Cyclic Peptide β-Catenin Inhibitors for Improved Cell Permeability
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Solution Overview
Problem
Existing inhibitors targeting the β-catenin/TCF interaction for Wnt signaling pathway have unfavorable physico-chemical properties and low bioavailability, limiting their therapeutic potential for diseases associated with hyperactive Wnt signaling, such as cancer.
Innovation Solution
Development of structurally characterized β-sheet mimicking monocyclic and bicyclic peptides that target β-catenin, incorporating specific amino acid sequences and linkers to enhance cell permeability and binding affinity, utilizing crystal structures for design optimization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional ligand-discovery approaches using small molecular scaffolds are used to target β-catenin/TCF interaction, then the interaction can be inhibited, but the inhibitors have unfavorable physico-chemical properties and low bioavailability
Solution Approach 1:
The patent changes the chemical parameters of the inhibitors by transitioning from small molecular scaffolds to cyclic peptide structures with specific amino acid compositions. This structural parameter change improves bioavailability and physico-chemical properties while maintaining binding affinity to the β-catenin/TCF interaction
Solution Approach 2:
The patent employs composite peptide structures combining multiple amino acid residues (X1-X6 and Y1-Y6) with specific properties (hydrophobic, charged, polar) to create a composite molecular structure that achieves both high binding affinity and improved bioavailability, resolving the contradiction between reliability and ease of manufacture
2Reliability
If β-hairpin peptide structures are used to inhibit protein-protein interactions, then selective and high-affinity ligands can be obtained, but they have low tendency to penetrate cells
Solution Approach 1:
The patent segments the β-hairpin structure into a cyclic peptide framework with specific amino acid positions (X1-X6, Y1-Y6) that can be independently optimized. This segmentation allows the structure to maintain binding affinity while improving cell permeability through the cyclic configuration and strategic placement of amino acid properties
Solution Approach 2:
The patent changes structural parameters by converting linear β-hairpin peptides into cyclic structures with specific turn mimetics and linker configurations. This parameter change enables the molecule to penetrate cells while retaining the high-affinity binding characteristics of the original β-hairpin structure
3Reliability
If macrocyclic binders with antiparallel β sheets are designed to target β-catenin, then binding affinity can be improved, but the molecular complexity increases
Solution Approach 1:
The patent designs a universal cyclic peptide template (X1-X6-Y1-Y6) that can target β-catenin through a conserved interaction mechanism. This universal structure reduces the need for complex, customized designs for each target, simplifying the overall molecular complexity while maintaining high binding affinity
Solution Approach 2:
The patent optimizes specific parameters of the macrocyclic structure, such as the turn mimetic configuration and linker length, to achieve the desired β-sheet conformation. By carefully controlling these parameters, the patent achieves high binding affinity without unnecessary molecular complexity
Data Source
AI summary
The invention relates to a cyclic peptide comprising the amino acid sequence N-terminal-X4X3X2X1-a-Y1Y2Y3Y4-C-terminal, wherein -a- represents a linker, and wherein the peptide comprises a linker -c- between the N-terminal amino acid and C-terminal amino acid, and/or wherein the two amino acids of one or two of the following amino acid pairs form a side chain-to-side chain bridged di-amino acid forming a bridge -b-: X1 and X1; X2 and Y2; X3 and Y3; and X4 and Y4. The invention further relates to the use of said cyclic peptide as a medicament, especially for inhibiting or preventing a Wingless/integrase-1 (Wnt)-dependent disease in an individual in need thereof.