Trigonal Peptidic Agonists for Metabolic Disorder Treatment

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Solution Overview

Problem

Current peptides for treating metabolic disorders like diabetes and obesity have limitations in stability, solubility, and receptor activation efficiency, particularly under acidic conditions and in the presence of antimicrobial preservatives.

Innovation Solution

Development of novel trigonal GLP-1/glucagon/GIP receptor agonists derived from exendin-4, with specific amino acid substitutions and functionalized side chains, enhancing solubility, stability, and receptor activation efficacy, including high activity on both glucagon and GIP receptors while maintaining GLP-1 receptor activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If peptides are designed to activate multiple receptors (GLP-1, glucagon, GIP), then receptor activation efficacy is improved, but molecular complexity increases

Engineering Contradiction:

Improvereceptor activation efficacyVSAvoidmolecular complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent combines multiple receptor activation functions into a single peptide molecule by integrating the N-terminal region of glucagon (residues 1-18) with the C-terminal region of exendin-4 (residues 20-39), creating a chimeric trigonal agonist that simultaneously activates GLP-1, glucagon, and GIP receptors through its unified structure

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The designed peptide achieves multi-functionality by being capable of binding and activating three different receptor types (GLP-1R, glucagonR, and GIPR) through specific structural motifs embedded in its sequence, allowing one molecule to perform multiple therapeutic functions for treating metabolic disorders

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Stability of the object's composition

If peptides are stored in acidic conditions with antimicrobial preservatives, then stability is improved, but solubility decreases

Engineering Contradiction:

Improvepeptide stabilityVSAvoidsolubility

Core Design Contradiction:

Stability of the object's compositionVSQuantity of substance

Solution Approach 1:

The patent modifies the peptide's amino acid sequence by substituting specific residues (e.g., introducing hydrophilic residues or adjusting charge distribution) to change its physicochemical parameters, enabling the peptide to maintain both high stability in acidic conditions with preservatives and adequate solubility through optimized molecular properties

Inventive Principle:

Principle #35Parameter changes

3Duration of action of moving object

If fatty acid side chains are added to extend duration of action, then duration of action is improved, but molecular weight increases

Engineering Contradiction:

Improveduration of actionVSAvoidmolecular weight

Core Design Contradiction:

Duration of action of moving objectVSWeight of moving object

Solution Approach 1:

The patent introduces fatty acid side chains at specific local positions within the peptide sequence (e.g., at particular amino acid residues) to achieve prolonged duration of action through extended circulation half-life, while maintaining the rest of the molecular structure compact and efficient, thus minimizing overall molecular weight increase

Inventive Principle:

Principle #3Local quality

Data Source

PatentEP3548062B1New compounds as peptidic GLP1/glucagon/GIP receptor agonists

Publication Date: 2022.01.12 SANOFI SA(FR)

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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.