Chimeric Polypeptide Reduces FGFR4 Signaling for Safer Metabolic Therapy
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Solution Overview
Problem
The development of therapeutic agents for metabolic disorders like diabetes and obesity is hindered by the mitogenic properties of FGF19, which can lead to hepatocellular carcinoma, necessitating a chimeric polypeptide that reduces FGFR4-mediated signaling activity without compromising glucose metabolism regulation.
Innovation Solution
A chimeric polypeptide is created by modifying the FGF19 scaffold with specific amino acid substitutions, such as replacing residues WGDPI, SGPHGLSS, and SSAKQRQLYKNRGFLPL, to decrease FGFR4-mediated signaling while maintaining glucose-lowering effects, and is encoded by nucleic acid molecules for pharmaceutical compositions and treatments.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If FGF19 is used as a therapeutic agent for metabolic disorders, then glucose metabolism regulation is improved, but hepatocellular carcinoma risk increases due to mitogenic properties
Solution Approach 1:
The patent extracts the harmful mitogenic signaling capability from FGF19 by creating chimeric polypeptides that selectively eliminate FGFR4-mediated signaling while preserving metabolic regulatory functions. This is achieved by replacing specific amino acid residues (WGDPI, SGPHGLSS, SSAKQRQLYKNRGFLPL) that are responsible for FGFR4 binding and activation, thereby removing the carcinogenic potential while maintaining therapeutic benefits.
Solution Approach 2:
The invention applies local quality modification by making targeted amino acid substitutions at specific regions of the FGF19 polypeptide chain. Rather than altering the entire molecule, only specific local sequences (residues 16-20, 28-35, and 124-140) are modified to decrease FGFR4-mediated signaling activity, while the rest of the polypeptide structure remains intact to preserve glucose metabolism regulation.
2Object-affected harmful factors
If amino acid substitutions are made to reduce FGFR4-mediated signaling, then hepatocellular proliferation is decreased, but therapeutic effectiveness may be compromised
Solution Approach 1:
The patent applies partial action by implementing a tiered approach to amino acid substitution. The modifications are designed to partially reduce FGFR4-mediated signaling rather than completely eliminate it, achieving a balance where hepatocellular proliferation is sufficiently decreased to reduce carcinoma risk while maintaining enough signaling activity to preserve metabolic regulation effectiveness.
3Object-affected harmful factors
If chimeric polypeptide structure is modified, then safety profile is improved, but molecular complexity increases
Solution Approach 1:
The invention changes the molecular parameters of FGF19 by substituting specific amino acid residues with alternative sequences. This parameter modification alters the polypeptide's binding properties to FGFR4, decreasing its mitogenicity while preserving its metabolic regulatory function. The changes are quantified by specific residue positions and substitution patterns that optimize the safety profile.
Data Source
AI summary
The disclosure provides nucleic acid molecules encoding chimeric polypeptides, chimeric polypeptides, pharmaceutical compositions comprising chimeric polypeptides, and methods for treating metabolic disorders such as diabetes and obesity using such nucleic acids, polypeptides, or pharmaceutical compositions.