Peptide Core Linker Units for Stable Click Chemistry Conjugation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing multi-arm linker units for pharmaceuticals face challenges in stability and conjugation efficacy due to unstable coupling reactions and limitations in solid-phase synthesis, particularly when incorporating cysteine residues, which affect the incorporation of functional groups like tetrazine, cyclooctene, and cyclooctyne in peptide cores.
Innovation Solution
A novel peptide core-based multi-arm linker unit with linking amino acid residues, spacers, and conjugating moieties that allow for stable conjugation of functional elements via click chemistry reactions, using azide, alkyne, tetrazine, and cyclooctyne groups, enabling efficient synthesis and improved stability through the use of PEGylated amino acids and specific spacer configurations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If thiol-maleimide coupling reaction is used to incorporate functional groups (tetrazine, cyclooctene, cyclooctyne) into the peptide core, then conjugation capability is improved, but stability of the conjugated linkers deteriorates due to reverse reaction and exchange reaction with adjacent thiol-group containing molecules
Solution Approach 1:
The patent removes the cysteine residue (thiol group) from the peptide core structure, extracting the source of instability. By using amino acids without reactive thiol groups as the peptide core, the reverse reaction and exchange reaction with adjacent thiol-group containing molecules are eliminated, thereby resolving the stability issue while maintaining conjugation capability through the linker's terminal functional groups
Solution Approach 2:
The patent introduces a stable intermediate structure by using a peptide core with amino acids that have amine or carboxyl groups instead of thiol groups. This intermediate structure serves as a stable platform that can still be conjugated to functional groups through alternative chemistry (e.g., amine-reactive or carboxyl-reactive groups), thereby maintaining conjugation capability while eliminating the instability caused by thiol-maleimide reverse reactions
2Adaptability or versatility
If cysteine residue is used in the peptide core to enable functional group incorporation, then conjugation functionality is improved, but ease of solid-phase synthesis deteriorates due to interference with continual branching synthesis
Solution Approach 1:
The patent extracts the cysteine residue from the peptide core, removing the thiol group that interferes with solid-phase synthesis. By using amino acids with amine or carboxyl groups instead, the peptide core becomes compatible with continual branching synthesis methods, as these groups do not react with the reagents used in solid-phase peptide synthesis, thereby improving ease of manufacture while maintaining conjugation functionality through the linker design
Solution Approach 2:
The patent creates a simplified version of the conjugation-capable structure by using a peptide core without cysteine residues. This copied structure maintains the essential function of providing attachment points for functional groups through alternative chemistry (amine or carboxyl groups), while eliminating the problematic thiol group that interferes with solid-phase synthesis, making the synthesis process easier and more compatible with standard methodologies
3Manufacturing precision
If alpha-amine group blocking is performed to enable linker conjugation, then conjugation specificity is improved, but productivity deteriorates due to extra blocking steps and reduced yield and purity
Solution Approach 1:
The patent removes the need for alpha-amine group blocking by selecting amino acids with side chain functional groups (amine or carboxyl) that can serve as conjugation sites. This eliminates the extra blocking and deprotection steps required when using the N-terminal alpha-amine group, thereby improving productivity and yield while maintaining conjugation specificity through the side chain groups
Solution Approach 2:
The patent enables the amino acid side chains to serve their own function as conjugation sites, eliminating the need for external blocking groups. The side chain amine or carboxyl groups naturally provide the necessary reactivity for conjugation without requiring additional chemical modifications, thereby streamlining the synthesis process and improving overall yield and purity
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 novel linker unit facilitates stable and efficient conjugation of targeting and therapeutic elements, enhancing pharmacokinetic properties and therapeutic efficacy while allowing for adjustable ratios of functional elements, thus overcoming the limitations of existing technologies.
Implementation Method 1
allow for stable conjugation of functional elements via click chemistry reactions, using azide, alkyne, tetrazine, and cyclooctyne groups
Data Source
AI summary
The present disclosure provides various linker units and molecular constructs, each of which has a targeting element and an effector element linked therewith. Methods for treating various diseases using such linker units and molecular constructs are also disclosed.