Chimeric FGF19/FGF21 Peptides for Glucose Regulation
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Solution Overview
Problem
Current treatments for diabetes, such as insulin injections, often fail to maintain ideal glucose levels and can lead to side effects like hypoglycemic shock, and long-term complications like cardiovascular diseases, while bariatric surgery offers temporary remission but lacks a clear molecular mechanism.
Innovation Solution
Development of chimeric peptides comprising specific N-terminal and C-terminal regions of FGF19 and FGF21 peptides that bind to FGFR4 with affinity comparable to FGF19, activating the receptor to an extent similar to FGF19, while reducing hepatocellular carcinoma formation and lipid elevation, and enhancing glucose lowering activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If FGF19 is used to lower glucose levels, then glucose lowering activity is improved, but hepatocellular carcinoma formation and lipid elevation occur
Solution Approach 1:
The FGF19 peptide sequence is divided into functional segments (N-terminal region with residues 1-15 and C-terminal region with residues 16-29). By selectively modifying specific segments while preserving others, the invention creates chimeric peptides that maintain glucose lowering activity through the conserved C-terminal region while reducing harmful effects through modifications in the N-terminal region.
Solution Approach 2:
The invention applies local quality changes by making specific amino acid substitutions at particular positions within the FGF19 sequence. For example, substituting hydrophobic residues at positions 2-6 with polar or charged residues locally modifies the peptide's interaction properties, reducing hepatocellular carcinoma formation and lipid elevation while preserving overall glucose lowering activity.
2Productivity
If insulin injections are administered to control glucose levels, then glucose regulation is improved, but hypoglycemic shock and long-term complications occur
Solution Approach 1:
The chimeric FGF19/FGF21 peptides act as intermediary molecules that mediate glucose regulation through a different physiological pathway than insulin. By targeting FGFR4 receptors and activating AMPK signaling, these peptides provide glucose control without the harmful side effects associated with insulin therapy, such as hypoglycemic shock and cardiovascular complications.
Solution Approach 2:
The invention changes the physiological parameters of glucose regulation by using FGF19/FGF21 chimeric peptides with modified amino acid sequences. These parameter changes include altered receptor binding affinity, modified signaling pathway activation, and changed metabolic effects, resulting in improved glucose control with reduced harmful side effects compared to insulin therapy.
3Productivity
If bariatric surgery is performed to achieve diabetes remission, then glucose homeostasis is improved, but the molecular mechanism remains unclear and remission may be temporary
Solution Approach 1:
The chimeric FGF19/FGF21 peptides self-regulate glucose homeostasis by activating intrinsic cellular pathways (AMPK signaling) without requiring external surgical intervention. The peptides serve their own therapeutic function by directly binding to FGFR4 receptors and initiating metabolic changes, providing a clear molecular mechanism for diabetes treatment that mimics and enhances the beneficial effects observed after bariatric surgery.
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 chimeric peptides effectively lower glucose levels, reduce lipid and cholesterol activity, and minimize lean mass reduction, offering a safer and more effective glucose regulation compared to FGF19 and FGF21 variants, potentially addressing the limitations of existing diabetes treatments.
Implementation Method 1
binds to fibroblast growth factor receptor 4 (FGFR4) with an affinity equal to or greater than FGF19 binding affinity for FGFR4; activates FGFR4 to an extent or amount equal to or greater than FGF19 activates FGFR4
Data Source
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AI summary
The invention relates to variants and fusions of fibroblast growth factor 19 (FGF19), variants and fusions of fibroblast growth factor 21 (FGF21), fusions of FGF19 and/or FGF21, and variants or fusions of FGF19 and/or FGF21 proteins and peptide sequences (and peptidomimetics), having one or more activities, such as glucose lowering activity, and methods for and uses in treatment of hyperglycemia and other disorders.