Cell Permeable Stapled Peptide Inhibitor of Wnt Signaling that Targets β-Catenin Protein-Protein Interactions.

Autor:	Dietrich L; Chemical Genomics Centre of the Max Planck Society, 44227 Dortmund, Germany; Department of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany., Rathmer B; Department of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany., Ewan K; School of Bioscience, Cardiff University, Cardiff CF10 3AX, UK., Bange T; Department of Mechanistic Cell Biology, Max-Planck-Institute of Molecular Physiology, 44227 Dortmund, Germany., Heinrichs S; Institute for Transfusion Medicine, University Hospital Essen, 45147 Essen, Germany., Dale TC; School of Bioscience, Cardiff University, Cardiff CF10 3AX, UK., Schade D; Department of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany; Institute of Pharmacy, Department of Pharmaceutical & Medicinal Chemistry, University of Greifswald, 17489 Greifswald, Germany., Grossmann TN; Chemical Genomics Centre of the Max Planck Society, 44227 Dortmund, Germany; Department of Chemistry and Pharmaceutical Sciences, VU University Amsterdam, 1081 HZ Amsterdam, the Netherlands. Electronic address: t.n.grossmann@vu.nl.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2017 Aug 17; Vol. 24 (8), pp. 958-968.e5. Date of Electronic Publication: 2017 Jul 27.
DOI:	10.1016/j.chembiol.2017.06.013
Abstrakt:	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. (Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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