FGF19 FGF21 Chimeric Peptides Modulating Bile Acid Homeostasis
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Solution Overview
Problem
Current therapeutic modalities for bile acid-related disorders, such as primary biliary cirrhosis, are inadequate for many patients, and there is a need for new treatment regimens that do not increase the risk of hepatocellular carcinoma (HCC) or elevate lipid profiles.
Innovation Solution
The use of variants and fusions of FGF19 and FGF21 peptide sequences, including chimeric peptides with specific N-terminal and C-terminal regions, in combination with other therapeutic agents to modulate bile acid homeostasis and treat bile acid-related disorders, while avoiding substantial HCC formation and lipid profile elevation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapeutic modalities are used for bile acid-related disorders, then treatment of bile acid disorders is achieved, but the risk of hepatocellular carcinoma increases and lipid profiles are elevated
Solution Approach 1:
The patent modifies the FGF19 peptide sequence by changing specific amino acid residues (such as substituting hydrophobic residues at positions 6-10 with less hydrophobic or polar residues) to alter the molecular parameters of the therapeutic agent. This parameter change reduces the peptide's ability to induce HCC and lipid profile elevation while maintaining its bile acid homeostasis modulation activity, thus resolving the contradiction between treatment effectiveness and harmful side effects
Solution Approach 2:
The patent creates chimeric peptides by fusing FGF19 sequence with FGF21 sequence or other peptide sequences. This composite structure combines the bile acid homeostasis benefits of FGF19 with the metabolic benefits of FGF21 (such as improved lipid profile) while reducing the harmful effects associated with native FGF19, thereby addressing both treatment effectiveness and safety concerns simultaneously
2Reliability
If FGF19 peptide sequences are used to treat bile acid disorders, then bile acid homeostasis is improved, but HCC formation and lipid profile elevation occur
Solution Approach 1:
The patent systematically modifies physical and chemical parameters of the FGF19 peptide including hydrophobicity, charge distribution, and molecular flexibility by substituting specific amino acid residues. These parameter changes reduce the peptide's oncogenic potential and lipid-elevating effects while preserving its ability to bind FGFR4 and modulate bile acid synthesis, thus maintaining therapeutic efficacy while eliminating harmful effects
Solution Approach 2:
The patent extracts and removes the harmful functional domains or specific amino acid sequences from native FGF19 that are responsible for HCC induction and lipid profile elevation, while retaining the essential bile acid homeostasis-modulating regions. This selective extraction creates a safer therapeutic peptide that maintains therapeutic benefits without adverse effects
Data Source
AI summary
Provided herein are methods of modulating bile acid homeostasis or treating a bile-acid related or associated disorder, comprising using 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), in combination with agents effective in modulating bile acid homeostasis or treating a bile-acid related or associated disorder.