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Bulletin of Experimental Biology and Medicine, Vol. 145, No. 1, 2008 PHARMACOLOGY AND TOXICOLOGY
51
Anticoagulant Activity of Original Synthetic Peptide Derivatives
N. N. Drozd, A. S. Tolstenkov, V. A. Makarov,N. T. Miphtakhova, T. L. Voyushina*, and M. E. Sergeev*
Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 145, No. 1, pp. 57-60, January, 2008 Original article submitted January 29, 2007
Original synthetic peptide derivatives exhibit anticoagulant activity in vitro and in vivo. They delayed fibrin clot formation from human blood plasma in tests for the intrinsic coagulation pathway (activated partial thromboplastin time) and final stage of plasma coagulation (thrombin time) and inhibited amidolytic activity of thrombin. We determined the minimum effective dose of the most active compound providing a 2-fold lengthening of blood clotting time (activated partial thromboplastin time test and thrombin time test), which persisted for 2-3 h.
Key Words: synthetic peptide derivatives; anticoagulant activity; thrombin inhibition; pharmacodynamics
Vascular thromboses often cause disability and death. Thrombin, the key enzyme of the blood coagulation cascade, which plays the major role in physiological (hemostasis) and pathological (thrombosis) processes, contributes to transformation of plasma-soluble fibrinogen into plasma-insoluble fibrin, and activates blood coagulation factors V, VIII, XI, and XIII and proteinase-activated platelet receptors [1,10]. Apart from standard anticoagulant heparin and warfarin, direct thrombin inhibitor proteins (recombinant hirudins and synthetic hirudin analogues capable of binding to the active site of thrombin and fibrinogen-binding site) [3-8] and analogues of amino acids and short peptides (agmatine, argatroban, and melagatran) are used in clinical practice for the prevention and therapy of thromboses.
This work was designed to perform a search for direct thrombin inhibitors among synthetic peptide derivatives with different structure.
MATERIALS AND METHODS
Peptide derivatives were synthesized at the Laboratory of Peptide Chemistry (Federal State Unitary Enterprise State Research Institute for Genetics and Selection of Industrial Microorganisms). Experiments were performed with ZAla-Ala-Arg-Pip*TFA (peptide 1, molecular weight 632 Da), ZAla-Ala-Arg-Mf*HBr (peptide 2, molecular weight 601 Da), As-Trp-Arg-Mf*HCl (peptide 3, molecular weight 508 Da), Fta-Gly-Arg-Pip*TFA (peptide 4, molecular weight 560 Da), and AsTrp-Arg-Pip*TFA (peptide 5, molecular weight 584 Da).
The ability of synthetic peptide derivatives 1, 2, and 3 to inhibit fibrin clot formation from human blood plasma was estimated in the activated partial thromboplastin time (APTT) test and thrombin time...