Bicyclic Peptide Ligands with sp3-Rich Scaffolds for Targeted Binding
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Solution Overview
Problem
Current molecular scaffolds for peptide binding are limited in variety, particularly lacking sp3 content, which affects physicochemical properties and selectivity, necessitating the development of more diverse scaffolds for effective peptide binders.
Innovation Solution
The development of compounds with specific molecular scaffolds that incorporate sp3 content, allowing for the creation of bicyclic constrained peptide binders with enhanced physicochemical properties and selectivity, specifically targeting CAIX, MT1-MMP, CD38, EphA2, or PBP1A for therapeutic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional molecular scaffolds are used for peptide binding, then the peptide binders can be generated, but the variety of scaffolds is limited and selectivity is reduced
Solution Approach 1:
The patent introduces sp3 content as a new parameter in molecular scaffold design. By incorporating sp3 hybridized carbons into the scaffold structure, the invention creates three-dimensional chiral environments that enhance peptide binder selectivity. This parameter change transforms flat, two-dimensional scaffolds into three-dimensional structures with unique spatial arrangements, enabling differentiated displays of peptide sequences and improving binding specificity to targets like CAIX, MT1-MMP, CD38, EphA2, and PBP1A.
2Reliability
If molecular scaffolds with sp3 content are developed, then selectivity and physicochemical properties are improved, but scaffold complexity increases
Solution Approach 1:
The patent divides the molecular scaffold into distinct functional segments: sp3-containing core structures, peptide attachment points, and peptide loops. This segmentation allows independent optimization of each component - the sp3 core provides chiral environment and selectivity, while the peptide loops provide target-specific binding. The scaffold is constructed as a modular assembly where cysteine residues in the peptide sequence can be covalently linked to the sp3 scaffold through defined attachment points, creating bicyclic constrained peptide binders with enhanced properties.
3Stability of the object's composition
If bicyclic constrained peptide binders are created using sp3 scaffolds, then binding affinity and stability are enhanced, but the complexity of peptide structure increases
Solution Approach 1:
The patent embeds peptide loops within the three-dimensional sp3 scaffold structure. The cysteine residues of the peptide sequence are covalently bound to the scaffold, creating nested bicyclic structures where the peptide loops are subtended between attachment points on the sp3 scaffold. This nesting approach confines the peptide in a specific three-dimensional arrangement, enhancing binding affinity and stability while maintaining a manageable structural complexity through the organized integration of peptide and scaffold components.
Data Source
AI summary
The present invention provides compounds, compositions thereof, and methods of using the same.