1. Bicyclic β‐Sheet Mimetics that Target the Transcriptional Coactivator β‐Catenin and Inhibit Wnt Signaling
- Author
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Alan Gerber, Sven Hennig, Rosa Bellavita, Isabel Everard, Thirza van Ramshorst, Elisabetta Chiarparin, Nina Louisa Efrém, Nicholas M Pearce, Paul R. J. Davey, Tom N. Grossmann, Paolo Grieco, Mathias Wendt, Mercedes Vazquez-Chantada, Organic Chemistry, AIMMS, Wendt, Mathia, Bellavita, Rosa, Gerber, Alan, Efrém, Nina-Louisa, van Ramshorst, Thirza, Pearce, Nicholas M., Davey, Paul R. J., Everard, Isabel, Vazquez-Chantada, Mercede, Chiarpari, Elisabetta, Grieco, Paolo, Hennig, Sven, Grossmann, Tom N., and Neurosurgery
- Subjects
cell-penetrating peptides ,Models, Molecular ,Peptidomimetics | Hot Paper ,Peptidomimetic ,Beta sheet ,protein–protein interactions ,010402 general chemistry ,01 natural sciences ,Catalysis ,Thioether crosslink ,Protein–protein interaction ,protein-protein interaction ,SDG 17 - Partnerships for the Goals ,Transcription factor ,thioether crosslinks ,Wnt Signaling Pathway ,Research Articles ,beta Catenin ,Bicyclic molecule ,Chemistry ,010405 organic chemistry ,Wnt signaling pathway ,General Chemistry ,General Medicine ,Bridged Bicyclo Compounds, Heterocyclic ,peptidomimetic ,Cell biology ,0104 chemical sciences ,macrocycles ,Catenin ,peptidomimetics ,Wnt Signaling ,macrocycle ,Peptides ,Intracellular ,Research Article - Abstract
Protein complexes are defined by the three‐dimensional structure of participating binding partners. Knowledge about these structures can facilitate the design of peptidomimetics which have been applied for example, as inhibitors of protein–protein interactions (PPIs). Even though β‐sheets participate widely in PPIs, they have only rarely served as the basis for peptidomimetic PPI inhibitors, in particular when addressing intracellular targets. Here, we present the structure‐based design of β‐sheet mimetics targeting the intracellular protein β‐catenin, a central component of the Wnt signaling pathway. Based on a protein binding partner of β‐catenin, a macrocyclic peptide was designed and its crystal structure in complex with β‐catenin obtained. Using this structure, we designed a library of bicyclic β‐sheet mimetics employing a late‐stage diversification strategy. Several mimetics were identified that compete with transcription factor binding to β‐catenin and inhibit Wnt signaling in cells. The presented design strategy can support the development of inhibitors for other β‐sheet‐mediated PPIs., Starting from a 52 amino acid protein binding epitope, a bicyclic β‐hairpin structure was developed to bind the transcriptional coactivator β‐catenin. Our structure‐based design approach was supported by screening a focused library of bicyclic mimetics which was generated via late‐stage diversification. The most active bicyclic β‐hairpin shows cell‐penetration and inhibits Wnt signaling in a cell‐based assay.
- Published
- 2021
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