Mutant Alpha-1-Antitrypsin Proteins for Enhanced Anti-Inflammatory Therapy
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Solution Overview
Problem
Mutations in the reactive center loop of alpha1-antitrypsin (AAT) often deprive it of its protease-inhibiting capacity, and little is known about the effects of these mutations on its anti-inflammatory properties, which are crucial for various therapeutic applications.
Innovation Solution
Development of mutant alpha1-antitrypsin polypeptides with specific amino acid mutations, such as proline to cysteine, alanine, or methionine at position 357, which exhibit enhanced anti-inflammatory and wound healing properties compared to recombinant human AAT, with improved pharmacokinetic properties like increased stability and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If mutations are introduced in the reactive center loop of AAT to modify its properties, then new therapeutic properties may be achieved, but the protease-inhibiting capacity is lost
Solution Approach 1:
The patent separates the protease-inhibiting function (RCL) from the anti-inflammatory function (globular surface). By mutating the RCL to abolish protease inhibition, the patent isolates and enhances the anti-inflammatory properties that reside in other regions of the protein structure, allowing independent optimization of therapeutic functions.
Solution Approach 2:
The patent applies local quality by making specific mutations at defined positions (e.g., Pro357Cys) in the RCL while leaving the rest of the protein structure intact. This localized modification approach preserves the globular surface properties that mediate anti-inflammatory effects while specifically altering the RCL to eliminate protease inhibition.
2Productivity
If specific amino acid mutations are introduced at position 357, then anti-inflammatory and wound healing properties are enhanced, but the protein structure may be altered
Solution Approach 1:
The patent systematically changes the amino acid parameter at position 357 (Proline to Cysteine, Alanine, or Methionine) to optimize anti-inflammatory and wound healing properties. These parameter changes are carefully selected to enhance therapeutic efficacy while maintaining overall protein structural integrity through the globular domain.
3Reliability
If mutant AAT polypeptides are developed with enhanced therapeutic properties, then treatment effectiveness improves, but the complexity of protein engineering increases
Solution Approach 1:
The patent extracts the anti-inflammatory and wound healing functions from the conventional protease-inhibition paradigm by abolishing the latter through RCL mutation. This extraction allows the patent to focus protein engineering efforts on enhancing only the desired therapeutic properties without the confounding variable of protease inhibition.
Data Source
AI summary
The present invention provides mutant alpha 1-antitrypsin proteins, pharmaceutical compositions comprising the same, and methods of use thereof in treatment of subjects with an inflammatory disease or disorder.