Thiol-ene Stapled Peptide Synthesis via Two-Component Coupling
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Solution Overview
Problem
Current methods for synthesizing stapled peptides face challenges due to rapid degradation, poor cell permeability, and lack of binding specificity, with existing reactions often resulting in low yields and undesirable side reactions, limiting their therapeutic potential.
Innovation Solution
The development of new methods for synthesizing stapled peptides using thiol-ene two-component coupling reactions, involving peptides with thiol functionalities and dienes, to form stable staples that enhance peptide stability and specificity, including structures represented by specific formulas and reaction processes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If ring-closing metathesis (RCM) is used to synthesize stapled peptides, then peptide stability is improved, but manufacturing precision deteriorates due to low yields and undesirable side reactions
Solution Approach 1:
The patent changes the chemical reaction parameters by replacing RCM with thiol-ene coupling reactions, which operate under different chemical conditions to achieve both high stability and high yield without the side reactions associated with metathesis
Solution Approach 2:
The patent extracts the problematic RCM step from the synthesis pathway and replaces it with alternative thiol-ene coupling methods, removing the source of low yields and side reactions while retaining the stabilizing staple structure
2Stability of the object's composition
If macrocyclization is performed to create stapled peptides, then peptide stability is improved, but device complexity increases due to entropically unfavorable processes
Solution Approach 1:
The patent substitutes the complex entropic process of macrocyclization with a simpler thiol-ene coupling mechanism that proceeds through a more favorable reaction pathway, reducing synthesis complexity while maintaining stability
3Manufacturing precision
If thiol-ene two-component coupling reactions are used to synthesize stapled peptides, then manufacturing precision is improved, but use of energy increases due to additional reaction components
Solution Approach 1:
The patent introduces dienes as intermediary components that facilitate the thiol-ene coupling reaction, enabling high-yield synthesis while the energy cost is offset by the elimination of side reactions and improved overall efficiency
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
These methods enable the production of stapled peptides with improved stability and specificity, suitable for therapeutic applications such as treating metabolic disorders and cancers, by forming stable staples that maintain peptide structure and function.
Implementation Method 1
thiol-ene two-component coupling reactions, involving peptides with thiol functionalities and dienes, to form stable staples
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.