Glucose-Responsive Insulin Analogues With Diol Conformational Switches
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Solution Overview
Problem
Current insulin therapies for diabetes mellitus face challenges in preventing hypoglycemia while maintaining blood glucose levels within a healthy range, as existing glucose-responsive insulin systems have shown modest glucose-responsive properties and are not clinically used due to suboptimal design, particularly with modifications that impair receptor binding or require large glucose-binding agents.
Innovation Solution
Development of insulin analogues with a glucose-regulated conformational switch using diol moieties attached to the B chain's main-chain atoms, allowing for high-affinity binding to the insulin receptor only at high glucose concentrations, achieved by attaching a glucose-binding element to the A chain's N terminus, enabling a reversible and cooperative binding mechanism.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional insulin therapies are used to control blood glucose, then glucose control is achieved, but hypoglycemia risk increases
Solution Approach 1:
The patent applies dynamics by creating an insulin analogue with a glucose-regulated conformational switch that dynamically changes its structure based on glucose concentration. The diol-containing side chain in the B chain can bind to glucose, causing a conformational change that activates or inhibits receptor binding, allowing the insulin to adapt its activity to current glucose levels and reduce hypoglycemia risk while maintaining glucose control.
Solution Approach 2:
The patent utilizes parameter changes by modifying the physical and chemical properties of insulin through the addition of diol moieties at specific positions in the B chain. These modifications alter the binding affinity and conformational stability of the insulin analogue, enabling glucose-dependent activation only under hyperglycemic conditions, thus resolving the contradiction between glucose control and hypoglycemia prevention.
2Adaptability or versatility
If glucose-responsive insulin systems are designed with modifications to achieve glucose-dependent activation, then glucose-responsive properties are improved, but receptor binding affinity is impaired
Solution Approach 1:
The patent applies segmentation by dividing the insulin molecule into functional regions: the A chain with its glucose-binding element and the B chain with its diol-containing side chain. This segmentation allows each region to perform its specific function independently - glucose sensing and conformational switching - while maintaining overall receptor binding affinity through the preserved core insulin structure.
Solution Approach 2:
The patent implements local quality by placing diol moieties at specific local positions in the B chain (such as positions 26-30) rather than uniformly modifying the entire molecule. This localized modification creates glucose-dependent conformational changes only in the critical binding region, enabling glucose-responsive activation without compromising the overall receptor binding affinity of the insulin analogue.
3Adaptability or versatility
If large glucose-binding agents are used to achieve glucose-dependent activation, then glucose-responsive properties are improved, but molecular size and complexity increase
Solution Approach 1:
The patent applies the taking out principle by extracting and minimizing the glucose-binding element to a small diol moiety that can be directly incorporated into the insulin B chain. This eliminates the need for large external glucose-binding agents, reducing molecular size and complexity while maintaining glucose-responsive properties through the diol's ability to bind glucose and trigger conformational changes.
Solution Approach 2:
The patent implements merging by combining the glucose-binding function and the conformational switching function into a single integrated insulin analogue structure. The diol-containing side chain in the B chain serves both as a glucose-binding element and as a conformational switch, eliminating the need for separate large glucose-binding agents and reducing overall molecular complexity.
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 novel insulin analogues exhibit improved glucose-dependent activation, reducing the risk of hypoglycemia and maintaining effective glucose control by ensuring high-affinity receptor binding only in hyperglycemic conditions, thus addressing the limitations of previous designs.
Implementation Method 1
enabling a reversible and cooperative binding mechanism
Data Source
AI summary
A two-chain insulin analogue is provided containing (a) a B chain modified by a C-terminal diol element such that one hydroxyl group substitutes for the C-terminal carboxylate function in combination with (b) a glucose-binding element attached to the A chain at or near its N terminus. Compositions comprising such insulin analogs are used in methods of treating a patient with diabetes mellitus.