Truncated DPPIV and LAP Enzymes Degrade Gluten Peptides
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Solution Overview
Problem
Current treatments for gluten-related disorders, such as celiac disease and non-celiac gluten sensitivity, rely on a strict gluten-free diet, but adherence is challenging due to the difficulty in avoiding trace gluten and cross-contamination, leading to persistent symptoms in some patients.
Innovation Solution
Development of truncated variants of dipeptidylpeptidase IV (DPPIV) and leucine aminopeptidase (LAP) polypeptides from Trichophyton rubrum, specifically ruDPPIV and ruLAPII, which are produced in a Pichia pastoris expression platform and retain enzymatic activity, capable of degrading gluten-immunogenic peptides into non-immunogenic fragments, thereby preventing immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a strict gluten-free diet is maintained, then immune responses are avoided, but adherence is challenging due to trace gluten and cross-contamination
Solution Approach 1:
The patent introduces truncated DPPIV and LAP enzymes as intermediary substances that mediate between gluten-containing foods and the human immune system. These enzymes selectively degrade immunogenic gluten peptides while leaving non-immunogenic peptides intact, thereby protecting patients from immune responses without requiring strict dietary avoidance. The enzymes act as a biochemical bridge that allows gluten consumption while preventing pathological immune activation.
2Ease of manufacture
If endogenous proteases are used for gluten digestion, then natural digestion occurs, but immunogenic peptides remain stable and resistant to degradation
Solution Approach 1:
The patent employs parameter changes by modifying the proteolytic enzyme system through truncation of DPPIV and LAP enzymes. These truncated variants exhibit enhanced peptidase activity specifically toward immunogenic gluten peptides containing proline and glutamine residues. The parameter change involves altering enzyme structure (truncation) to optimize substrate specificity and catalytic efficiency for degrading resistance peptides that evade endogenous protease degradation.
Solution Approach 2:
The truncated enzymes serve as intermediary agents that supplement and enhance the natural digestion process. Rather than replacing endogenous proteases, these engineered enzymes work alongside them to specifically target and degrade immunogenic peptides that naturally resist digestion. This intermediary approach maintains the natural digestion pathway while adding specialized capability to handle resistant substrates.
3Reliability
If full-length DPPIV and LAP enzymes are used, then complete degradation capability is achieved, but production efficiency and cost-effectiveness are reduced
Solution Approach 1:
The patent applies the extraction principle by removing unnecessary portions of the full-length DPPIV and LAP enzymes. The truncated variants retain the essential catalytic domains required for degrading immunogenic gluten peptides while eliminating regions that do not contribute to this specific function. This extraction of essential functional elements maintains degradation capability while reducing molecular weight and production complexity.
Solution Approach 2:
The truncated enzymes represent a simplified, more economical version of the full-length enzymes. By reducing the size and complexity of the protein structure, the truncated variants are easier and less costly to produce through recombinant expression systems. The design prioritizes essential function over complete structural integrity, accepting that smaller, simpler protein structures are more economically viable for therapeutic applications.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The truncated polypeptides effectively degrade gluten-immunogenic peptides, potentially reducing symptoms and improving adherence to a gluten-free diet by ensuring complete breakdown of immunogenic fragments, even in the presence of trace gluten, thus offering a therapeutic option for gluten-related disorders.
Implementation Method 1
dipeptidylpeptidase IV (DPPIV)...leucine aminopeptidase (LAP)...capable of degrading gluten-immunogenic peptides into non-immunogenic fragments
Data Source
AI summary
The present disclosure relates to polypeptides with peptidase activity that are truncated variants of dipeptidylpeptidase IV (DPPIV) and leucine aminopeptidase (LAP) polypeptides, nucleic acids such as vectors encoding them, as well as host cells comprising the nucleic acids described herein and optionally expressing the polypeptides described herein. The polypeptides and nucleic acids described herein are useful in medical applications such as in the treatment of gluten-related disorders including celiac disease (CeD) and non-celiac gluten sensitivity (NCGS) as well as other diseases that may profit from a gluten-free diet (GFD).