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

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

  • Cell Chem Biol. 2017 Aug 17;24(8):958-968.e5. doi: 10.1016/j.chembiol.2017.06.013.
Laura Dietrich 1 Bernd Rathmer 2 Kenneth Ewan 3 Tanja Bange 4 Stefan Heinrichs 5 Trevor C Dale 3 Dennis Schade 6 Tom N Grossmann 7
Affiliations

Affiliations

  • 1 Chemical Genomics Centre of the Max Planck Society, 44227 Dortmund, Germany; Department of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany.
  • 2 Department of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany.
  • 3 School of Bioscience, Cardiff University, Cardiff CF10 3AX, UK.
  • 4 Department of Mechanistic Cell Biology, Max-Planck-Institute of Molecular Physiology, 44227 Dortmund, Germany.
  • 5 Institute for Transfusion Medicine, University Hospital Essen, 45147 Essen, Germany.
  • 6 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.
  • 7 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.
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.

Keywords

Wnt signaling; cell-penetrating peptides; new modalities; peptidomimetics; protein-protein interaction.

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