Selective Cyclic Imide Peptide Synthesis via Unprotected Side Chains
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Solution Overview
Problem
The production of peptides and proteins through solid phase synthesis often results in a high percentage of undesired by-products, including cyclic imide groups like aspartimides and glutarimides, which are difficult to purify due to their susceptibility to further reactions, making targeted synthesis challenging.
Innovation Solution
A method involving the use of unprotected amino acid building blocks with COOH or CONH2 side chains during peptide synthesis at specific positions, combined with increased coupling time and repeated addition of coupling reagents, allows for the selective formation of cyclic imide groups in predetermined positions without affecting other parts of the peptide sequence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If solid phase synthesis is used to produce peptides, then peptide production is achieved, but a high percentage of undesired by-products including cyclic imide groups are generated
Solution Approach 1:
The patent applies preliminary action by introducing unprotected amino acid building blocks with COOH or CONH2 side chains at specific positions during the synthesis process. This preliminary setup enables the cyclic imide groups to form selectively at predetermined positions rather than as random by-products, allowing controlled formation of the desired peptide structure with specific cyclic imide modifications.
Solution Approach 2:
The patent implements local quality by selectively forming cyclic imide groups only at specific predetermined positions within the peptide sequence. By using unprotected amino acid building blocks at specific locations and protected ones at others, the method creates localized cyclic imide structures where needed while maintaining the integrity of other peptide regions, thus achieving position-specific modification.
2Quantity of substance
If forced degradation procedures are used to generate cyclic imide groups, then cyclic imide products are obtained, but numerous other degradation products are produced making purification difficult
Solution Approach 1:
Instead of using forced degradation procedures that create mixed products, the patent applies preliminary action by pre-installing unprotected amino acid building blocks with COOH or CONH2 side chains at specific positions during synthesis. This preliminary configuration enables the cyclic imide groups to form selectively and controllably at predetermined positions, avoiding the random degradation that produces complex mixtures of unwanted by-products.
Solution Approach 2:
The patent converts the potentially harmful effect of cyclic imide formation (which normally occurs as unwanted degradation) into a beneficial targeted synthesis approach. By using unprotected amino acid building blocks at specific positions during synthesis, the method transforms what would be random degradation products into deliberately created cyclic imide structures with high purity and defined positions.
3Manufacturing precision
If increased coupling time and repeated addition of coupling reagents are used, then selective formation of cyclic imide groups is achieved, but synthesis time is extended
Solution Approach 1:
The patent applies local quality by using unprotected amino acid building blocks with COOH or CONH2 side chains at specific predetermined positions where cyclic imide formation is desired, while using protected building blocks at other positions. This spatial differentiation enables selective cyclic imide formation at specific locations without requiring extended coupling times throughout the entire synthesis, as only the specific positions needing modification require the prolonged coupling conditions.
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 targeted synthesis of cyclic imide peptides in high yield and purity, facilitating their use as reference materials for quality control of pharmaceutical peptides like lixisenatide, while minimizing the presence of degradation products.
Implementation Method 1
coupling a synthesis building block of formula (II) to a peptide product of formula (III) under conditions wherein the cyclic imide group of formula (I) is formed
Implementation Method 2
the cyclisation involves removal of ammonia (NH3) and in the latter case, removal of water (H2O)
Implementation Method 3
In the latter case, the cyclisation involves removal of water (H2O)
Data Source
AI summary
The present invention relates to a method of synthesizing a peptide product comprising at least one cyclic imide group. Further, the invention relates to a peptide product comprising at least one cyclic imide group, which is substantially free from degradation products. The peptide product may be used as a reference material for the quality control of pharmaceutical peptides, particularly for the quality control of a GLP-1 agonist like exendin peptides.