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Inhibition of Df-protease--induced kinin release by synthetic inhibitors
Y Noguchi1, A Matsushima, R Ohmura
1Toin Human Science and Technology Center, Department of Material Science and Technology, Toin University of Yokohama, Japan.
Abstract:
A protease (Df-protease) from house dust mite (D. farinae) is closely associated with mite-induced allergy: Df-protease has a similar substrate specificity to blood coagulation factor XIIa and catalyzes the activation of kallikrein-kinin system in human plasma. With the purpose of prevention of kinin-formation in plasma by Df-protease, inhibition of Df-protease with synthetic inhibitors was tested in vivo and in vitro. Among the inhibitors, including amidine and guanidine derivatives, N-allyl-N-[4-(4-amidinophenoxycarbonyl)-alpha-methylcinnamoyl++ +]glycine ethyl ester mesylate was the most effective to inhibit Df-protease with Ki = 9 x 10(-9) M and also to prevent kinin-release from Df-protease in human plasma. Enhancement of vascular permeability in guinea pigs caused by kinin-release was stoichiometrically suppressed by the inhibitor.
Insights
A house dust mite protease triggers allergic reactions by activating the kinin system. A novel synthetic inhibitor effectively blocked this protease, preventing kinin release and reducing allergic inflammation in vivo.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- House dust mite (D. farinae) protease (Df-protease) is linked to mite-induced allergies.
- Df-protease activates the kallikrein-kinin system in human plasma, similar to coagulation factor XIIa.
Purpose of the Study:
- To prevent kinin formation in plasma mediated by Df-protease.
- To identify and evaluate synthetic inhibitors of Df-protease.
Main Methods:
- In vitro and in vivo testing of synthetic inhibitors, including amidine and guanidine derivatives.
- Assay of Df-protease inhibition and kinin release.
- Assessment of vascular permeability changes in guinea pigs.
Main Results:
- N-allyl-N-[4-(4-amidinophenoxycarbonyl)-alpha-methylcinnamoyl]glycine ethyl ester mesylate demonstrated potent inhibition of Df-protease (Ki = 9 x 10(-9) M).
- The inhibitor effectively prevented Df-protease-induced kinin release in human plasma.
- Stoichiometric suppression of kinin-induced vascular permeability enhancement was observed in guinea pigs.
Conclusions:
- A specific synthetic inhibitor can effectively block Df-protease activity.
- Inhibition of Df-protease offers a potential therapeutic strategy for mite-induced allergies by preventing kinin pathway activation.