FGF21 Mutant Polypeptides for Metabolic Disorder Treatment
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Solution Overview
Problem
Human FGF21 has a short half-life in vivo, limiting its therapeutic application for treating metabolic disorders like type 2 diabetes and obesity, as it requires frequent dosing and is prone to degradation and aggregation.
Innovation Solution
Development of FGF21 mutant polypeptides with specific amino acid substitutions, engineered disulfide bonds, and fusion proteins to enhance stability, half-life, and reduce aggregation, including mutations at positions like L98R, P171G, and A180E, and fusion with IgG constant domains or polymers like PEG for improved pharmacokinetics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If FGF21 protein is used as a therapeutic for treating metabolic disorders, then therapeutic efficacy is improved, but half-life is too short requiring frequent dosing
Solution Approach 1:
The patent applies parameter changes by modifying amino acid residues at specific positions (98, 171, 180) in the FGF21 protein sequence. These substitutions alter the protein's physicochemical properties to increase stability and half-life while preserving biological activity, directly resolving the contradiction between therapeutic efficacy and duration of action
Solution Approach 2:
The patent creates composite structures by introducing engineered disulfide bonds within the FGF21 protein and by fusing FGF21 with IgG constant domains or PEG polymers. These composite configurations enhance protein stability and extend half-life, allowing less frequent dosing while maintaining therapeutic efficacy
2Reliability
If FGF21 protein is administered therapeutically, then metabolic disorder treatment is achieved, but protein degradation occurs reducing effectiveness
Solution Approach 1:
By substituting amino acids at positions 98, 171, and 180, the patent modifies the protein's resistance to proteolytic degradation. These parameter changes in the amino acid sequence enhance stability against enzymatic breakdown while preserving the protein's biological function and therapeutic effectiveness
Solution Approach 2:
The engineered disulfide bonds act as a protective mechanism against degradation. By pre-establishing these stable covalent bonds within the protein structure, the patent creates inherent resistance to denaturation and degradation before exposure to harsh physiological conditions, cushioning the protein against stability-destroying factors
3Reliability
If FGF21 protein is used for treatment, then therapeutic benefit is provided, but aggregation occurs leading to reduced activity
Solution Approach 1:
The amino acid substitutions at positions 98, 171, and 180 alter surface properties and intermolecular interaction patterns of the FGF21 protein. These parameter changes reduce propensity for aggregation while preserving monomeric structural integrity and biological activity, ensuring therapeutic benefit is maintained
Data Source
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AI summary
The invention provides nucleic acid molecules encoding FGF21 mutant polypeptides, FGF21 mutant polypeptides, pharmaceutical compositions comprising FGF21 mutant polypeptides, and methods for treating metabolic disorders using such nucleic acids, polypeptides, or pharmaceutical compositions.