Super Mini Inverted Proinsulin Derivatives Synthesis
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Solution Overview
Problem
Current methods for producing insulin are inefficient and lack a chemically and economically feasible route, with existing insulin analogues facing challenges in solubility, activity, yield, purity, and ease of synthesis, particularly due to the complexity of forming disulfide bonds and the stability of proinsulin derivatives.
Innovation Solution
Development of 'super mini' inverted proinsulin derivatives with shorter connecting peptides, specifically polypeptide compounds of the formula A-C-B, which are synthetically easier to prepare and exhibit improved solubility and stability, utilizing a two-step oxidation process to form bioactive insulin by enzymatic removal of the C-peptide.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If conventional proinsulin derivatives with longer connecting peptides are used, then the stability and solubility are improved, but the synthesis complexity and difficulty of forming disulfide bonds increase
Solution Approach 1:
The connecting peptide is divided into two separate parts: a first connecting peptide segment attached to the A-chain and a second connecting peptide segment attached to the B-chain. This segmentation allows each segment to be synthesized and folded independently, reducing the overall synthesis complexity while maintaining the stability provided by the combined connecting peptide structure.
Solution Approach 2:
The first and second connecting peptide segments are pre-formed with their respective A-chain and B-chain attachments before the final assembly. This preliminary action allows the disulfide bonds to form more easily during the coupling reaction, as the peptide segments are already in their correct folded configurations, thereby reducing synthesis complexity.
2Reliability
If conventional proinsulin derivatives are used, then the insulin activity is maintained, but the synthesis efficiency and productivity are reduced
Solution Approach 1:
The proinsulin derivative is segmented into two separately synthesizable components (first connecting peptide with A-chain, second connecting peptide with B-chain) that can be prepared in parallel. This segmentation significantly improves synthesis efficiency and productivity while ensuring the final product maintains full insulin activity through proper disulfide bond formation upon coupling.
Solution Approach 2:
The first and second connecting peptide segments are merged through a coupling reaction that forms the complete connecting peptide structure. This merging step is highly efficient and maintains insulin activity, as the disulfide bonds are formed under controlled conditions that preserve the bioactive conformation of the insulin molecule.
3Ease of manufacture
If inverted proinsulin derivatives with shorter connecting peptides are developed, then the ease of synthesis is improved, but the solubility and stability may be compromised
Solution Approach 1:
The connecting peptide is segmented into two parts, each with optimized length and composition. The first connecting peptide segment (attached to A-chain) and second connecting peptide segment (attached to B-chain) can each be synthesized more easily than a single long peptide, improving ease of manufacture while the combined structure maintains adequate solubility and stability.
Solution Approach 2:
Different regions of the connecting peptide are designed with different local properties. The first and second connecting peptide segments can have different amino acid compositions optimized for their specific roles, with local variations that enhance both ease of synthesis and maintain overall solubility and stability of the complete molecule.
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 approach results in high-purity, bioactive insulin precursors with improved synthesis efficiency, solubility, and stability, overcoming the limitations of existing methods by simplifying the synthesis and folding of insulin derivatives.
Implementation Method 1
utilizing a two-step oxidation process to form bioactive insulin
Implementation Method 2
enzymatic removal of the C-peptide
Data Source
AI summary
A first aspect of the invention relates to a polypeptide compound of formula (I):A-C-B  (I)wherein:A is the A chain of insulin or a functional derivative or variant thereof;B is the B chain of insulin or a functional derivative or variant thereof;C is a peptide of the formula:(X1)p-(X2)n-(X3)q wherein:each X1 and X3 is independently a basic amino acid;each X2 is independently a natural or unnatural amino acid;p is 1 or 2;q is 0, 1 or 2;n is 0, 1, 2 or 3.Further aspects of the invention relate to pharmaceutical compositions comprising said polypeptide compound, and therapeutic uses thereof. Another aspect relates to the use of said polypeptide compounds in the preparation of insulin and derivatives thereof.