Insulin Derivatives with Cyclic Amino Acids for Faster Onset
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Solution Overview
Problem
Current diabetic therapies, particularly recombinant human insulin formulations, experience a delay in activity due to the time required for insulin hexamers to dissociate into the active monomeric state, which can slow down the onset of insulin action, necessitating the development of insulin analogs with improved therapeutic profiles.
Innovation Solution
The introduction of cyclic amino acids, such as (2S, 4R)-4-hydroxy-L-proline and (4R)-1,3-thiazolidine-4-carboxylic acid, at positions B28 or B29 of the insulin B chain, which reduces the dimer association constant and enhances the stability and activity of insulin derivatives, allowing for faster onset and prolonged action.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If zinc ions are added to stabilize insulin formulation by inducing hexamer formation, then long-term stability is improved, but onset of activity is delayed due to time required for hexamer dissociation
Solution Approach 1:
The patent modifies the amino acid sequence of insulin by substituting residues at positions B28 and/or B29 with alternative amino acids (such as Asn, Gln, Lys, Arg, Ala, Val, Leu, Ile, Met, Phe, Tyr, Trp, His, Asp, or Glu). These parameter changes in the primary structure alter the hexamer-dissociation kinetics, enabling the insulin analog to maintain stability in hexameric form during storage while dissociating more rapidly into active monomers upon administration, thus resolving the contradiction between stability and onset speed.
2Speed
If insulin analogs are engineered with substitutions at B28 and B29 positions, then speed of action is improved, but structural complexity increases
Solution Approach 1:
The patent applies local quality modification by making targeted substitutions only at specific positions (B28 and B29) of the insulin B-chain, rather than modifying the entire molecule. This localized approach to structural engineering achieves improved dissociation kinetics and speed of action while minimizing overall structural complexity changes, as the rest of the insulin molecule remains unchanged and retains its native properties.
Data Source
AI summary
In some aspects, the invention relates to an insulin derivative, comprising a cyclic amino acid at position B28 or B29, wherein the cyclic amino acid is not L-proline. In some aspects, the invention relates to a method of making said insulin derivative. In some aspects, the invention relates to a pharmaceutical composition comprising said insulin derivative. In some aspects the invention relates to a method of treating a disease or condition in a subject comprising administering to the subject a composition comprising said insulin derivative.