“…The conjugate demonstrated effective cell uptake and inhibition of this pump, thereby restoring drug sensitivity in a cancer cell line resistant to chemotherapeutics due to overexpression of P-glycoprotein. 9 …”