Abstract
Thrombin is a key enzyme of blood coagulation system which has multiple functions including pro- and anticoagulant, platelet aggregating and inflammatory activities. Unsurprisingly, this enzyme has been a target for anticoagulant drug development for decades. Among the most interesting direct thrombin inhibitors with intravenous administration route are the following ones: 1) hirudins, proteins with bivalent binding mode to the thrombin, 2) bivalirudin, the peptide with bivalent binding mode to the thrombin, 3) argatroban, the chemical that binds to the thrombin active site, and 4) G-quadruplex DNA aptamers, structured oligonucleotides with an affinity to protein-binding site of the thrombin. Efficiency of all these inhibitors has been studied in vivo in preclinical and clinical trials, as well as in vitro with various tests, allowing to compare them thoroughly.
In the review three levels of comparison were used to highlight the features of each inhibitor: 1) thrombin inhibition constants as a characteristic of inhibitor potency in simple enzymatic system; 2) inhibition of fibrin fiber formation and thrombin generation in coagulation cascade as a characteristic of anticoagulant potency in human blood plasma; and 3) therapeutic doses used and therapeutic profiles obtained after intravenous administration into animals and humans. The data clearly demonstrate weak and strong aspects of thrombin binding aptamers providing a solid background for further novel anticoagulant development.
Keywords: Anticoagulant, Aptamer, Coagulation, Inhibitor, Thrombin, Thrombin generation test.
Current Medicinal Chemistry
Title:G-Quadruplex Aptamers to Human Thrombin Versus Other Direct Thrombin Inhibitors: The Focus on Mechanism of Action and Drug Efficiency as Anticoagulants
Volume: 23 Issue: 21
Author(s): Elena Zavyalova, Nikita Ustinov, Andrey Golovin, Galina Pavlova and Alexey Kopylov
Affiliation:
Keywords: Anticoagulant, Aptamer, Coagulation, Inhibitor, Thrombin, Thrombin generation test.
Abstract: Thrombin is a key enzyme of blood coagulation system which has multiple functions including pro- and anticoagulant, platelet aggregating and inflammatory activities. Unsurprisingly, this enzyme has been a target for anticoagulant drug development for decades. Among the most interesting direct thrombin inhibitors with intravenous administration route are the following ones: 1) hirudins, proteins with bivalent binding mode to the thrombin, 2) bivalirudin, the peptide with bivalent binding mode to the thrombin, 3) argatroban, the chemical that binds to the thrombin active site, and 4) G-quadruplex DNA aptamers, structured oligonucleotides with an affinity to protein-binding site of the thrombin. Efficiency of all these inhibitors has been studied in vivo in preclinical and clinical trials, as well as in vitro with various tests, allowing to compare them thoroughly.
In the review three levels of comparison were used to highlight the features of each inhibitor: 1) thrombin inhibition constants as a characteristic of inhibitor potency in simple enzymatic system; 2) inhibition of fibrin fiber formation and thrombin generation in coagulation cascade as a characteristic of anticoagulant potency in human blood plasma; and 3) therapeutic doses used and therapeutic profiles obtained after intravenous administration into animals and humans. The data clearly demonstrate weak and strong aspects of thrombin binding aptamers providing a solid background for further novel anticoagulant development.
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Zavyalova Elena, Ustinov Nikita, Golovin Andrey, Pavlova Galina and Kopylov Alexey, G-Quadruplex Aptamers to Human Thrombin Versus Other Direct Thrombin Inhibitors: The Focus on Mechanism of Action and Drug Efficiency as Anticoagulants, Current Medicinal Chemistry 2016; 23 (21) . https://dx.doi.org/10.2174/0929867323666160517120126
DOI https://dx.doi.org/10.2174/0929867323666160517120126 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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