Linker-Deleted Recombinant Galectin-9 for Lupus Treatment
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Solution Overview
Problem
Current treatments for lupus and glomerulonephritis, such as immunosuppressive agents, have harmful side effects and there is no definitive cure, while galectin-9 proteins face issues of protease sensitivity, low solubility, and low yield, limiting their therapeutic potential.
Innovation Solution
A recombinant stabilized galectin-9 protein with modified linker peptide and C-terminal carbohydrate recognition domain is developed, retaining glycan-recognition activity and enhanced stability, used in pharmaceutical and health functional food compositions to treat or prevent lupus and glomerulonephritis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional wild-type galectin-9 is used, then it binds to Tim-3 and induces apoptosis of Th1 cells, but it suffers from protease sensitivity, low solubility, and low yield
Solution Approach 1:
The patent removes the linker peptide region from the galectin-9 protein structure, extracting the problematic segment that causes protease sensitivity and instability. This results in a truncated protein consisting only of the two carbohydrate recognition domains, which dramatically improves protease resistance and production yield while maintaining the essential Tim-3 binding function.
Solution Approach 2:
The patent modifies the protein structure by changing the amino acid sequence parameters - specifically deleting the linker peptide and modifying the C-terminal carbohydrate recognition domain. This structural parameter change transforms the protein from a unstable, protease-sensitive form to a stable, protease-resistant form with improved solubility and yield.
2Reliability
If immunosuppressive agents are administered to treat lupus, then disease symptoms are suppressed, but harmful side effects occur in treated patients
Solution Approach 1:
The patent creates a recombinant version of galectin-9 that copies the essential therapeutic function of natural galectin-9 (binding to Tim-3 and inducing apoptosis of pathogenic Th1 cells) but with improved stability and safety characteristics. This recombinant protein serves as a safer alternative to conventional immunosuppressive agents, maintaining therapeutic efficacy while reducing harmful side effects.
Solution Approach 2:
The patent modifies the protein parameters by deleting the linker peptide and optimizing the C-terminal domain, which changes the protein's stability, solubility, and biological activity parameters. These parameter changes enable the protein to function as a safe therapeutic agent that targets specific pathogenic cells without the broad immunosuppression and side effects of conventional drugs.
3Reliability
If the linker peptide of galectin-9 is cleaved to generate G9Null, then protease resistance is enhanced, but solubility and yield remain limited
Solution Approach 1:
The patent extracts not only the linker peptide but also optimizes the C-terminal carbohydrate recognition domain structure. This dual extraction and optimization approach removes the sources of instability while preserving the functional domains, resulting in a protein that achieves both protease resistance and improved solubility and yield.
Solution Approach 2:
The patent creates a composite protein structure consisting of two stable carbohydrate recognition domains directly connected without the problematic linker peptide, with optimized C-terminal domain features. This composite structure combines the stability of the CRD regions with improved solubility characteristics, achieving multiple improvements simultaneously.
Data Source
AI summary
The present invention relates to a composition for preventing or treating lupus or glomerulonephritis comprising a recombinant stabilized Galectin-9 protein. Specifically, the recombinant stabilized Galectin-9 protein of the present invention has been confirmed to exhibit safety in a systemic lupus erythematosus (SLE) animal model, reduce skin lesions, lymphadenopathy, and proteinuria caused by lupus, ameliorate lupus nephritis and glomerulonephritis, and decrease the concentration of anti-dsDNA antibodies in plasma. Accordingly, the recombinant stabilized Galectin-9 protein of the present invention can be effectively used as an active ingredient in a composition for preventing or treating lupus or glomerulonephritis.