Bicyclic β-Sheet Mimetics that Target the Transcriptional Coactivator β-Catenin and Inhibit Wnt Signaling

Mathias Wendt, Rosa Bellavita, Alan Gerber, Nina Louisa Efrém, Thirza van Ramshorst, Nicholas M. Pearce, Paul R.J. Davey, Isabel Everard, Mercedes Vazquez-Chantada, Elisabetta Chiarparin, Paolo Grieco, Sven Hennig, Tom N. Grossmann*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)13937-13944
Number of pages8
JournalAngewandte Chemie - International Edition
Issue number25
Publication statusPublished - 14 Jun 2021

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