title: Evaluation of antithrombotic activity of thrombin DNA aptamers by a murine thrombosis model.
abstract: Aptamers are nucleic acid based molecular recognition elements with a high potential for the theranostics. Some of the aptamers are under development for therapeutic applications as promising antithrombotic agents; and G-quadruplex DNA aptamers, which directly inhibit the thrombin activity, are among them. RA-36, the 31-meric DNA aptamer, consists of two thrombin binding pharmacophores joined with the thymine linker. It has been shown earlier that RA-36 directly inhibits thrombin in the reaction of fibrinogen hydrolysis, and also it inhibits plasma and blood coagulation. Studies of both inhibitory and anticoagulation effects had indicated rather high species specificity of the aptamer. Further R&D of RA-36 requires exploring its efficiency in vivo. Therefore the development of a robust and adequate animal model for effective physiological studies of aptamers is in high current demand. This work is devoted to in vivo study of the antithrombotic effect of RA-36 aptamer. A murine model of thrombosis has been applied to reveal a lag and even prevention of thrombus formation when RA-36 was intravenous bolus injected in high doses of 1.4-7.1 µmol/kg (14-70 mg/kg). A comparative study of RA-36 aptamer and bivalirudin reveals that both direct thrombin inhibitors have similar antithrombotic effects for the murine model of thrombosis; though in vitro bivalirudin has anticoagulation activity several times higher compared to RA-36. The results indicate that both RA-36 aptamer and bivalirudin are direct thrombin inhibitors of different potency, but possible interactions of the thrombin-inhibitor complex with other components of blood coagulation cascade level the physiological effects for both inhibitors.
authors.affiliation: Chemistry Department of Lomonosov Moscow State University, Moscow, Russian Federation; 'APTO-PHARM' LTD, Moscow, Russian Federation.
authors.forename: Elena
authors.initials: E
authors.lastname: Zavyalova
authors.affiliation: 'APTO-PHARM' LTD, Moscow, Russian Federation; Institute of Gene Biology of Russian Academy of Sciences, Moscow, Russian Federation.
authors.forename: Nadezhda
authors.initials: N
authors.lastname: Samoylenkova
authors.affiliation: Institute of Gene Biology of Russian Academy of Sciences, Moscow, Russian Federation.
authors.forename: Alexander
authors.initials: A
authors.lastname: Revishchin
authors.affiliation: 'APTO-PHARM' LTD, Moscow, Russian Federation; Department of Bioengineering and Bioinformatics of Lomonosov Moscow State University, Moscow, Russian Federation.
authors.forename: Andrey
authors.initials: A
authors.lastname: Golovin
authors.affiliation: 'APTO-PHARM' LTD, Moscow, Russian Federation; Institute of Gene Biology of Russian Academy of Sciences, Moscow, Russian Federation.
authors.forename: Galina
authors.initials: G
authors.lastname: Pavlova
authors.affiliation: Chemistry Department of Lomonosov Moscow State University, Moscow, Russian Federation; 'APTO-PHARM' LTD, Moscow, Russian Federation.
authors.forename: Alexey
authors.initials: A
authors.lastname: Kopylov
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use; D000991:Antithrombins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D052157:Aptamers, Nucleotide / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005340:Fibrinogen / Q000187:drug effects / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D054856:G-Quadruplexes; D006629:Hirudins / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013917:Thrombin / Q000037:antagonists & inhibitors; D013927:Thrombosis / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D052157:Aptamers, Nucleotide; D005343:Fibrinolytic Agents; D006629:Hirudins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D005340:Fibrinogen; D013917:Thrombin; C074619:bivalirudin