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Effect of a synthetic thrombin-inhibitor MD805 on the reaction between thrombin and plasma antithrombin-III
A Hijikata-Okunomiya1, S Okamoto, K Wanaka
1School of Allied Medical Sciences, Kobe University, Japan.
Abstract:
MD805, a synthetic thrombin-inhibitor, effectively retarded the time-dependent inactivation of thrombin which was generated endogeneously or added exogeneously in human plasma. The kinetical study of the time-dependent inactivation indicated that the type of inhibition was competitive and the obtained Ki of MD805 for thrombin was 3 x 10(-8)M. MD805 also inhibited the formation of thrombin-ATIII complex. These results indicated that the active site of thrombin was involved in the reaction between thrombin and ATIII, and that MD805 competed with ATIII for thrombin in exactly the same manner as it competed with fibrinogen or synthetic peptide substrates. As a result, MD805 would serve as a protective agent for ATIII from being consumed, in addition to its potent thrombin-inhibitory activity without the aid of ATIII. By contrast, heparin accelerated the time-dependent inactivation rate of thrombin and the formation of thrombin-ATIII complex, which indicates that heparin accelerates the consumption of ATIII.
Insights
MD805, a synthetic thrombin inhibitor, protects antithrombin III (ATIII) from consumption by inhibiting thrombin. This contrasts with heparin, which accelerates ATIII consumption.
Area of Science:
- Biochemistry
- Pharmacology
- Hematology
Background:
- Thrombin plays a crucial role in hemostasis.
- Thrombin inactivation and complex formation with antithrombin III (ATIII) are key regulatory mechanisms.
- Understanding inhibitors of thrombin is vital for anticoagulant therapy.
Purpose of the Study:
- To investigate the inhibitory mechanism of MD805 on thrombin.
- To determine the effect of MD805 on thrombin-antithrombin III (ATIII) complex formation.
- To compare the action of MD805 with heparin regarding ATIII consumption.
Main Methods:
- Kinetical study of time-dependent thrombin inactivation in human plasma.
- Assay of thrombin-ATIII complex formation.
- Competitive inhibition analysis.
Main Results:
- MD805 significantly retarded the inactivation of both endogenous and exogenous thrombin.
- MD805 demonstrated competitive inhibition of thrombin with a Ki of 3 x 10(-8)M.
- MD805 inhibited thrombin-ATIII complex formation, indicating competition for thrombin's active site.
- Heparin accelerated thrombin inactivation and thrombin-ATIII complex formation, thus increasing ATIII consumption.
Conclusions:
- MD805 acts as a potent thrombin inhibitor by competitively binding to its active site.
- MD805 protects ATIII from consumption, offering a potential therapeutic advantage.
- MD805's mechanism differs from heparin, which promotes ATIII consumption.