GIP Peptide Analogues With Amino Acid Substitutions for pH Stability
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Solution Overview
Problem
Existing GIP peptide analogues, such as GIP(3-30), are poorly soluble and unstable at physiological pH, making them unsuitable for pharmaceutical use and lack improved solubility and/or physical stability, which impedes their application in ready-to-use liquid pharmaceutical formulations.
Innovation Solution
The development of GIP peptide analogues with amino acid substitutions A13Aib and/or N24E, optionally conjugated with a fatty acid, to enhance solubility and stability, allowing for their use in stable liquid pharmaceutical formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If GIP(3-30) is used as a GIPR antagonist, then antagonistic activity is achieved, but solubility at physiological pH is poor
Solution Approach 1:
The patent applies parameter changes by substituting specific amino acid residues in the GIP(3-30) sequence. Position 13 is substituted with amino acids having different side chain properties (bulky hydrophobic, polar uncharged, or charged residues), and position 24 is substituted with glutamic acid or aspartic acid. These parameter changes in the molecular structure improve solubility at physiological pH while preserving antagonistic activity at the GIP receptor.
2Reliability
If GIP(3-30) is used as a GIPR antagonist, then antagonistic activity is achieved, but physical stability in aqueous liquid medium is insufficient
Solution Approach 1:
The patent improves physical stability through parameter changes in the peptide sequence. Substitution at position 13 with amino acids having diverse side chain characteristics and at position 24 with acidic residues (glutamic acid or aspartic acid) modifies the peptide's conformational stability and resistance to aggregation in aqueous media, while maintaining its antagonistic function.
3Quantity of substance
If GIP peptide analogues are designed for improved solubility, then solubility is enhanced, but antagonistic effect may be compromised
Solution Approach 1:
The patent applies local quality by making targeted substitutions at specific positions (13 and 24) in the GIP peptide sequence rather than modifying the entire molecule. These localized changes affect solubility properties without disrupting the critical regions required for GIP receptor binding and antagonistic activity, thus preserving therapeutic efficacy while improving pharmaceutical properties.
Data Source
AI summary
Disclosed are glucose-dependent insulinotropic peptide (GIP)-derived peptide analogues which are antagonists of the GIP receptor. These GIP peptide analogues are optimized by comprising amino acid substitutions A13Aib and/or N24E, and are fatty acid conjugated with/without a linker, so to have improved solubility and/or physical stability.