Bicyclic Peptide Ligands for MT1-MMP Binding
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Solution Overview
Problem
Current therapies lack effective, targeted approaches for inhibiting membrane type 1 metalloprotease (MT1-MMP), which is overexpressed in various solid tumors and contributes to tumor angiogenesis and extracellular matrix remodeling.
Innovation Solution
Development of peptide ligands specifically binding to MT1-MMP, comprising polypeptides with three cysteine residues covalently attached to a 1,1′,1″-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one molecular scaffold, forming bicyclic structures that act as high-affinity binders, and their conjugation with effector groups for targeted cancer therapy and imaging.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If linear peptides are used to bind MT1-MMP, then the peptides can be synthesized easily, but the binding affinity and specificity are insufficient
Solution Approach 1:
The peptide is divided into multiple loops (first loop between first and second cysteine residues, second loop between second and third cysteine residues) that can be independently designed and optimized. Each loop contributes specific binding interactions with MT1-MMP, allowing the overall binding affinity to be enhanced through cumulative effects of multiple segmented binding regions.
Solution Approach 2:
The peptide structure employs nested loops where the first loop and second loop are arranged such that their binding surfaces are positioned to interact with complementary sites on MT1-MMP. The loops are nested in space such that both can simultaneously engage the target protein, creating a multi-point binding architecture that significantly increases affinity.
2Reliability
If cyclic peptide structures are used to increase binding affinity, then the binding specificity improves, but the conformational flexibility is reduced which may limit adaptability to target variations
Solution Approach 1:
The peptide structure incorporates dynamic elements through the loop regions that can adopt different conformations depending on the binding context. The loops are designed with sufficient length and appropriate amino acid compositions to allow conformational adjustments while maintaining the overall bicyclic framework that provides structural stability and specificity.
Solution Approach 2:
Different regions of the peptide have different structural properties: the loop regions provide flexibility and adaptability for specific binding interactions, while the cysteine-scaffold connections provide rigid structural framework. This local differentiation allows the peptide to simultaneously achieve high specificity through the rigid scaffold and adaptability through the flexible loops.
3Reliability
If multiple cysteine residues are tethered to a molecular scaffold to form bicyclic structures, then the binding affinity to MT1-MMP increases, but the synthesis complexity increases
Solution Approach 1:
The molecular scaffold is designed with pre-positioned attachment points that correspond to the cysteine residues in the peptide sequence. This preliminary arrangement of attachment points allows for streamlined synthesis where the peptide can be assembled and then cyclized by forming disulfide bonds with the scaffold, reducing the overall synthesis complexity compared to traditional macrocyclization methods.
Solution Approach 2:
The molecular scaffold acts as an intermediary structure that facilitates the formation of the bicyclic peptide. The scaffold provides a stable platform with multiple attachment points that simplifies the tethering process and enables controlled formation of the peptide loops, making the synthesis more manageable and reproducible.
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 peptide ligands demonstrate dose-dependent antitumor activity and specificity for MT1-MMP, offering a promising approach for targeted cancer treatment by inhibiting MT1-MMP activity and potentially reducing tumor growth.
Implementation Method 1
a molecular scaffold which forms covalent bonds with the cysteine residues of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold
Implementation Method 2
Cyclic peptides are able to bind with high affinity and target specificity to protein targets... Good binding properties result from a relatively large interaction surface formed between the peptide and the target
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 membrane type 1 metalloprotease (MT1-MMP). The invention also describes drug conjugates comprising said peptides, conjugated to one or more effector and/or functional groups which have utility in imaging and targeted cancer therapy.