Thrombin Stabilization Peptides Autolysis Inhibition
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Solution Overview
Problem
Current methods for stabilizing thrombin in liquid formulations are inadequate, as they either lead to autolytic degradation or require refrigeration and protease inhibitors, which can compromise thrombin activity and are not feasible in all clinical settings.
Innovation Solution
The use of isolated peptides comprising the thrombin gamma loop sequence or interacting molecules that inhibit thrombin autolysis while preserving biological activity, allowing for extended shelf-life and stable thrombin activity without the need for refrigeration or dilution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If refrigeration is used to maintain thrombin stability, then thrombin shelf-life is extended, but clinical feasibility is reduced due to storage requirements
Solution Approach 1:
The patent changes the chemical parameter by introducing specific protease inhibitors (benzamidine, p-aminobenzamidine) that selectively inhibit thrombin autolysis without affecting its fibrinogen-cleaving activity. This allows thrombin to be stored at room temperature (changing storage temperature parameter) while maintaining stability, eliminating the need for refrigeration and improving clinical feasibility.
2Stability of the object's composition
If protease inhibitors are added to stabilize thrombin, then thrombin stability is improved, but thrombin activity is reduced due to inhibition
Solution Approach 1:
The patent applies local quality by using protease inhibitors that act selectively on specific aspects of thrombin behavior. Benzamidine and p-aminobenzamidine specifically inhibit thrombin's autolytic activity (protecting against self-degradation) while leaving its catalytic activity toward fibrinogen largely unaffected. This localized inhibition allows simultaneous achievement of stability and reliability.
Solution Approach 2:
The patent employs partial action by using sub-inhibitory concentrations of benzamidine or p-aminobenzamidine that are sufficient to prevent autolysis but do not completely block thrombin's fibrinogen-cleaving activity. The inhibitor concentration is carefully controlled to achieve partial protection without excessive inhibition, maintaining both stability and therapeutic effectiveness.
3Duration of action of stationary object
If thrombin is formulated with inhibitors to prevent autolysis, then shelf-life is extended, but effectiveness is reduced due to inhibition requiring dilution
Solution Approach 1:
The patent uses small molecule inhibitors (benzamidine, p-aminobenzamidine) that are chemically stable, inexpensive to produce, and can be easily formulated into the thrombin preparation. These small molecules provide long-term protection against autolysis without requiring complex stabilization systems, enabling extended shelf-life while maintaining simplicity and cost-effectiveness in the formulation.
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
These peptides effectively stabilize thrombin activity, maintaining its effectiveness towards fibrinogen conversion into fibrin, even at room temperature for extended periods, without significant inhibition, thus addressing the limitations of existing stabilization methods.
Implementation Method 1
isolated peptides comprising the amino acid sequence of the thrombin gamma loop and isolated peptides that are capable of interacting with the gamma loop of the thrombin
Data Source
AI summary
The present invention is directed to compounds useful in stabilizing thrombin activity, thrombin compositions comprising the compounds, methods of using the compounds and methods of identifying compounds capable of stabilizing thrombin activity. The compounds are preferably isolated peptides comprising or interacting with the gamma loop of thrombin.