Co-operative membrane disruption between cell-penetrating peptide and cargo: implications for the therapeutic use of the Bcl-2 converter peptide D-NuBCP-9-r8

Watkins, Catherine Louise, Sayers, Edward John ORCID: https://orcid.org/0000-0002-2621-1119, Allender, Christopher John, Barrow, David Anthony ORCID: https://orcid.org/0000-0003-2096-7262, Fegan, Christopher Daniel ORCID: https://orcid.org/0000-0001-9685-0621, Brennan, Paul ORCID: https://orcid.org/0000-0001-8792-0499 and Jones, Arwyn Tomos ORCID: https://orcid.org/0000-0003-2781-8905 2011. Co-operative membrane disruption between cell-penetrating peptide and cargo: implications for the therapeutic use of the Bcl-2 converter peptide D-NuBCP-9-r8. Molecular Therapy 19 (12) , pp. 2124-2132. 10.1038/mt.2011.175

Full text not available from this repository.

Abstract

Delivering apoptosis inducing peptides to cells is an emerging area in cancer and molecular therapeutics. Here, we have identified an alternative mechanism of action for the proapoptotic chimeric peptide D-NuBCP-9-r8. Integral to D-NuBCP-9-r8 is the Nur-77-derived D-isoform sequence fsrslhsll that targets Bcl-2, and the cell-penetrating peptide (CPP) octaarginine (r8) that is required for intracellular delivery. We find that the N-terminal phenylalanine of fsrslhsll acts in synergy with the cell-penetrating moiety to enhance peptide uptake at low nontoxic levels and cause rapid membrane blebbing and cell necrosis at higher (IC50) concentrations. These effects were not observed when a single phenylalanine–alanine mutation was introduced at the N-terminus of D-NuBCP-9-r8. Using primary samples from chronic lymphocytic leukemia (CLL) patients and cancer cell lines, we show that NuBCP-9-r8 induced toxicity, via membrane disruption, is independent of Bcl-2 expression. Overall, this study demonstrates a new mechanism of action for this peptide and cautions its use as a highly specific entity for targeting Bcl-2. For delivery of therapeutic peptides the work emphasizes that key amino acids in cargo, located several residues away from the cell-penetrating sequence, can significantly influence their cellular uptake and mode of action.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Pharmacy Schools > Medicine Schools > Engineering
Subjects:	R Medicine > R Medicine (General) R Medicine > RM Therapeutics. Pharmacology
Publisher:	Nature Publishing Group: Open Access Hybrid Model Option B
ISSN:	1525-0016
Last Modified:	06 Jan 2024 04:33
URI:	https://orca.cardiff.ac.uk/id/eprint/15593

Citation Data

Cited 21 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item