Issue 5, 2020

Cyclic peptide scaffold with ability to stabilize and deliver a helical cell-impermeable cargo across membranes of cultured cancer cells

Abstract

Cell penetrating peptides (CPPs) are valuable tools for developing anticancer therapies due to their ability to access intracellular targets, including protein–protein interactions. cPF4PD is a newly described CPP designed from a transduction domain of the human defense protein platelet factor 4 (PF4), that also has antimalarial activity. The cPF4PD peptide recapitulates the helical structure of the PF4 domain and maintains activity against intracellular malaria parasites via a selective membrane-active mechanism. We hypothesized that cPF4PD and PF4-derived peptide analogues would enter cancer cells and have utility as scaffolds for delivering a peptide dual inhibitor (pDI) sequence with ability to inhibit p53:MDM2/X interactions and reactivate the p53 pathway. Here we designed and produced PF4 peptide and PF4 peptide-pDI grafted analogues with low micromolar activity toward melanoma and leukemia. Two grafted analogues achieved a stable helical structure and inhibited interaction with MDM2 and MDMX. These peptides reached the cytoplasm of cells but were unable to reactivate the p53 pathway. Instead, the cytotoxic mechanism was attributed to peptide binding to mitochondrial membranes that perturbed function within two hours of treatment. These studies of PF4-derived CPPs suggest their potential as scaffolds for delivering cell-impermeable cargoes into the cytoplasm of cells and highlight the importance of characterizing the internalization and cell death mechanism of designer peptide-based drugs.

Graphical abstract: Cyclic peptide scaffold with ability to stabilize and deliver a helical cell-impermeable cargo across membranes of cultured cancer cells

Supplementary files

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Article information

Article type
Paper
Submitted
16 6月 2020
Accepted
01 10月 2020
First published
20 10月 2020
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2020,1, 405-420

Cyclic peptide scaffold with ability to stabilize and deliver a helical cell-impermeable cargo across membranes of cultured cancer cells

N. Lawrence, G. J.-B. Philippe, P. J. Harvey, N. D. Condon, A. H. Benfield, O. Cheneval, D. J. Craik and S. Troeira Henriques, RSC Chem. Biol., 2020, 1, 405 DOI: 10.1039/D0CB00099J

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