Stapled Polypeptides for GLP-1R, GIPR, and GCGR Activity
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Solution Overview
Problem
Existing compounds targeting GLP-1, GIP, or GCG receptors have deficiencies in therapeutic effects and metabolic behavior, limiting their druggability and clinical application for metabolic diseases.
Innovation Solution
Development of polypeptides with a modified structure, specifically a staple structure, that act on GLP-1R, GIPR, and GCGR receptors, forming a stapled body through condensation connections of amino or carboxyl groups on side chains, enhancing their efficacy in treating metabolic diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Device complexity
If compounds act on a single receptor (GLP-1, GIP, or GCG), then the compound structure is simpler and easier to develop, but the therapeutic effects and metabolic behavior are deficient
Solution Approach 1:
The patent combines multiple receptor-targeting functions into a single polypeptide compound that can act on GLP-1R, GIPR, and/or GCGR simultaneously. This is achieved by designing a polypeptide with specific amino acid sequences (Formulas Z-1 to Z-13) that contain recognition motifs for multiple incretin receptors, thereby merging the functions of separate single-receptor agonists into one multifunctional molecule.
Solution Approach 2:
The disclosed polypeptides are designed with universal multi-functionality to act as agonists for multiple incretin receptors (GLP-1R, GIPR, and GCGR). The molecular structure incorporates key amino acid residues that enable binding and activation of different receptor types, allowing a single compound to perform multiple therapeutic functions related to glucose metabolism, lipid metabolism, and weight regulation.
2Reliability
If compounds act on multiple targets (GLP-1R/GIPR/GCGR), then the therapeutic effects and metabolic behavior are improved, but the compound structure and development complexity increase
Solution Approach 1:
The patent applies local quality by introducing specific modified amino acid residues at particular positions within the polypeptide sequence. These localized modifications (such as amino or carboxyl groups on side chains) create specific binding characteristics for different receptors while maintaining the overall polypeptide structure. The modifications are strategically placed to enhance multi-receptor affinity without requiring complete structural redesign.
Solution Approach 2:
The polypeptide compounds represent composite molecular structures combining natural amino acid sequences with modified residues. The composite nature allows the molecule to exhibit properties of multiple single-receptor agonists simultaneously. The structure integrates hydrophilic and hydrophobic regions, charged and neutral residues, creating a composite molecular architecture that can interact with diverse receptor surfaces.
3Reliability
If polypeptides are modified with staple structure, then the in-vitro effects on GLP-1R, GIPR, and GCGR are enhanced, but the manufacturing process becomes more complex
Solution Approach 1:
The patent employs parameter changes by modifying specific amino acid residues within the polypeptide sequence to enhance receptor binding affinity and stability. The modifications include introducing amino or carboxyl groups on side chains at specific positions, which alter the electrostatic, hydrophobic, or hydrogen-bonding parameters of the molecule. These parameter adjustments improve in-vitro efficacy while maintaining a relatively straightforward synthetic approach using standard peptide chemistry techniques.
Data Source
AI summary
The present invention provides a series of polypeptides containing a modified structure. The series of polypeptides act on three targets, i.e., GLP-1, GIP and GCG, and has prospects of being developed into drugs for the prevention or treatment of metabolic diseases, wherein the sequence of the polypeptides is as shown in formula Z-3. X5X0X6GT FTSDY SIX1X7X8 KX9X10X11X0 X4FX12X13X14 LLX15GG PSSGA PPPS0 Z-3