O-linked carbohydrate-modified insulin analogues for thermal stability
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Solution Overview
Problem
Current insulin analogues face challenges in achieving rapid absorption while maintaining resistance to fibrillation above room temperature, leading to limitations in glycemic control and insulin pump functionality, especially in regions without consistent refrigeration.
Innovation Solution
The development of insulin analogues with O-linked carbohydrate modifications at positions B27 and/or B30, combined with standard or non-standard amino-acid substitutions, to enhance biological potency, pharmacokinetics, and resistance to thermal fibrillation, using trypsin-mediated semi-synthesis to introduce monosaccaride pyranoside adducts that protect against fibrillation without interfering with receptor binding.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If modifications are made to accelerate insulin absorption following subcutaneous injection, then the pharmacokinetic properties are improved, but the resistance of insulin to chemical and/or physical degradation worsens
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of insulin through O-linked carbohydrate attachments at specific positions (B27 and/or B30). This structural modification changes the physical and chemical parameters of the insulin molecule, enabling accelerated absorption while simultaneously improving resistance to thermal degradation and fibrillation. The carbohydrate moieties alter the hexamer dissociation kinetics and thermal stability parameters without compromising biological activity.
Solution Approach 2:
The patent creates composite structures by attaching carbohydrate moieties to the insulin polypeptide chain, forming a hybrid molecule that combines the biological activity of insulin with the stabilizing properties of carbohydrate structures. This composite approach allows the molecule to exhibit both rapid absorption characteristics and enhanced resistance to degradation, resolving the contradiction between speed and reliability.
2Productivity
If insulin analogues are designed for rapid absorption, then glycemic control is improved, but resistance to thermal fibrillation worsens
Solution Approach 1:
The patent changes the thermal and kinetic parameters of insulin analogues through O-linked carbohydrate modification. The carbohydrate attachments alter the temperature-dependent aggregation behavior and fibrillation kinetics, enabling the insulin to maintain stability at elevated temperatures while preserving rapid absorption and glycemic control properties.
3Ease of manufacture
If standard insulin formulations are used, then manufacturing simplicity is maintained, but resistance to fibrillation at elevated temperatures is insufficient
Solution Approach 1:
The patent modifies key stability parameters of insulin through targeted carbohydrate attachment at B27 and/or B30 positions. This structural parameter change dramatically improves thermal stability and fibrillation resistance while maintaining compatibility with standard pharmaceutical manufacturing processes and formulation approaches.
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
These modifications enable rapid hexamer disassembly and enhanced resistance to fibrillation, maintaining biological activity and stability, thus improving glycemic control and insulin pump performance, even at elevated temperatures.
Implementation Method 1
O-linked carbohydrate-modified insulin analogues... attachment of O-link carbohydrate moieties... resistance to thermal fibrillation
Implementation Method 2
augmented resistance to thermal fibrillation above room temperature... resistance to thermal fibrillation... stability, thus improving glycemic control and insulin pump performance, even at elevated temperatures
Implementation Method 3
modifications to the insulin molecule that lead to accelerated disassembly of the insulin hexamer are thought to promote more rapid absorption of insulin monomers and dimers from the subcutaneous depot into the bloodstream... rapid hexamer disassembly
Implementation Method 4
trypsin-mediated semi-synthesis to introduce monosaccaride pyranoside adducts... O-linked carbohydrate modifications... attachment of O-link carbohydrate moieties at positions B27 and/or B30
Implementation Method 5
trypsin-mediated semi-synthesis... semi-synthetic preparation of insulin analogues containing one or more carbohydrate adducts
Data Source
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AI summary
An insulin analogue comprises an insulin B-chain polypeptide modified with an O-linked monosaccaride pyranoside adduct at the side chain of residue B27 or an O-linked monosaccaride pyranoside adduct at the side chain of residue B30, or both, where the positions are recited relative to human insulin. The monosaccaride may be a manopyranoside, an N-acetyl-galactopyranoside, or a glucopyranoside. The insulin analogue may additionally comprise containing a foreshortened B-chain polypeptide lacking residues B1-B3, an extension of 1 or 2 Glu residues on the carboxy terminal end of the B-chain polypeptide, an extension of ornithine at the carboxy-terminal end of the B-chain, the substitutions Lys at position B28 and Pro at position B29, an ornithine substitution at position B29, or combinations thereof. The analogue may be an analogue of a mammalian insulin, such as human insulin. A method of treating a patient comprises administering a physiologically effective amount of the insulin analogue.