Bicyclic Peptide Ligands for High-Affinity Nectin-4 Binding
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Solution Overview
Problem
Existing peptide therapeutics targeting Nectin-4 lack sufficient affinity and specificity, limiting their effectiveness in preventing or treating diseases mediated by this protein.
Innovation Solution
Development of bicyclic peptide ligands with specific loop sequences and molecular scaffolds that form covalent bonds with cysteine residues, enhancing binding affinity and specificity to Nectin-4.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If linear peptide structures are used to target Nectin-4, then the peptide can be synthesized and delivered, but the binding affinity and specificity to Nectin-4 are insufficient
Solution Approach 1:
The peptide is divided into multiple cysteine-containing loops that are independently tethered to a molecular scaffold. Each loop can be optimized for specific binding interactions, and the modular structure allows for systematic improvement of affinity and specificity through library screening while maintaining synthetic feasibility.
Solution Approach 2:
Multiple peptide loops are nested onto a central molecular scaffold structure, creating a hierarchical organization where the scaffold provides the structural framework and the loops provide the binding interfaces. This nested architecture increases binding complexity without proportionally increasing synthesis complexity.
2Adaptability or versatility
If peptide flexibility is increased to improve binding adaptability, then more target conformations can be accessed, but entropy loss upon binding increases reducing binding affinity
Solution Approach 1:
The peptide structure incorporates dynamic loops that can adopt different conformations during binding, allowing the peptide to adapt to various target conformations. The loops maintain flexibility for binding adaptability while the cyclic structure and scaffold provide overall structural constraints that limit excessive conformational sampling, reducing entropy loss.
Solution Approach 2:
The invention changes the structural parameters by converting linear peptides into cyclic structures tethered to scaffolds. This parameter change restricts the conformational space available to the peptide backbone while preserving loop flexibility, thereby reducing the entropy penalty upon binding while maintaining adaptability to different target conformations.
3Reliability
If macrocyclization is used to reduce conformational flexibility and improve binding affinity, then entropy loss is reduced, but the ability to lock target-specific conformations and achieve high specificity is limited compared to multicyclic structures
Solution Approach 1:
The peptide is segmented into multiple independent loops that can each contribute to binding specificity. This segmentation allows different loops to recognize different epitopes or conformational features of the target, achieving high specificity through multiple independent recognition events rather than relying on a single rigid structure.
Solution Approach 2:
The invention creates a composite structure combining cyclic peptide loops with a synthetic molecular scaffold. This composite architecture integrates the binding advantages of cyclic peptides (reduced entropy loss) with the structural versatility of scaffold-based designs, enabling both high affinity and high specificity through the synergistic combination of multiple loops in defined spatial arrangements.
Data Source
AI summary
The present invention relates to polypeptides which are covalently bound to molecular scaffolds such that two or more peptide loops are subtended between attachment points to the scaffold. In particular, the invention describes peptides which are high affinity binders of Nectin-4. 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 Nectin-4.