Peptide Aptamer Linker Evolution for Binding and Cell Permeability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing methods for engineering peptide aptamers face challenges in achieving high cell permeability and stability while maintaining high binding affinity to target proteins, due to limitations in scaffold optimization and limited conformation sampling.
Innovation Solution
A method involving the insertion of a hypervariable region in a scaffold protein to generate peptide aptamers with linkers between the peptide motif and scaffold, allowing for improved binding affinity and stability, using specific amino acid sequences for the linkers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If peptide aptamers are engineered by inserting single amino acid sequences into hypervariable loops or mutating residues in rigid secondary structural elements, then binding epitopes are presented within scaffold protein context, but cell permeability and proteolytic stability are limited
Solution Approach 1:
The patent applies dynamics by replacing rigid secondary structural elements with flexible hypervariable linkers, allowing the peptide motif to sample multiple conformations and adapt to the target binding interface. This dynamic approach enables the peptide aptamer to maintain stability while improving cell permeability and proteolytic resistance through conformational adaptability.
Solution Approach 2:
The patent changes structural parameters by transitioning from fixed rigid motifs to flexible linkers with variable lengths and compositions. By optimizing linker parameters (amino acid sequence, length, flexibility), the patent achieves improved cell permeability and proteolytic stability while maintaining high binding affinity through the peptide motif-scaffold architecture.
2Ease of manufacture
If rigid motifs are used for peptide engineering, then specific loop sequences can be inserted into scaffolds, but sampling of 3-dimensional space is limited affecting binding affinity
Solution Approach 1:
The patent replaces static rigid motifs with dynamic flexible linkers that can sample multiple conformations in 3-dimensional space. This allows the peptide motif to explore a broader conformational landscape and find optimal binding orientations, thereby improving binding affinity while maintaining engineering feasibility through standardized scaffold platforms.
Solution Approach 2:
The patent employs flexible hypervariable linkers as connective elements between the scaffold and peptide motif, allowing these linkers to adopt various conformations to optimize the spatial arrangement for target binding. This flexibility enables better sampling of 3-dimensional space compared to rigid structural elements.
3Adaptability or versatility
If scaffolds are not optimized to stabilize conformations when bound to target molecule, then peptide sequences can be inserted, but binding affinity and stability are reduced
Solution Approach 1:
The patent applies local quality by designing specific hypervariable linkers with tailored amino acid sequences and properties to stabilize particular conformations of the peptide motif when bound to the target. Different linker regions can be optimized for different functional requirements, providing both versatility in sequence insertion and high binding affinity through localized conformational stabilization.
Data Source
AI summary
The present invention relates to methods of engineering and identifying a peptide aptamer that binds to a target protein of interest, and peptide aptamers engineered and identified using these methods and methods to identify a candidate peptide or nucleic acid that binds to a target protein in a live cell. The peptide aptamers defined herein may be useful for treating a condition associated with dysregulated cap-dependent translation, dysregulated DNA replication, dysregulated DNA repair and/or dysregulated mRNA translation such as cancer, diseases associated with a viral infection and obesity.