title: A highly constrained cyclic (S,S)-CDC- peptide is a potent inhibitor of carotid artery thrombosis in rabbits.
abstract: Inhibition of platelet aggregation is indispensable for the treatment of acute arterial thrombotic episodes. We have previously reported the synthesis of a highly constrained cyclic peptide, that incorporates the -CDC- sequence, (S,S) PSRCDCR-NH(2), which potently inhibits aggregation and fibrinogen binding to human platelets in vitro. We have tested the safety and efficacy of the peptide on the electrically induced carotid artery thrombosis experimental rabbit model. The peptide's effects on carotid blood flow, thrombus weight, in vitro and ex vivo platelet aggregation, and bleeding and hemostatic parameters were evaluated. The peptide was administered via the femoral vein. Carotid blood flow was continuously monitored for 90 min after electrical thrombus formation. The peptide, at 12 mg/kg, prevented total artery occlusion and significantly preserved carotid artery's patency compared with placebo and eptifibatide. Furthermore, (S,S) PSRCDCR-NH(2) administration at 12 mg/kg reduced thrombus weight, whereas it inhibited ex vivo ADP, arachidonic acid (AA) and collagen-induced platelet aggregation. Moreover (S,S) PSRCDCR-NH(2) at 12 mg/kg presented significantly higher inhibitory effects on AA and collagen-induced ex vivo platelet aggregation compared to eptifibatide. The peptide at any dose did not affect the coagulation cascade, the bleeding times or the hemostatic response of the animals. Thus highly constrained cyclic peptides like (S,S) PSRCDCR-NH(2) that incorporate the -CDC- motif and fulfil certain conformational criteria represent novel compounds that potently inhibit thrombus formation, ex vivo platelet aggregation and carotid artery occlusion superiorly to other non-RGD peptides, such as YMESRADR, without causing hemorrhagic complications in a rabbit model of arterial thrombosis.
authors.affiliation: University of Ioannina, Department of Cardiology, Ioannina, Greece.
authors.forename: Vassiliki D
authors.initials: VD
authors.lastname: Roussa
authors.forename: Eleni M
authors.initials: EM
authors.lastname: Stathopoulou
authors.forename: Nikolaos D
authors.initials: ND
authors.lastname: Papamichael
authors.forename: Constantinos V
authors.initials: CV
authors.lastname: Englezopoulos
authors.forename: Kleopatra I
authors.initials: KI
authors.lastname: Rousouli
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Trypou
authors.forename: Vassilios
authors.initials: V
authors.lastname: Moussis
authors.forename: Constantinos C
authors.initials: CC
authors.lastname: Tellis
authors.forename: Christos S
authors.initials: CS
authors.lastname: Katsouras
authors.forename: Vassilios
authors.initials: V
authors.lastname: Tsikaris
authors.forename: Alexandros D
authors.initials: AD
authors.lastname: Tselepis
authors.forename: Lampros K
authors.initials: LK
authors.lastname: Michalis
mesh_terms: D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects*; D002339:Carotid Arteries / Q000187:drug effects* / Q000473:pathology; D002341:Carotid Artery Thrombosis / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D003094:Collagen / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004558:Electric Stimulation; D000077542:Eptifibatide; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D011817:Rabbits; D013927:Thrombosis / Q000188:drug therapy / Q000517:prevention & control
chemical_list: D010455:Peptides; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D016718:Arachidonic Acid; D000244:Adenosine Diphosphate; D003094:Collagen; D000077542:Eptifibatide