Modified Glucagon Peptides for Prolonged Action
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Solution Overview
Problem
Glucagon peptides have limited potential in pharmaceuticals due to fast clearance, poor physical and chemical stability, and short duration of action, which complicates maintaining stable blood glucose levels, especially in diabetes treatment where weight gain is a concern.
Innovation Solution
Modified glucagon peptides with substitutions at specific amino acid positions and attachment of a substituent comprising three or more negative charged moieties, improving stability, solubility, and pharmacokinetic properties, leading to a protracted action profile.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If glucagon is administered to increase blood glucose levels, then hypoglycemia is prevented, but the duration of action is too short (less than an hour) requiring repeated administrations
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of glucagon through specific amino acid substitutions (Asp21 to Lys, Asn22 to Asp, Asp24 to Lys) and C-terminal modifications. These structural parameter changes result in analogues with extended half-life and prolonged duration of action, directly resolving the contradiction between short duration and need for repeated administrations.
Solution Approach 2:
The patent creates composite structures by combining modified glucagon peptides with albumin binding moieties. This composite approach allows the glucagon analogue to bind to albumin in circulation, extending its half-life from minutes to hours, thereby reducing the frequency of administrations needed to maintain therapeutic effect.
2Ease of operation
If glucagon is dissolved in aqueous solution for administration, then it can be delivered systemically, but it forms gels and fibrils within hours or days due to poor physical stability
Solution Approach 1:
The patent modifies physical and chemical parameters of glucagon through amino acid substitutions that reduce aggregation propensity. The specific substitutions (Asp21 to Lys, Asn22 to Asp, Asp24 to Lys) change the charge distribution and hydrophilicity, allowing the peptide to remain soluble in aqueous solutions at neutral pH without forming gels or fibrils, thus resolving the contradiction between solubility and physical stability.
3Reliability
If glucagon is administered to diabetic patients, then blood glucose control is improved, but weight gain occurs which is undesirable in obese/over-weight patients
Solution Approach 1:
The patent applies local quality by designing glucagon analogues with selective receptor interaction properties. The modified peptides maintain glucagon receptor agonist activity for blood glucose control while having reduced effects on appetite regulation pathways. The specific amino acid modifications create localized changes in receptor binding that decouple the glucose-raising effect from the appetite-stimulating effect, thus resolving the contradiction between effective glucose control and weight gain.
4Duration of action of moving object
If glucagon is formulated with extended release mechanisms to prolong action, then duration of action is increased, but the formulation becomes more complex and may not be generally applicable
Solution Approach 1:
The patent resolves this contradiction by changing the intrinsic parameters of the glucagon molecule itself rather than relying on complex external delivery systems. The amino acid substitutions and C-terminal modifications create peptides that are inherently stable and have extended half-life in circulation, achieving prolonged duration of action through molecular design rather than complex formulation technologies.
Data Source
Figure 1
AI summary
The present invention relates to novel glucagon peptides, to the use of said glucagon peptides in therapy, to methods of treatment comprising administration of said glucagon peptides to patients in need thereof, and to the use of said glucagon peptides in the manufacture of medicaments. The glucagon peptides of the present invention are of particular interest in relation to the treatment of hyperglycemia, diabetes and obesity, as well as a variety of diseases or conditions associated with hyperglycemia, diabetes and obesity.