FGF21 C-terminal peptide optimization for Klotho beta binding
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Solution Overview
Problem
Current FGF21 therapies could benefit from analogs with greater potency at the FGF receptor to enhance efficacy in treating metabolic disorders, as existing FGF21 interactions with the FGF receptor are limited to tissues expressing the cofactor Klotho β, primarily in the liver and adipose tissue.
Innovation Solution
Development of optimized FGF21 analogs by modifying the C-terminal 25 amino acid peptide fragment to enhance binding to Klotho β, including substitutions with non-charged amino acids like alanine, and additional modifications at specific positions to increase potency, which can be incorporated into full-length proteins or conjugated with other bioactive peptides for enhanced activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If FGF21 is used to treat metabolic disorders, then therapeutic effects are achieved, but potency at the FGF receptor is limited
Solution Approach 1:
The patent applies parameter changes by modifying the C-terminal amino acid sequence of FGF21 (positions 153-181) to create analogs with enhanced receptor binding affinity. Specific amino acid substitutions at key positions (e.g., 161, 163, 166, 168, 171, 179, 180) alter the molecular parameters of the protein to increase its potency at the FGF receptor while preserving its therapeutic effects on metabolic disorders.
2Adaptability or versatility
If FGF21 interacts with FGF receptor in tissues expressing Klotho β, then tissue specificity is achieved, but efficacy is limited to liver and adipose tissue
Solution Approach 1:
The patent applies local quality by making specific localized modifications to the C-terminal region of FGF21 (amino acid positions 153-181), particularly around positions 161, 163, 166, 168, and 171. These localized changes enhance the interaction with Klotho β in a tissue-specific manner, optimizing efficacy in liver and adipose tissue where Klotho β is predominantly expressed, while maintaining the natural tissue specificity pattern.
Data Source
AI summary
Disclosed herein are modified C-terminal fragments of FGF21 optimized for binding to Klotho β or antagonizing FGF21 activity. FGF21 peptides modified to comprise modifications to the C-terminal amino acid sequence are disclosed that have enhanced activity at the FGF21 receptor. Additionally, conjugates formed between the optimized FGF21 peptide fragments and insulin like peptides or nuclear hormone receptor ligands are provided.