Stapled GLP-1 and Glucagon Co-Agonist Peptides Against Degradation
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Solution Overview
Problem
Existing glucagon and GLP-1 receptor agonists face challenges such as rapid proteolytic degradation, self-association, and aggregation, leading to reduced efficacy and potential immunogenic reactions, which complicates their use in treating metabolic disorders like diabetes and obesity.
Innovation Solution
Development of stapled co-agonist peptides with an alpha-helical conformation stabilized by intramolecular ring formation, reducing proteolytic degradation and aggregation, thereby enhancing stability and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional glucagon and GLP-1 receptor agonists are used, then therapeutic activity is achieved, but rapid proteolytic degradation occurs leading to reduced efficacy
Solution Approach 1:
The peptide sequence is divided into two functional segments: a glucagon receptor agonist segment (amino acids 1-29 of preproglucagon) and a GLP-1 receptor agonist segment (amino acids 72-108 of preproglucagon). This segmentation allows the single peptide molecule to simultaneously activate both receptor types, achieving dual therapeutic activity while maintaining peptide stability through the stapled alpha-helical structure.
Solution Approach 2:
The invention creates a composite peptide structure by stapling two different amino acid sequences (glucagon and GLP-1 derived) into a single stable alpha-helical molecule. This composite approach combines the beneficial properties of both parent peptides while eliminating their individual instability issues through the stapled helical framework.
2Reliability
If conventional peptide agonists are administered, then receptor activation occurs, but self-association and aggregation lead to precipitation and immunogenic reactions
Solution Approach 1:
The stapled alpha-helical structure introduces local structural rigidity and specificity at the peptide core, preventing random self-association. The intramolecular staple bonds create a defined three-dimensional conformation that locally excludes aggregation-prone regions, thereby preventing precipitation and immunogenic reactions while maintaining receptor activation capability.
Solution Approach 2:
Instead of allowing peptides to remain as flexible, aggregation-prone linear chains, the invention inverts the approach by imposing rigid alpha-helical structure through stapling. This inversion from flexible to rigid conformation prevents the self-association that would otherwise occur, eliminating precipitation and immunogenicity issues.
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
The stapled peptides exhibit increased physical stability, allowing for lower doses and improved therapeutic effects on metabolic disorders by minimizing precipitation and immunogenic reactions.
Implementation Method 1
The stapled peptides of the present invention have an alpha-helical conformation due to intramolecular ring formation between two peptide amino acids
Implementation Method 2
The alpha helical structure of the stapled peptides of the present invention results in an increase in physical stability due to decreased proteolytic degradation
Data Source
AI summary
The stapled peptides of the present invention, and pharmaceutically acceptable salts thereof, are co-agonists of the glucagon and GLP-1 receptors, and may be useful in the treatment, prevention and suppression of diseases mediated by the glucagon receptor and the GLP-1 receptor, including but not limited to, metabolic disorders such as diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and obesity.