Insulin Analogues with Cyclohexanylalanine for Rapid Absorption
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current insulin analogues for diabetes management are limited by their slow absorption rates and increased susceptibility to thermal fibrillation, which hampers glycemic control and the use of insulin pumps, especially in regions without consistent refrigeration.
Innovation Solution
Development of insulin analogues with non-standard amino acid substitutions, such as Cyclohexanylalanine at position B24, to enhance rapid hexamer disassembly and maintain biological activity while improving thermal stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If modifications are made to accelerate insulin absorption following subcutaneous injection, then the absorption rate is improved, but the resistance to chemical and physical degradation worsens
Solution Approach 1:
The patent applies parameter changes by substituting specific amino acid residues at defined positions in the insulin molecule with alternative amino acids having different chemical properties. These substitutions modify the pharmacokinetic parameters to accelerate absorption while maintaining or improving stability against degradation, thereby resolving the technical contradiction between absorption rate and degradation resistance
Solution Approach 2:
The patent implements local quality by making targeted amino acid substitutions at specific positions (e.g., B28, B29, A8) rather than throughout the entire molecule. Each substitution is strategically placed to affect specific properties: some positions are modified to accelerate absorption while other positions are preserved or modified to enhance stability, allowing simultaneous optimization of both absorption rate and degradation resistance
2Speed
If standard amino acid substitutions are made to improve absorption, then the absorption kinetics are enhanced, but the thermal stability deteriorates
Solution Approach 1:
The patent creates composite amino acid sequences by combining standard and non-standard amino acid substitutions in specific patterns. This composite approach allows the insulin analogue to possess dual characteristics: accelerated absorption kinetics from certain substitutions and enhanced thermal stability from complementary substitutions, effectively resolving the contradiction between absorption speed and thermal stability
3Loss of time
If insulin analogues are designed for rapid absorption, then the glycemic control speed is improved, but the susceptibility to fibrillation increases
Solution Approach 1:
The patent employs disposable amino acid substitutions that are strategically positioned to facilitate rapid hexamer disassembly and absorption, accepting that these specific substituted regions may be more susceptible to fibrillation. However, the overall molecule is designed with compensatory stable regions that prevent aggregate formation, effectively managing the trade-off between rapid action and fibrillation resistance
Data Source
AI summary
An insulin analog comprises a B-chain polypeptide containing a cyclohexanylalanine substitution at position B24 and optionally containing additional amino-acid substitutions at positions A8, B28, and/or B29. A proinsulin analog or single-chain insulin analog containing a B domain containing a cyclohexanylalanine substitution at position B24 and optionally containing additional amino-acid substitutions at positions A8, B28, and/or B29. The analog may be an analog of a mammalian insulin, such as human insulin. A nucleic acid encoding such an insulin analog is also provided. A method of lowering the blood sugar of a patient comprises administering a physiologically effective amount of the insulin analog or a physiologically acceptable salt thereof to a patient. A method of semi-synthesis using an unprotected octapeptide by means of modification of an endogenous tryptic site by non-standard amino-acid substitutions.