Exendin-4 Derivatives Modulating GIP and Glucagon Receptors
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current dual GLP-1/glucagon receptor agonists do not adequately address the risk of hypoglycemia due to high activity on the GIP receptor, and existing GLP-1 receptor agonists like exendin-4 have stability issues and limited duration of action.
Innovation Solution
Development of exendin-4 derivatives with specific modifications, such as replacing methionine at position 14 with an amino acid carrying a lipophilic side chain and incorporating an Aib at position 27, which reduce GIP receptor activity and enhance glucagon receptor activation, while maintaining GLP-1 receptor activity, thereby improving stability and duration of action.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If dual GLP-1/glucagon receptor agonists are designed to activate both GLP-1 and glucagon receptors, then weight loss and glucose control are improved, but the risk of hypoglycemia increases due to high GIP receptor activity
Solution Approach 1:
The patent applies local quality by making specific modifications at particular positions of the exendin-4 molecule. Position 14 is modified with amino acids having lipophilic side chains to reduce GIP receptor activity, while position 27 is modified with Aib to enhance glucagon receptor activation. This localized modification approach allows selective optimization of receptor interactions without affecting the entire molecule uniformly, thereby reducing hypoglycemia risk while maintaining therapeutic efficacy.
Solution Approach 2:
The patent employs parameter changes by systematically varying the amino acid composition at specific positions (particularly position 14 with different lipophilic amino acids and position 27 with Aib). These parameter modifications alter the molecule's interaction properties with different receptors, enabling fine-tuning of GIP receptor activity downregulation while preserving or enhancing glucagon and GLP-1 receptor activation, thus managing hypoglycemia risk.
2Reliability
If exendin-4 is used as a pure GLP-1 receptor agonist, then glycemic control is achieved, but the duration of action is limited and stability issues occur
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of exendin-4 at specific positions to alter its pharmacokinetic properties. The introduction of Aib at position 27 and lipophilic amino acids at position 14 changes the molecule's stability profile and duration of action, extending its therapeutic effect while maintaining glycemic control reliability.
Solution Approach 2:
The patent creates a composite structure by combining modified amino acid residues (Aib, lipophilic amino acids) with the native exendin-4 sequence. This composite approach integrates the stability and duration-extending properties of the modified residues with the glucose-dependent insulinotropic activity of the native exendin-4 framework, achieving both extended duration of action and reliable glycemic control.
3Object-affected harmful factors
If modifications are made to exendin-4 to reduce GIP receptor activity, then hypoglycemia risk is reduced, but the complexity of the molecule increases
Solution Approach 1:
The patent applies local quality by limiting modifications to specific positions (primarily position 14 and position 27) rather than throughout the entire molecule. This localized approach reduces GIP receptor activity and hypoglycemia risk while minimizing the increase in overall molecular complexity, as only discrete regions of the molecule are altered rather than the entire structure.
Data Source
Figure 1
Figure 2
Figure 3
AI summary
The present invention relates to dual GLP-1 / glucagon 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.