Phage Selection of Peptide Macrocycles against β‐Catenin To Interfere with Wnt Signaling. (26th January 2016)

• Record Type: Journal Article
• Authors: Bertoldo, Davide; Khan, Maola M. G.; Dessen, Pierre; Held, Werner; Huelsken, Joerg; Heinis, Christian
• Is Part Of: ChemMedChem. Volume 11:Number 8(2016)
• Page Start: 834
• Page End: 839
• Publication Date: 2016-01-26
• Subjects: cyclic peptides -- phage display -- protein–protein interactions -- Wnt signaling -- β-catenin; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500557
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Upregulation of β‐catenin, the primary mediator of the Wnt signaling pathway, plays an important role in the tumorigenesis of several types of human cancer. Targeting β‐catenin to interfere with its ability to serve as a translational co‐activator is considered an attractive therapeutic approach. However, the development of inhibitors has been challenging because of the lack of obvious binding pockets for ligands, and because inhibitors should not interfere with other β‐catenin functions. Only two ligands with known molecular interactions with β‐catenin have been developed so far, and are based on stabilized α‐helical peptides. In this study, we screened a large combinatorial library of bicyclic peptides by phage display. Binders to different surface regions of β‐catenin were identified. The binding site of one group of ligands was mapped to the interaction region of the translational Wnt inhibitor ICAT (inhibitor of β‐catenin and Tcf), which is a prime target site on β‐catenin for therapeutic intervention, and to which no ligands could be developed before. Abstract : Hit the target within a target : Bicyclic peptides that bind to different surface regions of β‐catenin were developed by phage display. Several of the ligands compete with the binding of ICAT and therefore bind to the prime target site on β‐catenin for therapeutic intervention.