Trigonal Peptide Agonists Acid Stability
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Solution Overview
Problem
Current peptides for treating metabolic disorders, such as diabetes and obesity, face challenges in stability and solubility, especially in acidic conditions and when combined with antimicrobial preservatives, limiting their efficacy and duration of action.
Innovation Solution
Development of novel trigonal GLP-1/glucagon/GIP receptor agonists derived from exendin-4, with specific amino acid substitutions and modifications, such as replacing Tyr10 and Tyr13 with Leu, and incorporating a lipophilic residue at position 14, enhancing solubility, stability, and receptor activation, including high activity on both glucagon and GIP receptors while maintaining GLP-1 receptor activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current peptides are used for treating metabolic disorders, then they can provide therapeutic effects, but they exhibit poor stability and solubility especially in acidic conditions and when combined with antimicrobial preservatives
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of exendin-4 through specific substitutions (Tyr10→Leu, Tyr13→Leu, Met14→Lys) to alter the peptide's physicochemical properties. These changes improve stability in acidic conditions and resistance to degradation by antimicrobial preservatives like m-cresol and phenol, while maintaining biological activity at all three receptors.
Solution Approach 2:
The patent applies local quality by making targeted modifications at specific positions (10, 13, and 14) of the exendin-4 sequence. The substitutions at these local positions confer acid stability and preservative resistance without compromising the overall structure-function relationship, allowing the peptide to maintain its trigonal agonist activity.
2Duration of action of moving object
If current peptides are used for treating metabolic disorders, then they can provide therapeutic effects, but they have limited duration of action
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of exendin-4 through specific substitutions (Tyr10→Leu, Tyr13→Leu, Met14→Lys) to alter the peptide's physicochemical properties. These changes improve stability in acidic conditions and resistance to degradation by antimicrobial preservatives like m-cresol and phenol, while maintaining biological activity at all three receptors.
3Reliability
If amino acid substitutions are made to improve stability, then solubility and stability improve, but receptor activation activity may be compromised
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of exendin-4 through specific substitutions (Tyr10→Leu, Tyr13→Leu, Met14→Lys) to alter the peptide's physicochemical properties. These changes improve stability in acidic conditions and resistance to degradation by antimicrobial preservatives like m-cresol and phenol, while maintaining biological activity at all three receptors.
Solution Approach 2:
The patent applies local quality by making targeted modifications at specific positions (10, 13, and 14) of the exendin-4 sequence. The substitutions at these local positions confer acid stability and preservative resistance without compromising the overall structure-function relationship, allowing the peptide to maintain its trigonal agonist activity.
Data Source
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AI summary
The present invention relates to trigonal GLP-1 / glucagon / GIP receptor agonists and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as for reduction of excess food intake.