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

Dietrich, Laura, Rathmer, Bernd, Ewan, Kenneth ORCID:, Bange, Tanja, Stefan, Heinrichs, Dale, Trevor Clive ORCID:, 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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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: 06 Nov 2023 21:24

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