Structure-Based Design of Bicyclic Helical Peptides That Target the Oncogene β-Catenin

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Structural Biology

Background:

• Inhibiting intracellular protein-protein interactions is difficult, especially with flat interfaces.
• Beta-catenin, a transcriptional co-activator and oncogene, presents a significant challenge due to its interface characteristics.
• Current high-affinity beta-catenin inhibitors are large, limiting therapeutic development.

Purpose of the Study:

• To design and develop novel, smaller molecular weight inhibitors targeting beta-catenin.
• To create a peptidomimetic scaffold mimicking the Axin-derived alpha-helical motif.
• To improve the biological activity of helix mimetics for therapeutic potential.

Main Methods:

• Design of a peptidomimetic scaffold based on the Axin-derived alpha-helical beta-catenin-binding motif.
• Sequence maturation and bicyclization to create a crosslinked peptide structure.
• X-ray crystallography to confirm binding mode and site.
• Cell-based assays to evaluate inhibitor activity.

Main Results:

• A novel, smaller peptidomimetic scaffold was successfully designed and synthesized.
• A unique crosslink architecture was achieved through sequence maturation and bicyclization.
• Crystal structure confirmed the binding mode and site of the inhibitor.
• The derived inhibitor demonstrated single-digit micromolar activity in a cell-based assay.

Conclusions:

• The study presents a successful strategy for designing reduced molecular weight helix mimetics.
• The developed peptidomimetic scaffold offers a promising approach for targeting challenging protein-protein interactions like beta-catenin.
• This work advances the development of smaller, more potent inhibitors for therapeutic applications.