Disruption of β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction Using Heterogeneous Peptidomimetic Foldamers
Peng Sang1,2,3, Jiacheng Wei4, Mingshuang Wu1
1State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, School of Pharmaceutical Sciences, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Abstract:
Aberrant activation of the Wnt/β-catenin-signaling pathway is closely linked to the development and progression of colorectal cancer (CRC) and other malignancies. Targeting and inhibiting this pathway has proved to be a promising approach for the development of antitumor drugs. In this study, we designed and synthesized a series of helical 1:1 α/sulfonyl-γ-AApeptide inhibitors aiming to disrupt the interaction between β-catenin and BCL9. Circular dichroism spectroscopy and modeling studies suggest that these 1:1 α/sulfonyl-γ-AApeptides adopt a right-handed helical conformation and effectively mimic the crucial side chains of BCL9, with the most potent compound exhibiting nanomolar affinity for β-catenin. Notably, these peptidomimetics possess excellent permeability, allowing them to penetrate CRC cancer cells, downregulate Wnt target genes, disrupt the cellular β-catenin/BCL9 protein-protein interaction (PPI), and significantly reduce the proliferation of Wnt-hyperactive cell lines. Furthermore, these hybrid peptidomimetics demonstrate enhanced serum stability, which augments their potential as therapeutic agents for future applications. In addition, this study paves a new way to modulate a myriad of PPIs.
Insights
New helical peptidomimetics inhibit Wnt/β-catenin signaling by disrupting β-catenin and BCL9 interactions. These compounds show potential as colorectal cancer therapeutics by reducing cell proliferation and improving serum stability.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Cancer Research
Background:
- Aberrant Wnt/β-catenin signaling drives colorectal cancer (CRC) and other malignancies.
- Inhibiting this pathway is a key strategy for developing novel antitumor drugs.
Purpose of the Study:
- To design and synthesize novel helical 1:1 α/sulfonyl-γ-AApeptide inhibitors.
- To disrupt the protein-protein interaction (PPI) between β-catenin and BCL9.
Main Methods:
- Peptide synthesis and characterization.
- Circular dichroism spectroscopy and molecular modeling.
- In vitro assays assessing cell permeability, gene expression, PPI disruption, and cell proliferation.
Main Results:
- Synthesized helical 1:1 α/sulfonyl-γ-AApeptides mimic BCL9 side chains and bind β-catenin with nanomolar affinity.
- Compounds exhibit excellent cell permeability, downregulate Wnt target genes, and disrupt β-catenin/BCL9 PPIs.
- Significant reduction in proliferation of Wnt-hyperactive CRC cell lines observed, alongside enhanced serum stability.
Conclusions:
- Novel hybrid peptidomimetics effectively inhibit Wnt/β-catenin signaling and CRC cell proliferation.
- These compounds demonstrate therapeutic potential due to cell penetration and serum stability.
- The study presents a new strategy for modulating protein-protein interactions.
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