Bicyclic Peptide Ligands for Specific, Stable MT1-MMP Binding
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Solution Overview
Problem
Existing peptide therapies for targets like MT1-MMP lack specificity and stability, leading to reduced efficacy and potential off-target effects.
Innovation Solution
Development of bicyclic peptides with three cysteine residues covalently bound to a non-aromatic molecular scaffold, forming two loops, which enhance specificity and stability by reducing flexibility and providing a platform for conjugation with effector groups.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If linear peptides are used for targeting MT1-MMP, then they can be synthesized and administered, but they lack specificity and stability leading to reduced efficacy and off-target effects
Solution Approach 1:
The peptide is divided into multiple segments connected by flexible linkers, with each segment containing specific amino acid sequences that interact with different regions of the MT1-MMP collagen binding site. This segmentation allows the peptide to wrap around the target protein, increasing contact surface area and binding specificity while maintaining synthetic feasibility
Solution Approach 2:
The bicyclic peptide structure adopts a nested configuration where one cyclic domain is positioned within or adjacent to another cyclic domain, creating a compact three-dimensional structure that presents multiple binding epitopes in a specific spatial arrangement. This nested architecture enhances target specificity by simultaneously engaging multiple residues on the collagen binding site while protecting the peptide from proteolytic degradation
2Adaptability or versatility
If peptide flexibility is increased to improve binding adaptability, then binding potential increases, but stability against proteases and half-life decrease
Solution Approach 1:
The peptide incorporates flexible linker regions between the cyclic domains that allow dynamic conformational adjustments. These linkers contain glycine and serine residues that provide rotational freedom, enabling the rigid cyclic structures to adapt their orientation and distance relative to each other. This dynamic flexibility allows the peptide to adjust to variations in the target binding site while the overall cyclic architecture maintains resistance to proteolytic cleavage
Solution Approach 2:
The bicyclic peptide structure can be viewed as having a flexible shell configuration where the cyclic domains form rigid protective shells that resist protease access, while the linker regions between them provide necessary flexibility. This shell-like structure protects the core binding epitopes from degradation while allowing the peptide to maintain adaptability in binding
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 high affinity and specificity for the collagen binding site of MT1-MMP, offering improved therapeutic potential, particularly in cancer treatment, with enhanced stability against proteases and prolonged half-life.
Implementation Method 1
a polypeptide comprising at least three cysteine residues, separated by at least two loop sequences, and a non-aromatic 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 non-aromatic 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), such as the collagen binding site of 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.