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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, Bange, Tanja, Stefan, Heinrichs, Dale, Trevor Clive, 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
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: 29 Jul 2018 08:20

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