Mutant IAPP Polypeptides Neutral pH Solubility Insulin Co-Formulation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for diabetes, particularly type-2 diabetes, face challenges due to the aggregation and toxicity of wild-type human islet amyloid polypeptide (hIAPP), which limits its solubility and effectiveness at physiological pH, and its inability to be co-formulated with insulin, hindering glycemic control and therapeutic efficacy.
Innovation Solution
Development of mutant-hIAPP polypeptides with specific amino acid substitutions, such as Asparagine to Lysine or Arginine at positions 21, 22, 31, and 35, that are soluble at neutral pH, prevent amyloid formation, and retain binding ability to human calcitonin and amylin receptors, allowing co-formulation with insulin.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type hIAPP is used for diabetes treatment, then it can bind to human calcitonin and amylin receptors to regulate glycemic control, but it aggregates and forms toxic amyloid fibrils at physiological pH, limiting its solubility and therapeutic effectiveness
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of hIAPP through specific substitutions (N21K, N22K, N31K, N35K) to alter its physicochemical properties. These mutations change the charge distribution and hydrophilicity of the peptide, transforming it from a hydrophobic, aggregation-prone molecule to a hydrophilic, soluble variant that maintains receptor binding activity while preventing amyloid formation at physiological pH
Solution Approach 2:
The patent creates a composite therapeutic formulation by co-formulating the mutant hIAPP (mIAPP) with insulin in a single injection system. This composite approach combines two different peptide hormones with complementary mechanisms of action - mIAPP for suppressing glucagon secretion and regulating gastric emptying, and insulin for glucose uptake - thereby achieving synergistic glycemic control while both peptides benefit from improved solubility and stability in the formulation
2Quantity of substance
If wild-type hIAPP is formulated at acidic pH to maintain solubility, then it remains soluble, but it cannot be co-formulated with insulin which requires neutral pH formulation
Solution Approach 1:
The patent fundamentally changes the pH-dependent solubility parameter of hIAPP through amino acid mutations. The introduction of positively charged lysine or arginine residues at positions 21, 22, 31, and 35 creates electrostatic repulsion and enhances hydrophilicity, allowing the peptide to maintain high solubility at neutral pH (7.0-7.4) without requiring acidic conditions. This parameter transformation enables compatibility with insulin formulations
3Reliability
If multiple separate injections are administered to achieve glycemic control, then insulin and hIAPP can be delivered, but it increases treatment complexity and reduces patient compliance
Solution Approach 1:
The patent merges two separate therapeutic agents (insulin and hIAPP) into a single co-formulated injection product. This consolidation combines insulin's glucose-lowering effect with mIAPP's glucagon-suppressing and gastric emptying-regulating effects, delivering comprehensive glycemic control through one injection. The mutant hIAPP's improved solubility at neutral pH makes this merging feasible, as both peptides can now be stably formulated together without precipitation or aggregation issues
Data Source
AI summary
Isolated non-naturally occurring, mutant-human islet amyloid polypeptides (IAPP) polypeptides, which are more soluble at neutral pH than the wild-type human islet amyloid polypeptide (hIAPP) protein are disclosed. These polypeptides can be formulated or co-formulated at physiological pH, which enable the polypeptides to be delivered to a subject in a single injection with an insulin agent. Methods and pharmacological compositions for treating an abnormal condition, such as an amyloid-based disease or type-1 diabetes in a subject are also disclosed.