Multicyclic Peptide Ligands via Scaffold Cyclization
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Solution Overview
Problem
Current methods for generating peptide ligands with high affinity and specificity for biological targets are limited by the challenge of cyclizing linear peptides, especially those with long chains or complex structures, which requires orthogonal ligation strategies and reagents, and often result in peptides with single specificity rather than multispecificity.
Innovation Solution
The development of peptide ligands that are cyclised by joining the N and C termini, forming multiple loops subtended between attachment points on a molecular scaffold, allowing for multispecificity and enabling binding to multiple targets, using methods such as enzymatic cyclisation with microbial transglutaminase or chemical cyclisation techniques.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If linear peptides with long chains or complex structures are cyclized using orthogonal ligation strategies, then cyclization can be achieved, but the process becomes complex and requires specialized reagents
Solution Approach 1:
The patent introduces a molecular scaffold as an intermediary structure that facilitates peptide cyclization. The scaffold provides pre-defined attachment points that simplify the cyclization process by eliminating the need for complex orthogonal ligation strategies. Peptides are attached to the scaffold in a linear fashion, and the scaffold's structure naturally guides the formation of cyclic structures, thereby reducing process complexity and specialized reagent requirements.
2Reliability
If multiple peptide loops are provided to bind to a single target, then binding affinity can be increased, but the peptides produce single specificity rather than multispecificity
Solution Approach 1:
The patent segments the peptide structure into multiple independent loops, each capable of binding to different targets. Instead of having multiple loops cooperate to bind to a single target (which produces single specificity), each loop is designed as an independent binding unit. This segmentation allows the peptide to exhibit multispecificity, where different loops can independently bind to different biological targets, thereby maintaining high binding affinity while achieving versatility.
Solution Approach 2:
The molecular scaffold serves as a universal platform that can accommodate multiple different peptide sequences. Each peptide loop attached to the scaffold can be optimized for binding to a specific target, while the scaffold itself provides a common structural framework. This multi-functionality enables the peptide construct to bind to multiple different targets simultaneously, achieving both high affinity and multisspecificity.
3Shape
If peptides are subtended between (n+1) attachment points to generate n loops, then loop formation is achieved, but the attachment points are not optimally utilized
Solution Approach 1:
The patent inverts the conventional approach by providing exactly n attachment points on the molecular scaffold to generate n loops, rather than using (n+1) attachment points. This inversion optimizes the utilization of attachment points, as each attachment point directly contributes to forming one loop. The scaffold's n attachment points are efficiently used to create n independent peptide loops, eliminating the underutilization that occurs when (n+1) attachment points are used to generate only n loops.
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
This approach enables the creation of peptide ligands with enhanced binding capabilities to multiple targets, increasing their affinity and specificity, and allows for the formation of tricyclic peptides with maintained or improved binding activities compared to their bicyclic counterparts.
Implementation Method 1
enzymatic cyclisation with microbial transglutaminase
Implementation Method 2
the formation of multicyclic ligands, that is ligands comprising n loops subtended between n attachment points on a molecular scaffold, can take place if the peptide is cyclised by joining the N and C termini
Data Source
Figure 1A~1B
Figure 2A~2B
Figure 3A~3B
AI summary
The invention relates to a peptide ligand comprising a polypeptide linked to a molecular scaffold at n attachment points, wherein said polypeptide is cyclised and forms n separate loops subtended between said n attachment points on the molecular scaffold, wherein n is greater than or equal to 2.