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- Title
Bicyclic β‐Sheet Mimetics that Target the Transcriptional Coactivator β‐Catenin and Inhibit Wnt Signaling.
- Authors
Wendt, Mathias; Bellavita, Rosa; Gerber, Alan; Efrém, Nina‐Louisa; Ramshorst, Thirza; Pearce, Nicholas M.; Davey, Paul R. J.; Everard, Isabel; Vazquez‐Chantada, Mercedes; Chiarparin, Elisabetta; Grieco, Paolo; Hennig, Sven; Grossmann, Tom N.
- 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.
- Subjects
WNT signal transduction; CATENINS; PROTEIN-protein interactions; TRANSCRIPTION factors; PROTEIN binding; PEPTIDOMIMETICS; MACROCYCLIC compounds
- Publication
Angewandte Chemie, 2021, Vol 133, Issue 25, p14056
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.202102082