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Phage Selection of Peptide Macrocycles against β-Catenin To Interfere with Wnt Signaling
Davide Bertoldo1, Maola M G Khan1, Pierre Dessen2
1Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland.
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.
Insights
Researchers developed novel bicyclic peptides targeting β-catenin, a key protein in Wnt signaling and cancer development. These peptides bind to a crucial site, offering a new therapeutic strategy for cancer treatment.
Area of Science:
- Molecular Biology
- Cancer Research
- Drug Discovery
Background:
- β-catenin is central to Wnt signaling and crucial in human cancer tumorigenesis.
- Targeting β-catenin as a translational co-activator is a promising therapeutic strategy.
- Developing specific β-catenin inhibitors is challenging due to its structure and essential functions.
Purpose of the Study:
- To identify novel ligands that can inhibit β-catenin function.
- To develop therapeutic agents targeting the Wnt signaling pathway.
- To overcome challenges in developing β-catenin inhibitors.
Main Methods:
- Screening of a large combinatorial library of bicyclic peptides using phage display.
- Identification of binders to various surface regions of β-catenin.
- Mapping the binding site of identified ligands.
Main Results:
- Novel bicyclic peptide binders to β-catenin were identified.
- One group of ligands binds to the ICAT interaction region on β-catenin.
- This region is a prime target for therapeutic intervention.
Conclusions:
- Bicyclic peptides represent a new class of potential therapeutics targeting β-catenin.
- The identified ligands bind to a previously undruggable site on β-catenin.
- This discovery opens new avenues for cancer therapy by modulating Wnt signaling.
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