Conjugated Hepcidin Mimetics With Disulfide-Linked Dimer Structures
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current hepcidin-based treatments for iron overload diseases and disorders, such as hereditary hemochromatosis and iron-loading anemias, face challenges due to difficult synthetic processes, low bioavailability, injection site reactions, immunogenicity, and high costs, necessitating the development of hepcidin analogues with improved solubility, stability, and potency.
Innovation Solution
Development of novel hepcidin peptide analogues and dimers with specific amino acid sequences, including cyclized structures and conjugations, to enhance stability and potency, and potentially improve half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If hepcidin is used as a drug, then iron overload diseases can be treated, but synthesis is difficult due to aggregation and precipitation during folding
Solution Approach 1:
The hepcidin molecule is divided into two 13-amino acid monomers that are linked by a disulfide bond. Each monomer contains a specific sequence of amino acids with cysteine residues at positions 6 and 13, allowing them to form intermolecular disulfide bonds to create the active dimer structure. This segmentation simplifies the synthesis process while maintaining biological activity.
Solution Approach 2:
The invention creates a composite structure where two peptide monomers are covalently linked through disulfide bonds to form a dimer. This composite architecture combines the advantages of peptide-based specificity with improved stability and reduced aggregation compared to the native 25-amino acid hepcidin structure.
2Reliability
If hepcidin is used as a drug, then iron overload diseases can be treated, but bioavailability is low
Solution Approach 1:
The invention modifies the physical and chemical parameters of hepcidin by reducing it from a 25-amino acid single chain to two smaller 13-amino acid monomers linked by disulfide bonds. This structural parameter change improves solubility and stability, thereby enhancing bioavailability while retaining the ability to bind ferroportin and regulate iron metabolism.
3Reliability
If hepcidin is used as a drug, then iron overload diseases can be treated, but injection site reactions occur
Solution Approach 1:
The disulfide-linked dimer structure is designed to be more stable and less immunogenic than native hepcidin, reducing local reactions at the injection site. The modified structure maintains sufficient half-life for therapeutic effect while minimizing adverse local effects.
4Reliability
If hepcidin is used as a drug, then iron overload diseases can be treated, but immunogenicity is high
Solution Approach 1:
By modifying the molecular structure from native 25-amino acid hepcidin to a disulfide-linked dimer of two 13-amino acid monomers, the invention changes the immunogenic parameters. The smaller, modified structure with specific disulfide bond positioning reduces recognition by the immune system while preserving the iron-regulatory function through ferroportin binding.
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 novel hepcidin analogues offer improved solubility, stability, and potency, making them suitable alternatives to hepcidin, potentially reducing burdensome treatments and side effects while effectively managing iron overload diseases.
Implementation Method 1
a peptide comprising an amino acid sequence of Formula (I′)... at least one of X1, X3-X5, X7-X10 is Cys, (D)Cys, aMeCys, hCys, Pen, (D)Pen, NMe-Cys, 4S_Mcp or 4R_Mcp, wherein the peptide is cyclized by taking the mercapto group on the side chain of one of X1, X3-X5 and X7-X10, the mercapto group on the side chain of X6 and Lx to form a —S-Lx-S— linkage
Data Source
AI summary
The present invention provides hepcidin analogues with improved in vivo half lives, and related pharmaceutical compositions and methods of use thereof. The present invention provides novel peptide analogues, including both peptide monomer analogues and peptide dimer analogues, having hepcidin activity, and also having other beneficial properties making the peptides of the present invention suitable alternatives to hepcidin.