Antithrombotic effects of NE-6505, a novel anion-binding exosite inhibitor.
NF-6505, a bi-O-Tyr-sulfated decapeptide, which specifically interacts with the anion-binding exosite of the thrombin molecule, was chemically synthesized and assessed for its antithrombotic effects in vitro and in vivo. The IC50 value of this peptide on fibrin-clot formation in vitro was about 0.05 microgram/ml, which indicated a potency similar to that of a recombinant hirudin. NF-6505 caused a 2-fold prolongation of activated partial thromboplastin time when intravenously administered at 1 mg/kg in rats. In a rat venous thrombosis model, a bolus intravenous administration of this peptide dose-dependently inhibited the thrombus formation with an ED50 value of 0.03 mg/kg, a value smaller than that of recombinant hirudin (ED50 = 0.1 mg/kg) or of argatroban (ED50 = 0.2 mg/kg). These results suggest that NF-6505 is a highly potent and safe agent for the clinical treatment of venous thrombosis diseases.
Muramatsu
R
R
Pharmaceuticals and Biotechnology Laboratory, Japan Energy Corporation, Saitama, Japan.
Sasaki
M
M
Watanabe
N
N
Goto
Y
Y
Okayama
T
T
Nukui
E
E
Morikawa
T
T
Hayashi
H
H
D000595:Amino Acid Sequence; D000818:Animals; D000838:Anions; D001665:Binding Sites; D001777:Blood Coagulation / Q000187:drug effects; D004195:Disease Models, Animal; D005337:Fibrin / Q000378:metabolism; D006629:Hirudins / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010314:Partial Thromboplastin Time; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013924:Thrombophlebitis / Q000097:blood / Q000188:drug therapy / Q000517:prevention & control*
D000838:Anions; D006629:Hirudins; C107767:NF 6505; D009842:Oligopeptides; D005337:Fibrin; D013917:Thrombin