Acid-Stable Gluten-Degrading Polypeptides for Celiac Sprue
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Solution Overview
Problem
Current therapies for celiac sprue, a disease triggered by gluten in wheat, barley, and rye, involve strict dietary restrictions with no effective oral therapeutic options due to the difficulty in developing enzymes that can degrade gluten-derived peptides effectively in the acidic digestive environment.
Innovation Solution
Development of polypeptides with specific amino acid sequences, such as SEQ ID NO:35 and SEQ ID NO:1, that degrade PQPQLP peptides at pH 4, enhancing protease activity by introducing targeted mutations like N102D, D169N, and D179H, improving enzyme efficiency in degrading gluten components.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If naturally-occurring enzymes are used as oral therapeutics for Celiac disease, then the disease can be treated, but the enzymes fail to meet the stringent physical and chemical requirements to specifically and efficiently degrade gluten-derived peptides in the harsh and highly acidic environment of the human digestive tract
Solution Approach 1:
The patent modifies the enzyme's amino acid sequence parameters to change its physical and chemical properties, enabling it to function effectively in the acidic stomach environment. Specific amino acid changes are made to enhance the enzyme's stability and catalytic activity at low pH, allowing it to degrade gluten peptides before they reach the intestine.
Solution Approach 2:
The patent converts the harmful acidic environment into a beneficial condition by selecting and engineering acid-stable enzymes that thrive in low pH conditions. The enzyme is designed to be most active in the acidic stomach environment, transforming the previously detrimental factor into the optimal operating condition for gluten degradation.
2Reliability
If total elimination of glutens from the diet is used as therapy, then the disease is treated, but it requires strict dietary restrictions
Solution Approach 1:
The patent introduces an enzyme therapeutic as an intermediary substance that mediates between the patient and gluten in the diet. Instead of requiring complete gluten elimination, the enzyme acts as a protective agent that degrades gluten peptides in the stomach, allowing patients to consume gluten-containing foods without triggering the autoimmune response.
3Productivity
If enzymes are designed to degrade gluten peptides, then therapeutic effectiveness is improved, but the enzymes must withstand the harsh acidic environment and maintain specific activity at pH 4
Solution Approach 1:
The patent systematically modifies the enzyme's amino acid sequence parameters to optimize both its stability and activity at pH 4. Multiple amino acid residues are changed to enhance the enzyme's structural stability in acidic conditions while maintaining or improving its catalytic efficiency for gluten peptide degradation.
Solution Approach 2:
The patent applies local quality changes by modifying specific amino acid residues at critical positions in the enzyme's active site and structural framework. These localized amino acid changes are designed to provide acid stability in specific regions while preserving the catalytic functionality needed for high-rate peptide degradation.
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 modified polypeptides demonstrate significantly enhanced protease activity against gluten-derived peptides, offering a potential therapeutic option for celiac sprue by specifically degrading immunogenic peptides in the stomach.
Implementation Method 1
the polypeptide degrades a PQPQLP (SEQ ID NO:34) peptide at pH 4
Implementation Method 2
degrade gluten-derived peptides in the harsh and highly acidic environment of the human digestive tract
Data Source
AI summary
The invention provides compositions and methods for treating celiac sprue.