Cell permeable stapled peptide inhibitor of Wnt signaling that targets β-catenin protein‒protein interactions

Dietrich, Laura, Rathmer, Bernd, Ewan, Kenneth ORCID: https://orcid.org/0000-0001-6622-9009, Bange, Tanja, Stefan, Heinrichs, Dale, Trevor Clive ORCID: https://orcid.org/0000-0002-4880-9963, Dennis, Schade and Grossmann, Tom N. 2017. Cell permeable stapled peptide inhibitor of Wnt signaling that targets β-catenin protein‒protein interactions. Cell Chemical Biology 24 (8) , pp. 958-968. 10.1016/j.chembiol.2017.06.013

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Abstract

The Wnt signaling pathway plays a critical role in cell proliferation and differentiation, thus it is often associated with diseases such as cancers. Unfortunately, although attractive, developing anti-cancer strategy targeting Wnt signaling has been challenging given that the most attractive targets are involved in protein-protein interactions (PPIs). Here, we develop a stapled peptide inhibitor that targets the interaction between β-catenin and T cell factor/lymphoid enhancer-binding factor transcription factors, which are crucially involved in Wnt signaling. Our integrative approach combines peptide stapling to optimize proteolytic stability, with lessons learned from cell-penetrating peptide (CPP) design to maximize cellular uptake resulting in NLS-StAx-h, a selective, cell permeable, stapled peptide inhibitor of oncogenic Wnt signaling that efficiently inhibits β-catenin-transcription factor interactions. We expect that this type of integrative strategy that endows stapled peptides with CPP features will be generally useful for developing inhibitors of intracellular PPIs.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Uncontrolled Keywords:	Cell-Penetrating Peptides, New Modalities, Peptidomimetics, Protein-Protein Interaction, Wnt Signaling
Publisher:	Elsevier
ISSN:	2451-9456
Date of First Compliant Deposit:	3 July 2017
Date of Acceptance:	27 June 2017
Last Modified:	02 Dec 2024 13:30
URI:	https://orca.cardiff.ac.uk/id/eprint/102002

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