4-Imidazolidinone-Fused Cyclic Peptides Cyclization
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Solution Overview
Problem
Current methods for synthesizing cyclic peptides face challenges such as C-terminal epimerization, cyclo-oligomerization, and formation of linear dimers and trimers, particularly when attempting to cyclize linear peptides with fewer than seven amino acid residues, due to unfavorable entropy changes and conformational equilibria.
Innovation Solution
The development of 4-imidazolidinone-fused cyclic peptides and derivatives, which involve adding an aldehyde group to linear peptides, incubating them in a solvent with a nucleophilic catalyst, and covalently cyclizing to form stable cyclic structures, thereby overcoming the limitations of existing cyclization strategies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional cyclization strategies are used on linear peptides with fewer than seven amino acid residues, then cyclic peptide formation is attempted, but C-terminal epimerization, cyclo-oligomerization, and formation of linear dimers and trimers occur due to unfavorable entropy changes and conformational equilibria
Solution Approach 1:
The patent applies preliminary action by pre-organizing the linear peptide into a specific conformational state before cyclization. The invention uses conformationally constrained precursors that are pre-formed to adopt the desired cyclic geometry, thereby reducing the entropy penalty during cyclization and preventing side reactions such as epimerization and oligomerization.
Solution Approach 2:
The patent employs parameter changes by modifying the conformational parameters of the linear peptide precursor. Specifically, the invention introduces conformational constraints that lock the peptide into a specific spatial arrangement, changing the entropy and conformational equilibrium parameters to favor intramolecular cyclization over intermolecular oligomerization.
2Productivity
If linear peptides are cyclized to form cyclic structures, then the desired cyclic peptide product is obtained, but unfavorable entropy changes and conformational equilibria lead to side reactions and reduced efficiency
Solution Approach 1:
The patent applies preliminary action by pre-organizing the linear peptide into a specific conformational state before cyclization. The invention uses conformationally constrained precursors that are pre-formed to adopt the desired cyclic geometry, thereby reducing the entropy penalty during cyclization and preventing side reactions such as epimerization and oligomerization.
Solution Approach 2:
The patent converts the harmful effect of conformational flexibility into a benefit by using it to pre-organize the peptide in a favorable conformation. The conformational constraints that would normally be considered limiting are actually utilized to direct the peptide into the correct geometry for efficient cyclization, turning potential harm into a productive advantage.
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 allows for efficient synthesis of cyclic peptides with enhanced stability and specificity, enabling effective inhibition of protein-protein interactions and potential therapeutic applications for diseases like cancer, Huntington's disease, cystic fibrosis, and Alzheimer's.
Implementation Method 1
incubating them in a solvent with a nucleophilic catalyst, and covalently cyclizing to form stable cyclic structures
Data Source
AI summary
The present invention relates, in part, to novel compounds comprising 4-imidazolidinone-fused cyclic peptides and compositions thereof. The present invention also relates to methods of generating said compounds and compositions thereof as well as methods of inhibiting protein-protein interaction using said compounds or compositions thereof. In another aspect, the present invention relates, in part, to methods of treating or preventing a various diseases or disorders using said compounds or compositions thereof.