Bicyclic Peptide Ligands for IL-17 Binding
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Solution Overview
Problem
Current therapeutic approaches lack effective, high-affinity binders for IL-17, which are crucial for treating diseases mediated by this cytokine, as existing peptides often suffer from low specificity and stability due to conformational flexibility and rapid degradation.
Innovation Solution
Development of bicyclic peptides covalently bound to molecular scaffolds, specifically designed to target IL-17 with high affinity, incorporating three cysteine residues and loop sequences that form stable loops on the scaffold, enhancing binding specificity and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If linear peptides are used to target IL-17, then they can be synthesized and administered, but they suffer from low binding affinity and high conformational flexibility leading to rapid degradation
Solution Approach 1:
The peptide is divided into multiple segments connected by flexible linkers, with each segment containing a cysteine residue that binds to the molecular scaffold. This segmentation allows the peptide to maintain flexibility for target binding while the scaffold provides overall structural stability
Solution Approach 2:
The invention combines synthetic peptide sequences with a rigid molecular scaffold (such as tris(bromomethyl)benzene derivatives) to create a hybrid structure. The peptide provides target-specific binding while the scaffold provides structural stability and reduces conformational flexibility, resolving the contradiction between flexibility and stability
2Reliability
If cyclic peptide structures are formed to reduce conformational flexibility, then binding affinity increases, but the complexity of synthesis and cyclization increases
Solution Approach 1:
The peptide is synthesized in a linear form with predetermined cysteine residues at specific positions, allowing easy synthesis using standard solid-phase peptide synthesis methods. The cyclization step is performed as a final step by reacting the cysteine residues with the molecular scaffold, simplifying the overall synthesis process while still achieving the binding affinity benefits of cyclic structures
Solution Approach 2:
The molecular scaffold acts as an intermediary that facilitates cyclization by providing reactive groups that covalently bind to the cysteine residues. This intermediary approach simplifies the cyclization process compared to direct peptide-to-peptide cyclization, reducing synthesis complexity while maintaining the structural benefits of cyclic peptides
3Manufacturing precision
If multiple cysteine residues are introduced to form loops on the scaffold, then binding specificity increases, but the risk of aggregation and improper folding increases
Solution Approach 1:
The peptide sequence is designed with cysteine residues positioned at specific locations to form loops of defined lengths (e.g., 6-12 amino acids). This local control over loop formation ensures that each cysteine participates in a controlled, localized interaction with the scaffold, preventing random aggregation while maintaining high binding specificity for the target
Solution Approach 2:
The invention optimizes parameters such as loop length, cysteine spacing, and scaffold geometry to minimize aggregation risk. By carefully controlling these parameters, the peptide forms well-defined loops that bind specifically to the target while reducing the likelihood of intermolecular interactions that lead to aggregation
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The bicyclic peptides demonstrate improved specificity and stability, effectively targeting IL-17, offering potential therapeutic solutions for diseases such as rheumatoid arthritis, psoriasis, and cancer by providing prolonged exposure and reduced proteolytic degradation.
Implementation Method 1
a molecular scaffold which forms covalent bonds with the cysteine residues of the polypeptide
Data Source
AI summary
The present invention relates to polypeptides which are covalently bound to molecular scaffolds such that two peptide loops are subtended between attachment points to the scaffold. In particular, the invention describes peptides which are high affinity binders of IL-17. The invention also includes drug conjugates comprising said peptides, conjugated to one or more effector and/or functional groups, to pharmaceutical compositions comprising said peptide ligands and drug conjugates and to the use of said peptide ligands and drug conjugates in preventing, suppressing or treating a disease or disorder mediated by IL-17.