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

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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:	Pharmacy Medicine 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

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