Alkylamino Linkages in Loop Peptides for Solubility
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing methods for forming looped peptide structures using thioether linkages have limitations in compatibility with different peptides, leading to issues with physiochemical properties such as solubility and biodistribution, and there is a need for alternative chemistries to achieve improved properties.
Innovation Solution
Replacing cysteine residues in peptides with amino acids having side-chain amino groups to form alkylamino linkages with a scaffold, which maintains affinity to target molecules while enhancing solubility and oxidation stability, and using specific bases and solvents in nucleophilic substitution reactions to improve yields.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If thioether linkages are used to form looped peptide structures, then covalent bonding between peptide and scaffold is achieved, but solubility and oxidation stability are compromised
Solution Approach 1:
The patent changes the chemical nature of the linkage from thioether (containing sulfur) to alkylamino (containing nitrogen). This parameter change in the chemical composition fundamentally alters the properties: alkylamino linkages eliminate the oxidation vulnerability of thioether bonds while introducing improved solubility characteristics through the different chemical nature of nitrogen-containing linkages.
2Adaptability or versatility
If cysteine residues are used for forming thioether linkages, then selective and biorthogonal reactivity is achieved, but compatibility with different peptides and physiochemical properties are limited
Solution Approach 1:
The alkylamino linkage chemistry provides a universal platform that can be applied across different peptide sequences and scaffold structures. By replacing the cysteine-specific thioether chemistry with amine-based alkylamino linkages, the system becomes compatible with a broader range of peptides that contain amino acid residues with nucleophilic amine groups, thereby achieving multi-functionality and enhanced adaptability.
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 use of alkylamino linkages in looped peptides achieves improved solubility and oxidation stability while conserving target molecule affinity, with increased yields in cyclization reactions, suggesting a more versatile and effective approach to peptide-scaffold interactions.
Implementation Method 1
The present inventors have found that replacement of one or more of the cysteine residues in a looped peptide by peptides having side-chain amino groups offers an opportunity to generate looped peptide derivatives having alkylamino linkages replacing the thioether linkages of the prior art.
Data Source
AI summary
A compound comprising at least one looped peptide structure attached via at least one alkylamino linkage to a scaffold. Preferably the looped peptide structure is a Bicycle structure comprising two peptide loops attached to the scaffold via two alkylamino linkages and one thioether linkage, one of the linkages being common to both loops. Also provided is a method of making a compound comprising at least one looped peptide structure attached via at least one alkylamino linkages to a scaffold, the method comprising: providing a peptide having at least two residues selected from cysteine, diaminopropionic acid, D-N-Alkyldiaminopropionic acid and β-N-Alkyldiaminopropionic acid, provided that at least one of the residues is diaminopropionic acid, D-N-Alkyldiaminopropionic acid and β-N-Alkyldiaminopropionic acid; providing a scaffold molecule having at least two reactive sites for forming alkylamino or thioether linkages with the said at least two residues; and forming said linkages between the peptide and the scaffold molecule.