Chimeric FGF23 Protein Reducing Heparin Binding
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Solution Overview
Problem
Current treatments for disorders related to fibroblast growth factor 23 (FGF23) imbalances, such as autosomal dominant hypophosphatemic rickets and familial tumoral calcinosis, are inadequate, and there is a need for effective therapies to manage hyperphosphatemia and soft tissue calcification.
Innovation Solution
A chimeric protein is developed by modifying the N-terminus of a paracrine FGF to decrease binding affinity for heparin and/or heparan sulfate, coupled with a C-terminus containing a C-terminal portion of FGF23, which facilitates FGFR-αKlotho co-receptor complex formation, allowing for enhanced endocrine activity and therapeutic application.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If the N-terminus of paracrine FGF is modified to decrease binding affinity for heparin and/or heparan sulfate, then endocrine activity is enhanced, but binding affinity for heparin/heparan sulfate is reduced
Solution Approach 1:
The patent applies local quality by making specific modifications only to the N-terminus region of the FGF molecule (residues 1-50), while leaving the C-terminal region (residues 51-150) unchanged. This localized modification approach allows the N-terminus to gain endocrine activity characteristics (reduced heparin binding) while preserving the C-terminus functionality for receptor interaction and stable folding, thus resolving the contradiction between enhancing endocrine activity and maintaining necessary binding properties.
Solution Approach 2:
The patent employs parameter changes by systematically varying the amino acid sequence at the N-terminus of FGF (positions 1-50) to achieve the desired reduction in heparin/heparan sulfate binding affinity. Through iterative modification of this specific region, the patent transforms paracrine FGF into endocrine-active chimeric proteins while maintaining overall structural integrity and biological function.
2Reliability
If chimeric FGF protein is designed to facilitate FGFR-αKlotho co-receptor complex formation, then therapeutic efficacy is improved, but protein structure complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the FGF protein into distinct functional regions: an N-terminal segment (residues 1-50) that confers endocrine activity and reduced heparin binding, and a C-terminal segment (residues 51-150) that maintains stable folding and receptor interaction capability. This segmented approach allows each region to perform its specific function independently, facilitating FGFR-αKlotho complex formation while keeping the overall design manageable.
Solution Approach 2:
The patent employs composite materials by creating chimeric FGF proteins that combine elements from different FGF sources (e.g., FGF1, FGF2, FGF10 N-termini with FGF23 C-termini). These composite structures integrate the beneficial properties of different FGF variants, achieving enhanced endocrine activity and therapeutic efficacy while maintaining structural stability through the conserved C-terminal core.
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 FGF23 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 a disorder, and methods of screening for compounds with enhanced binding affinity for the αKlotho-FGF receptor complex involving the use of chimeric proteins of the present invention.