Molecular grafting can generate bioactivities within the cyclic peptide PDP-23

22 May 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


The stability of cyclic peptides, coupled with their structural diversity and ability to host an extensive range of bioactivities, make them promising leads for the development of new drugs. PawS-Derived Peptide-23 (PDP-23) is a head-to-tail macrocyclic peptide with two disulfide bonds produced in plant seeds. Its unusual fold comprises two -hairpins connected by hinges that allow the structure to adapt to different environments. In water two PDP-23 molecules form a compact intertwined dimer that buries hydrophobic residues, whereas in membrane mimicking conditions it adopts an open monomeric form that expose them. Here we investigate PDP-23 as a novel scaffold for the grafting of bioactive epitopes and conjugation of small molecules. To explore the plasticity of PDP-23 we introduced the bioactive loop of sunflower trypsin inhbitor-1 (SFTI-1) or an integrin binding RGD motif into either of the -hairpins. Solution NMR spectroscopy revealed that although the variants were unable to dimerise, the structural features of both the graft and scaffold were retained. SFTI-1 hybrid variants showed trypsin inhibitory activity. PDP-23 has previously been used as a cell permeable drug scaffold targeting drug-resistant cancer cells by inhibiting the drug efflux pump P-glycoprotein and restoring their sensitivity to chemotherapeutic. Introducing the RGD motif into such PDP-23 conjugates significantly improve their potency, suggesting that the RGD sequence targets the peptide to the membrane of cancer cells and improve cell uptake. In conclusion, this study highlights PDP-23 as a stable and versatile scaffold for molecular grafting of bioactivities and targeted delivery of pharmaceutical payloads.


PawS-Derived Peptide
trypsin inhibition
peptide-drug conjugate
cancer resistance
multidrug exporter

Supplementary materials

Supplementary Data
HPLC traces and MS data for the synthetic peptides. Cell toxicity data.


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