Cyclic Peptoid-Peptide Hybrids for Protease Resistance
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current peptide-based therapeutics face challenges in stability, specificity, and diversification, as stapled peptides lack the benefits of peptoids and peptoid-peptide hybrids such as easy side chain diversification and enhanced stability.
Innovation Solution
Development of cyclic peptoid-peptide hybrids with specific chemical structures and intramolecular cross-linking through side chain-to-side chain linkages or backbone cyclization, creating stable beta-hairpin-like structures that are resistant to protease degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If stapled peptides are used to stabilize protein-protein interaction inhibitors, then cell penetration and stability are improved, but side chain diversification and ease of placing stabilizing side chains are limited
Solution Approach 1:
The patent merges the stable backbone structure of peptides with the diversifiable side chains of peptoids by creating peptoid-peptide hybrids. The peptide portion provides structural stability through stapling, while the peptoid portion enables easy side chain diversification at the N-substitution position, thus combining the advantages of both molecular types.
Solution Approach 2:
The invention creates composite molecular structures by alternating peptide and peptoid residues within the same oligomer chain. This composite approach allows different segments to fulfill different functions: peptide segments for structural integrity and peptoid segments for chemical diversity and stability.
2Reliability
If peptoids are used as therapeutics, then stability and resistance to peptidase enzymes are improved, but self-assembled secondary structure formation is reduced
Solution Approach 1:
The peptoid-peptide hybrid combines the protease resistance of peptoids with the secondary structure-forming capability of peptides. The alternating sequence allows peptide segments to adopt beta-hairpin structures while peptoid segments provide protease resistance, achieving both properties simultaneously.
Solution Approach 2:
Different regions of the oligomer are assigned different properties: peptide residues in regions requiring secondary structure formation and peptoid residues in regions requiring protease resistance. This local differentiation allows each segment to optimize its function while contributing to the overall molecular performance.
3Stability of the object's composition
If cyclic peptoid-peptide hybrids are designed with beta-hairpin-like secondary structure, then structural stability is improved, but manufacturing complexity increases
Solution Approach 1:
The cyclic structure and beta-hairpin conformation are pre-designed into the molecular sequence during synthesis planning. By incorporating cyclic constraints and secondary structure-promoting elements into the primary sequence design, the desired three-dimensional structure is achieved automatically during folding, reducing the need for complex post-synthesis assembly steps.
Data Source
AI summary
The current invention pertains to stabilized peptoids or peptoid-peptide hybrids. The peptoids or peptoid-peptide hybrids are stabilized by side chain-side to side chain linkages and/or backbone cyclization. The current invention also provides a positional library scanning method for identification of peptoids or peptoid-peptide hybrids having a desired biological activity.