Triple Agonist Peptide Composition With Physiological pH Solubility
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current peptide therapies targeting GLP-1, GIP, and NPY2 receptors for obesity and diabetes lack solubility at physiological pH and require multiple dosing units, which complicates formulation and increases manufacturing costs.
Innovation Solution
Development of peptide compounds with a lipid-linker moiety covalently attached to the epsilon-amino group of Lys at position-29, enhancing solubility and stability at physiological pH, allowing for a single dosing unit via subcutaneous injection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If peptide compounds are designed to target GLP-1, GIP, and NPY2 receptors simultaneously, then therapeutic efficacy for obesity and diabetes is improved, but solubility at physiological pH deteriorates
Solution Approach 1:
The peptide is segmented into distinct functional domains: an N-terminal region for GLP-1 receptor binding, a central region for GIP receptor interaction, and a C-terminal region containing the lipid-linker attachment site for NPY2 receptor selectivity. This segmentation allows each region to independently contribute to receptor binding while maintaining overall solubility through the lipid-modified C-terminal segment.
Solution Approach 2:
The invention creates a composite peptide structure combining hydrophilic peptide sequences with a hydrophobic lipid moiety (C12-C22 fatty acid chain) connected via a linker. This composite structure provides amphipathic characteristics that enhance solubility at physiological pH while maintaining receptor binding affinity. The lipid component improves membrane permeability and prolongs circulation half-life.
2Adaptability or versatility
If multiple dosing units are used to achieve receptor targeting, then therapeutic coverage is improved, but device complexity and manufacturing costs increase
Solution Approach 1:
The invention merges multiple receptor-targeting functions into a single peptide molecule. The unified triple-agonist peptide simultaneously binds to GLP-1, GIP, and NPY2 receptors, eliminating the need for separate dosing units for each receptor target. This consolidation simplifies the dosing regimen to a single subcutaneous injection while maintaining comprehensive therapeutic coverage for obesity and diabetes.
3Ease of manufacture
If peptide structure is modified to enhance solubility, then formulation feasibility is improved, but receptor selectivity may deteriorate
Solution Approach 1:
The peptide structure incorporates local quality variations with specific amino acid sequences optimized for each receptor binding site. The N-terminal region maintains high sequence homology to native GLP-1 for selective GLP-1 receptor binding, while the central region contains GIP-specific motifs. The C-terminal region with lipid attachment provides solubility enhancement without interfering with the structured binding regions, thus maintaining receptor selectivity while improving formulation feasibility.
Data Source
AI summary
The present invention relates to peptide compounds that agonize the GIP, GLP-1 and neuropeptide Y2 (NPY2) receptors, agonists, processes for their preparation, pharmaceutical compositions thereof, and their medical use in the treatment and/or prevention of a variety of diseases such as obesity, diabetes, metabolic syndrome, and/or MASH/NASH. The peptide compounds of the invention are suitable for subcutaneous administration.