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

Transparent peer review

To support increased transparency, we offer authors the option to publish the peer review history alongside their article.

View this article’s peer review history

Article information

Article type
Paper
Submitted
16 jun 2020
Accepted
01 okt 2020
First published
20 okt 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

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements