Alpha/Beta-Peptide Foldamers for VEGF Binding
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Developing modulating agents for protein-protein interactions is challenging due to the large and irregularly shaped interfaces involved, with traditional small molecule-based approaches being inefficient and peptide-based solutions facing issues like rapid proteolytic degradation, limiting their therapeutic utility.
Innovation Solution
Design and development of α/β-peptide foldamers that mimic the Z-domain scaffold, specifically targeting the receptor recognition surface of VEGF, using truncated analogues with β-amino acid residues to enhance binding affinity and stability, and incorporating disulfide bonds to promote the correct conformation for protein interaction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If traditional small molecule-based approaches are used to modulate protein-protein interactions, then the molecular size is small and易于administration, but the binding affinity and selectivity for large and irregularly shaped interfaces are insufficient
Solution Approach 1:
The patent employs peptidomimetic compounds that combine features of both small molecules and peptides. These compounds use non-natural amino acid residues and backbone modifications to create hybrid structures that maintain the small size advantage for administration while achieving high binding affinity and selectivity for protein-protein interaction interfaces through optimized molecular recognition elements
2Reliability
If peptide-based modulating agents are used to target protein surfaces with high affinity, then the binding affinity and selectivity are improved, but the bioavailability is reduced due to rapid proteolytic degradation
Solution Approach 1:
The patent fundamentally changes the chemical parameters of peptide backbones by incorporating non-natural amino acid residues with modified backbone structures. These parameter changes include using residues with alternative amide bond geometries, cyclic constraints, and non-proteinogenic side chains that confer resistance to proteolytic enzymes while preserving the ability to form stable, selective interactions with target protein surfaces
Solution Approach 2:
The peptidomimetic compounds represent composite structures that integrate natural amino acid recognition elements with non-natural backbone modifications. This composite approach combines the high binding affinity characteristics of natural peptides with the proteolytic resistance of synthetic analogs, creating hybrid molecules that overcome the limitations of both pure peptide and pure small molecule approaches
3Duration of action of moving object
If D-peptides are used to decrease susceptibility to proteolytic degradation, then the proteolytic stability is improved, but the cost-effectiveness and feasibility for larger proteins are reduced
Solution Approach 1:
Rather than converting entire peptides to D-stereoisomers (which is costly and complex), the patent applies localized backbone modifications at specific positions within the peptide sequence. This local quality approach uses non-natural amino acid residues with modified backbones at key positions to confer proteolytic resistance while maintaining L-amino acid composition elsewhere, significantly reducing manufacturing complexity and cost
Solution Approach 2:
The patent creates simplified copies or analogs of natural peptide structures that replicate the essential binding features while using chemically modified residues. These peptidomimetic copies maintain the ability to bind target proteins with high affinity but use non-natural backbone structures that are inherently more resistant to degradation, providing a cost-effective alternative to full D-peptide synthesis
Data Source
AI summary
Described are α/β-peptide mimics of Z-domain scaffold peptides, methods of making them, and methods of using them. The α/β-peptide mimics include β-amino acid residues and, optionally, disulfide bonds to stabilize the conformation of the mimics. The compounds may be truncated as compared to conventional Z-domain scaffold peptides and are resistant to proteolytic degradation due to the presence of β-amino acid residues. The mimics can be made so as to bind selectively to a desired target.