Glucagon/GLP-1 Peptide Variants with Receptor Selectivity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for diabetes and obesity lack effective peptides that simultaneously target glucose regulation, insulin secretion, and appetite suppression with enhanced potency and selectivity for the GLP-1 receptor while maintaining activity at the glucagon receptor.
Innovation Solution
Development of peptides and variants that exhibit enhanced activity at both the glucagon and GLP-1 receptors, with at least 100-fold selectivity for the GLP-1 receptor over the GIP receptor, and are conjugated with heterologous moieties or modified for improved stability, solubility, and resistance to proteases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If peptides are designed to target both glucagon and GLP-1 receptors, then therapeutic efficacy for diabetes and obesity is improved, but selectivity between GLP-1 and GIP receptors becomes difficult to maintain
Solution Approach 1:
The patent applies local quality by making specific, localized amino acid substitutions at key positions (such as positions 17, 20, 21, 24, 27, 28) within the glucagon peptide sequence. These targeted modifications enhance GLP-1 receptor binding affinity while preserving glucagon receptor activity, allowing the peptide to differentiate between receptor types through localized structural changes rather than global sequence alteration.
Solution Approach 2:
The patent employs parameter changes by systematically varying amino acid properties (hydrophobicity, charge, steric bulk) at specific positions to tune receptor selectivity. For example, substituting hydrophobic residues at position 17 or basic residues at position 28 alters the peptide's electrostatic and hydrophobic interactions with receptor binding pockets, thereby adjusting selectivity parameters between GLP-1 and GIP receptors while maintaining dual-agonist activity.
2Power
If peptide modifications are made to enhance GLP-1 receptor activity, then potency is improved, but stability and solubility may deteriorate
Solution Approach 1:
The patent converts the potential harm of peptide aggregation and proteolytic degradation into benefit by introducing specific amino acid modifications that enhance solubility and stability. For instance, substituting hydrophobic residues with hydrophilic ones reduces aggregation propensity, while strategic placement of protease-resistant amino acids (such as D-amino acids or non-natural residues) converts vulnerability to degradation into enhanced stability without compromising receptor binding potency.
Solution Approach 2:
The patent employs composite material strategies by combining natural amino acids with non-natural, protease-resistant amino acids or chemically modified residues within the peptide sequence. This creates a composite peptide structure that integrates the benefits of natural receptor recognition with enhanced stability and solubility properties of modified residues, achieving high potency while resisting degradation.
3Reliability
If multiple amino acid substitutions are introduced to enhance dual receptor activity, then therapeutic benefit is improved, but peptide complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the peptide optimization into discrete, modular amino acid position modifications. Each substitution at a specific position (e.g., position 17, 20, 21) is treated as an independent module that can be optimized separately for its contribution to glucagon or GLP-1 receptor activity. This modular approach allows systematic evaluation and combination of substitutions to achieve desired dual-agonist properties without overwhelming complexity.
Solution Approach 2:
The patent achieves universality by designing amino acid substitutions that simultaneously contribute to multiple functions: enhancing GLP-1 receptor affinity, maintaining glucagon receptor activity, and improving solubility or stability. For example, certain substitutions at position 28 can simultaneously increase GLP-1 selectivity and enhance protease resistance, thereby reducing the total number of modifications needed and simplifying the overall peptide structure while achieving multiple therapeutic goals.
Data Source
Figure 1
Figure 2
Figure 3A~3B
AI summary
Provided herein are peptides and variant peptides that exhibit enhanced activity at the GLP-1 receptor, as compared to native glucagon.