Disulfide-Rich Peptide Scaffold Libraries for Higher Hit Probability
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Solution Overview
Problem
Existing peptide-based drug development faces challenges in engineering disulfide-rich peptides (DRPs) to specifically bind to protein targets due to a lack of structural complementarity and the risk of sequence redundancy in phage libraries, leading to low hit probabilities.
Innovation Solution
A system comprising multiple disulfide-rich peptide scaffold libraries, each with shared three-dimensional structural features, is used to identify DRPs that bind to a target through methods like phage display, ensuring structural diversity and increasing the likelihood of finding a hit.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a single phage display library is used to screen for DRPs, then the screening process is simple, but the probability of finding a hit is low due to sequence redundancy and lack of structural diversity
Solution Approach 1:
The invention divides a single large phage display library into multiple smaller, structurally distinct DRP scaffold libraries. Each library contains peptides with specific structural features (e.g., different disulfide bond patterns, secondary structures), reducing sequence redundancy within each library while maintaining overall diversity across the collection. This segmentation increases hit probability by ensuring better structural complementarity to diverse protein targets.
Solution Approach 2:
The invention adds a structural dimension to library organization by classifying DRPs based on their three-dimensional structural features rather than just sequence similarity. This creates multiple libraries differentiated by structural characteristics (e.g., knottin folds, hairpin structures, disulfide bond arrangements), enabling the selection of libraries with appropriate structural complementarity for specific target proteins.
2Stability of the object's composition
If DRPs are engineered with disulfide bonds to improve stability, then chemical and biological stability increases, but the ability to bind specific targets decreases due to structural constraints
Solution Approach 1:
The invention applies different disulfide bond patterns and structural features to specific regions of the DRP libraries. Each library is designed with localized structural characteristics (e.g., specific loop configurations, secondary structure elements) that maintain overall stability while providing diverse binding surfaces. This allows individual peptides within each library to have optimized stability-binding property balances suitable for different target types.
Solution Approach 2:
The invention systematically varies key structural parameters across the DRP libraries, including disulfide bond positions, loop lengths, and secondary structure content. By creating libraries with different parameter combinations (e.g., varying the number and arrangement of disulfide bonds), the system enables selection of peptides with optimal parameter sets for both stability and binding specificity to particular protein targets.
Data Source
AI summary
Provided herein are libraries of structurally diverse disulfide-rich peptides (DRPs) and related methods of screening these libraries to identify DRPs that bind to a desired target.