Modified Chaperonin 10 for Targeted Immunotherapy
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Solution Overview
Problem
The site(s) within the Cpn10 molecule responsible for mediating its immunomodulatory activity have remained elusive, limiting the understanding and application of Cpn10 in treating autoimmune and inflammatory diseases.
Innovation Solution
Cpn10 polypeptides with specific amino acid substitutions, deletions, or additions, particularly in the mobile loop and roof β-hairpin regions, are developed to retain or enhance immunomodulatory activity while minimizing protein folding activity, allowing for targeted immunotherapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type Cpn10 is used, then both protein folding activity and immunomodulatory activity are present, but the site responsible for immunomodulatory activity remains unknown and protein folding activity may interfere with therapeutic application
Solution Approach 1:
The Cpn10 protein is divided into functional regions: the mobile loop region (residues 1-18) responsible for protein folding activity and the roof β-hairpin region (residues 19-33) responsible for immunomodulatory activity. By segmenting the protein and selectively deleting or modifying the mobile loop region, the patent isolates the immunomodulatory function from the protein folding function, enabling targeted therapeutic application without interference from folding activity.
Solution Approach 2:
The patent extracts the mobile loop region (residues 1-18) from the full-length Cpn10 protein through deletion or truncation. This extraction removes the protein folding activity while preserving the roof β-hairpin region (residues 19-33) that contains the immunomodulatory activity. The extracted mobile loop is replaced with alternative sequences or completely removed, leaving only the immunomodulatory domain for therapeutic use.
2Reliability
If the mobile loop region is modified or deleted to reduce protein folding activity, then immunomodulatory activity is enhanced for therapy, but the protein loses its native chaperone function
Solution Approach 1:
Instead of using the native Cpn10 protein with dual functions for therapy, the patent inverts the approach by creating a modified protein that deliberately loses the protein folding function (mobile loop deletion) to preserve and enhance the immunomodulatory function. This inversion prioritizes the therapeutic function over the native chaperone function, creating a specialized therapeutic agent rather than a general-purpose protein.
Solution Approach 2:
The patent applies local quality modification by selectively altering only the mobile loop region (residues 1-18) while leaving the roof β-hairpin region (residues 19-33) unchanged. The mobile loop is deleted or replaced with alternative sequences that do not interfere with immunomodulatory activity. This localized modification allows the protein to maintain its immunomodulatory function while losing its protein folding function, creating a specialized therapeutic protein with optimized properties for a specific purpose.
3Reliability
If amino acid substitutions are made in the mobile loop region, then immunomodulatory activity is retained or enhanced, but the protein folding activity is compromised
Solution Approach 1:
The patent applies parameter changes by substituting specific amino acids in the mobile loop region with alternative amino acids that have different properties. These substitutions are designed to maintain or enhance immunomodulatory activity while compromising protein folding activity. The specific amino acid sequences in the mobile loop are altered through site-directed mutagenesis or chemical modification, changing the protein's structural and functional parameters to achieve the desired therapeutic effect.
Data Source
Figure 1A~1B
Figure 2A~2B
Figure 3A~3F
AI summary
The present invention relates to isolated Chaperonin 10 polypeptides possessing immunomodulatory activity, but lacking, or substantially lacking, protein folding activity.