Volume 11, Issue 8 p. 834-839
Communication

Phage Selection of Peptide Macrocycles against β-Catenin To Interfere with Wnt Signaling

Davide Bertoldo

Davide Bertoldo

Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland

Search for more papers by this author
Dr. Maola M. G. Khan

Dr. Maola M. G. Khan

Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland

Search for more papers by this author
Pierre Dessen

Pierre Dessen

Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland

Search for more papers by this author
Prof. Werner Held

Prof. Werner Held

Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland

Search for more papers by this author
Prof. Joerg Huelsken

Prof. Joerg Huelsken

Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland

Search for more papers by this author
Prof. Christian Heinis

Corresponding Author

Prof. Christian Heinis

Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland

Search for more papers by this author
First published: 26 January 2016
Citations: 28

Graphical 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.

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.