Stapled Peptides Modulating Beta-Catenin Axin Binding
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Solution Overview
Problem
Current methods face challenges in selectively modulating beta-catenin functions, particularly at Axin binding sites, due to the difficulty in targeting protein-protein interactions with extended surface areas, which are crucial for addressing beta-catenin-related diseases such as cancer.
Innovation Solution
Development of stapled peptides that physically interact with beta-catenin at specific sites, competing with Axin for binding and modulating beta-catenin functions, utilizing structural elements like hydrocarbon or heteroatom-containing staples to enhance solubility, cell permeability, and specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Area of stationary object
If conventional methods are used to target beta-catenin protein-protein interactions, then the extended surface area binding sites can be addressed, but selectivity and specificity are reduced
Solution Approach 1:
The patent applies local quality by designing stapled peptides that concentrate binding specificity at particular local regions of the beta-catenin surface rather than attempting to engage the entire extended binding interface. The stapling modification creates localized structural features that enhance binding affinity and selectivity at specific epitopes while maintaining the overall peptide sequence simplicity
Solution Approach 2:
The patent employs parameter changes by chemically modifying the peptide backbone through stapling, which alters the physical and chemical parameters of the peptide structure. This includes changes in conformational flexibility, hydrophobicity, and spatial arrangement of side chains, thereby enhancing binding selectivity without requiring engagement of the entire extended binding surface
2Manufacturing precision
If stapled peptides are designed to compete with Axin for beta-catenin binding, then selectivity at Axin sites is improved, but complexity of peptide structure increases
Solution Approach 1:
The patent applies segmentation by dividing the peptide structure into distinct functional regions: the stapled core region that provides structural stability and binding affinity, and the terminal regions that can be optimized for specific binding properties. This modular approach allows selective enhancement of Axin-site competition while maintaining overall structural manageability
Solution Approach 2:
The patent employs composite materials by combining natural amino acid residues with non-natural stapling linkages to create hybrid peptide structures. The staple acts as a composite element that integrates with the natural peptide backbone, providing enhanced structural properties and binding characteristics without completely replacing the natural amino acid sequence
3Reliability
If peptides are modified with staples to enhance solubility and cell permeability, then bioavailability is improved, but manufacturing complexity increases
Solution Approach 1:
The patent applies this principle by using relatively short peptide sequences (typically 10-30 amino acids) with stapling modifications that can be synthesized using standard solid-phase peptide synthesis methods. The stapling reaction, while additional, uses commercially available reagents and procedures, keeping manufacturing complexity manageable despite the structural enhancement
Data Source
AI summary
Among other things, the present disclosure provides technologies for modulating functions of beta-catenin. In some embodiments, the present disclosure provides stapled peptides that interact with beta-catenin. In some embodiments, provided stapled peptides interact with beta-catenin at an Axin-binding site of beta-catenin. In some embodiments, the present disclosure provides compounds, compositions and methods for preventing and/or treating conditions, disorders and diseases that are associated with beta-catenin.