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 Blood, 2 July 2009, Vol. 114, No. 1, pp. 195-201.
Prepublished online as a Blood First Edition Paper on May 4, 2009; DOI 10.1182/blood-2008-08-169243.

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THROMBOSIS AND HEMOSTASIS

Structural and therapeutic insights from the species specificity and in vivo antithrombotic activity of a novel {alpha}IIb-specific {alpha}IIbβ3 antagonist

Robert Blue1, M. Anna Kowalska2, Jessica Hirsch2, Marta Murcia3, Christin A. Janczak1, Amanda Harrington1, Marketa Jirouskova1, Jihong Li1, Rudy Fuentes2, Michael A. Thornton4, Marta Filizola3, Mortimer Poncz2, and Barry S. Coller1

1 Laboratory of Blood and Vascular Biology, Rockefeller University, New York, NY; 2 Division of Hematology, Children's Hospital of Philadelphia, PA; 3 Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY; and 4 Department of Biology, Florida A&M University, Tallahassee

We previously reported on a novel compound (Compound 1; RUC-1) identified by high-throughput screening that inhibits human {alpha}IIbβ3. RUC-1 did not inhibit {alpha}Vβ3, suggesting that it interacts with {alpha}IIb, and flexible ligand/rigid protein molecular docking studies supported this speculation. We have now studied RUC-1's effects on murine and rat platelets, which are less sensitive than human to inhibition by Arg-Gly-Asp (RGD) peptides due to differences in the {alpha}IIb sequences contributing to the binding pocket. We found that RUC-1 was much less potent in inhibiting aggregation of murine and rat platelets. Moreover, RUC-1 potently inhibited fibrinogen binding to murine platelets expressing a hybrid {alpha}IIbβ3 receptor composed of human {alpha}IIb and murine β3, but not a hybrid receptor composed of murine {alpha}IIb and human β3. Molecular docking studies of RUC-1 were consistent with the functional data. In vivo studies of RUC-1 administered intraperitoneally at a dose of 26.5 mg/kg demonstrated antithrombotic effects in both ferric chloride carotid artery and laser-induced microvascular injury models in mice with hybrid h{alpha}IIb/mβ3 receptors. Collectively, these data support RUC-1's specificity for {alpha}IIb, provide new insights into the {alpha}IIb binding pocket, and establish RUC-1's antithrombotic effects in vivo.


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