Long-acting Glucagon GLP-1 Co-agonist Peptides

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Solution Overview

Problem

Current glucagon and GLP-1 receptor agonists have short durations of action and require frequent administration, which complicates their use in treating metabolic disorders like diabetes and obesity, and they often come with risks such as hyperglycemia and poor stability in humans.

Innovation Solution

Development of long-acting glucagon analogs with activity at both GLP-1 and glucagon receptors, featuring prolonged blood serum half-lives of at least one day, achieved through specific amino acid substitutions and conjugations that confer resistance to dipeptidyl peptidase IV degradation and enhanced biophysical stability, allowing for less frequent administration.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If current glucagon and GLP-1 receptor agonists are used, then they can treat metabolic disorders like diabetes and obesity, but they have short durations of action and require frequent administration

Engineering Contradiction:

Improveduration of actionVSAvoidadministration frequency

Core Design Contradiction:

Duration of action of moving objectVSEase of operation

Solution Approach 1:

The patent applies parameter changes by modifying the peptide structure through specific amino acid substitutions (e.g., replacing Thr2 with alpha-aminoisobutyric acid or D-Serine) and conjugating fatty acids to lysine residues. These structural parameter changes confer resistance to dipeptidyl peptidase IV degradation and enhance biophysical stability, thereby extending the duration of action from hours to at least one day, allowing once-daily or less frequent administration.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If current glucagon and GLP-1 receptor agonists are used, then they can treat metabolic disorders, but they often come with risks such as hyperglycemia and poor stability in humans

Engineering Contradiction:

ImprovestabilityVSAvoidhyperglycemia risk

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by making specific localized modifications to the peptide structure: substituting amino acids at positions 2 and 16 with residues that confer enzymatic resistance, and conjugating fatty acids at specific lysine positions (20, 21, 24, or 28). These localized structural changes enhance stability without compromising the dual receptor activity profile, thereby reducing hyperglycemia risk while maintaining therapeutic reliability.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent creates composite structures by combining the peptide backbone with fatty acid moieties through amide bonds. This composite architecture integrates the peptide's receptor-binding capability with the fatty acid's resistance to proteolytic degradation, resulting in a molecule with enhanced stability and reduced harmful effects in human subjects.

Inventive Principle:

Principle #40Composite materials

3Duration of action of moving object

If long-acting glucagon analogs with dual receptor activity are developed, then they provide sustained metabolic regulation, but they require specific amino acid substitutions and conjugations that increase structural complexity

Engineering Contradiction:

Improvetherapeutic durationVSAvoidmolecular structure complexity

Core Design Contradiction:

Duration of action of moving objectVSDevice complexity

Solution Approach 1:

The patent applies segmentation by dividing the peptide structure into distinct functional domains: the N-terminal region (residues 1-16) containing the glucagon receptor binding site with specific substitutions at positions 2 and 16, the central region (residues 17-28) with variable lysine positions for fatty acid conjugation, and the C-terminal region. This segmented approach allows systematic optimization of each domain's function while managing overall structural complexity.

Inventive Principle:

Principle #1Segmentation

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

These co-agonist peptides provide sustained metabolic regulation, effectively treating conditions like diabetes, obesity, and non-alcoholic fatty liver disease with improved safety and tolerability by maintaining therapeutic levels for extended periods.

Implementation Method 1

specific amino acid substitutions and conjugations that confer resistance to dipeptidyl peptidase IV degradation

Methodology Applied

Scientific EffectEnzyme resistance: Enzyme

Implementation Method 2

long-acting co-agonist peptides of the glucagon and GLP-1 receptors... display activity at the GLP-1 receptor (GLP-1) and the glucagon (GCG) receptor

Methodology Applied

Scientific EffectReceptor activation:

Data Source

PatentUS11566057B2Long-acting co-agonists of the glucagon and GLP-1 receptors

Publication Date: 2023.01.31 MERCK SHARP & DOHME LLC

AI summary

Long-acting co-agonists of the glucagon and GLP-1 receptors are described.