Chimeric FGF Protein Engineering for Metabolic Regulation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for type 2 diabetes, such as thiazolidinediones and glucagon-like peptide-1 agonists, have limited efficacy, significant adverse effects, and do not directly target cardiovascular complications, necessitating the development of safer and more effective therapies that improve glycemic control and reduce cardiovascular risk factors.
Innovation Solution
A chimeric fibroblast growth factor (FGF) protein is created by modifying the N-terminus of a paracrine FGF to decrease binding affinity for heparin and/or heparan sulfate and coupling it with a C-terminal portion of FGF19, enhancing endocrine activity and facilitating FGFR-βKlotho co-receptor complex formation for improved metabolic regulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If current diabetes treatments (thiazolidinediones, GLP-1 agonists) are used to improve glycemic control, then blood glucose levels are reduced, but significant adverse effects occur including weight gain, cardiovascular risk, and limited efficacy
Solution Approach 1:
The invention segments the FGF molecule into distinct functional domains (N-terminal paracrine FGF portion and C-terminal endocrine FGF19 portion) to create a chimeric protein that combines beneficial metabolic effects while eliminating adverse effects associated with conventional treatments
Solution Approach 2:
The chimeric FGF protein is a composite molecule combining portions of different FGF family members (paracrine FGF and FGF19) to create a novel therapeutic agent with improved safety and efficacy profile compared to existing monotherapy options
2Quantity of substance
If paracrine FGF is used for its metabolic effects, then insulin sensitivity improves, but binding to heparin and heparan sulfate limits endocrine activity and systemic distribution
Solution Approach 1:
The invention modifies specific local properties of the FGF molecule by replacing the C-terminal portion with FGF19 sequence, which has reduced heparin/heparan sulfate binding affinity, thereby enabling systemic distribution while maintaining metabolic activity
Solution Approach 2:
The chimeric structure changes the binding parameters of the FGF molecule, specifically reducing affinity for heparin and heparan sulfate while maintaining affinity for FGFR-βKlotho co-receptor complex, enabling transition from paracrine to endocrine mode of action
3Reliability
If FGF proteins are engineered to decrease heparin binding affinity to enhance endocrine activity, then systemic distribution improves, but binding affinity for FGFR may be reduced
Solution Approach 1:
The invention merges the N-terminal portion of paracrine FGF (which provides strong FGFR binding) with the C-terminal portion of FGF19 (which provides reduced heparin binding and endocrine activity), creating a chimera that exhibits both strong receptor binding and systemic distribution capabilities
Solution Approach 2:
The chimeric FGF protein performs multiple functions: it maintains high affinity for FGFR through the paracrine FGF N-terminus while simultaneously achieving systemic distribution through reduced heparin binding from the FGF19 C-terminus, and activates βKlotho co-receptor for metabolic effects
Data Source
AI summary
The present invention relates to a chimeric protein that includes an N-terminus coupled to a C-terminus, where the N-terminus includes a portion of a paracrine fibroblast growth factor (“FGF”) and the C-terminus includes a C-terminal portion of an FGF19 molecule. The portion of the paracrine FGF is modified to decrease binding affinity for heparin and/or heparan sulfate compared to the portion without the modification. The present invention also relates to pharmaceutical compositions including chimeric proteins according to the present invention, methods for treating a subject suffering from diabetes, obesity, or metabolic syndrome, and methods of screening for compounds with enhanced binding affinity for the βKlotho-FGF receptor complex involving the use of chimeric proteins of the present invention.