Cross-linked Peptides via Bismethylene Aryl Moieties
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Solution Overview
Problem
Peptides struggle to penetrate cell membranes due to their inability to reach intracellular targets, and existing strategies for improving cell permeability often require extensive chemical modifications and result in cytotoxicity or significant mass addition.
Innovation Solution
Cross-linking peptides or proteins using a cysteine-alkylation reaction with a rigid, distance-matching bismethylene aryl moiety between cysteine or α-methylcysteine residues at specific positions, enhancing cell penetration and stability while maintaining biological activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If peptides are used to target intracellular protein-protein interactions, then bioactivity is achieved, but cell membrane penetration is insufficient
Solution Approach 1:
The patent changes the chemical parameters of the peptide by introducing cross-links between cysteine residues at specific positions (i and i+7), transforming the peptide from a flexible chain to a constrained structure with improved membrane penetration capability while preserving bioactivity
Solution Approach 2:
The patent creates a composite structure by combining the peptide backbone with cross-linking moieties (such as styrene or other vinyl-containing groups) that form cyclic structures, resulting in a hybrid molecule with properties of both the original peptide and the cross-linking agent
2Ease of operation
If chemical strategies are used to improve cell permeability, then cell penetration is enhanced, but extensive chemical modifications are required
Solution Approach 1:
The patent applies cross-linking modifications only at specific local positions (cysteine residues at i and i+7) rather than throughout the entire peptide structure, minimizing the extent of chemical modification while achieving the desired effect on cell penetration
Solution Approach 2:
The patent incorporates cysteine residues at predetermined positions during peptide synthesis, preparing the peptide in advance for cross-linking. This preliminary positioning of reactive groups simplifies the subsequent cross-linking step and reduces the complexity of modifications required
3Ease of operation
If cross-linking strategies are used to improve cell permeability, then cell penetration is enhanced, but cytotoxicity increases
Solution Approach 1:
The patent carefully controls the cross-linking parameters including the choice of cross-linker chemistry, reaction conditions, and cross-link density to achieve optimal cell penetration while maintaining cytotoxicity at acceptable levels. The constrained cyclic structure formed by cross-linking at i and i+7 positions provides a balance between permeability and biocompatibility
4Stability of the object's composition
If rigid cross-linkers are used to form cross-links, then structural stability is improved, but flexibility is reduced
Solution Approach 1:
The patent introduces rigidity only at specific local regions where cross-links are formed between cysteine residues, while the rest of the peptide chain retains its natural flexibility. This localized stiffening provides structural stability where needed without compromising the overall adaptability of the peptide
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 cross-linked peptides exhibit improved cell permeability, enzymatic stability, and biological activity with reduced cytotoxicity, allowing for effective delivery of bioactive molecules into cells without significant mass addition.
Implementation Method 1
The cross link is formed through a cysteine-alkylation reaction with a rigid, distance-matching cross linker
Implementation Method 2
BMA is a bismethylene aryl moiety and is connected to the protein or peptide through two thioether bonds
Data Source
Figure 1
Figure 2a~3
Figure 4a~4b
AI summary
Cross-linked proteins and peptides, and methods of making and uses of such cross-linked proteins and peptides. The cross-linked proteins and peptides have rigid, distance-matching bismethylene aryl cross-linking moieties. Compositions comprising the cross-linked proteins and peptides can be used as pharmaceutical delivery formulations. The cross-linked proteins and peptides can have improved properties, such as cell permeability, as compared to the parent protein or peptide.