Bicyclic β-Sheet Mimetics that Target the Transcriptional Coactivator β-Catenin and Inhibit Wnt Signaling.
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Wendt M, Bellavita R, Gerber A, Efrém NL, van Ramshorst T, Pearce NM, Davey PRJ, Everard I, Vazquez-Chantada M, Chiarparin E, Grieco P, Hennig S, Grossmann TN
Angew. Chem. Int. Ed. Engl. 60 (25) 13937-13944 [2021-06-14; online 2021-05-05]
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.
PubMed 33783110
DOI 10.1002/anie.202102082
Crossref 10.1002/anie.202102082