Thiol-yne Stapled Peptides for Metabolic and Cancer Therapy
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Solution Overview
Problem
Current methods for synthesizing stapled peptides face challenges such as rapid degradation, poor cell permeability, and lack of binding specificity due to conformational flexibility, with limited synthetic methods capable of producing peptides with desired properties and ease of synthesis, and a need for methods that allow further functionalization without modifying the peptide sequence.
Innovation Solution
The development of methods involving peptides with two thiol functionalities reacted with linkers having alkyne or alkenes, forming alkenyl sulfide moieties, and optionally reacting with radical or nucleophilic agents to create stapled peptides, including glucagon, axin, and p53 homologues, which can be further functionalized without altering the peptide sequence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If peptide stapling is performed using conventional methods (olefin-containing amino acids followed by ring-closing metathesis), then peptide stability is improved, but synthesis complexity and cost increase due to requiring unnatural amino acids and specialized reactions
Solution Approach 1:
The invention changes the chemical parameters of the stapling reaction by using thiol-yne click chemistry instead of traditional RCM. This allows the reaction to proceed under milder conditions with natural amino acids containing thiol groups, eliminating the need for unnatural amino acids and complex metathesis catalysts while maintaining stapling effectiveness and peptide stability
Solution Approach 2:
The invention employs readily available thiol-containing natural amino acids and simple alkyne linkers that can be incorporated through standard recombinant expression and purification, replacing expensive unnatural amino acids and specialized RCM reagents. This makes peptide stapling accessible through conventional biochemical methods
2Reliability
If peptide stapling is performed to reduce conformational flexibility, then binding specificity is improved, but cell permeability deteriorates due to macrocyclization
Solution Approach 1:
The invention applies local quality by using short alkyne linkers that provide minimal steric bulk and maintain a degree of flexibility in the staple structure. This localized approach to crosslinking stabilizes the critical binding region while preserving overall peptide dynamics needed for cell membrane penetration, unlike rigid macrocyclic structures
3Stability of the object's composition
If conventional stapling methods are used, then peptide helix stabilization is achieved, but functionalization capabilities are limited due to sequence modification requirements
Solution Approach 1:
The invention achieves universality by using the genetically encoded amino acid cysteine (containing thiol groups) as the stapling handle, which can be incorporated at any position in the peptide sequence through standard genetic code. This allows functionalization at multiple sites without requiring unnatural amino acids, enabling diverse applications including drug delivery, imaging, and protein-protein interaction studies
Solution Approach 2:
The alkyne-containing linker serves as an intermediary that can be easily modified with various functional groups (fluorophores, cell-penetrating peptides, drug moieties) through click chemistry. This intermediary approach allows the stapling function and functionalization to be decoupled, maintaining helix stabilization while providing versatile attachment points
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 production of stapled peptides with improved stability and functionalization capabilities, suitable for therapeutic applications in diseases like diabetes and cancer, by stabilizing the peptides and enhancing their biological activity.
Implementation Method 1
peptides having two thiol functionalities with a linker having two unstaturated functionalities comprising two alkyne moieties or comprising one alkyne moiety and one alkene moiety
Implementation Method 2
first reacting step of the two thiol functionalities with the two unsaturated functionalities, thereby providing two alkenyl sulfide moieties
Data Source
AI summary
In one aspect, the invention relates to compositions comprising stapled peptides, methods of making same, pharmaceutical compositions comprising same, and methods of treating various diseases, including, but not limited to, metabolic disorders such as diabetes, and cancers. The disclosed compounds comprise stapled peptides, including, but not limited to, stapled glucagon, axin, and p53 peptide homologues, which are useful as therapeutic agents for a variety of diseases as disclosed herein. The disclosed methods are useful in the preparation of a variety of stapled peptides, including stapled peptide homologues of glucagon, axin, and p53. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.