Bicyclic Beta-Sheet Mimetics That Target The Transcriptional Coactivator Beta-Catenin And Inhibit Wnt Signaling

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 beta-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 beta-sheet mimetics targeting the intracellular protein beta-catenin, a central component of the Wnt signaling pathway. Based on a protein binding partner of beta-catenin, a macrocyclic peptide was designed and its crystal structure in complex with beta-catenin obtained. Using this structure, we designed a library of bicyclic b-sheet mimetics employing a late-stage diversification strategy. Several mimetics were identified that compete with transcription factor binding to bcatenin and inhibit Wnt signaling in cells. The presented design strategy can support the development of inhibitors for other beta-sheet-mediated PPIs.