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Blood. 2009 Jul 2;114(1):195-201. doi: 10.1182/blood-2008-08-169243. Epub 2009 May 4.

Structural and therapeutic insights from the species specificity and in vivo antithrombotic activity of a novel alphaIIb-specific alphaIIbbeta3 antagonist.

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1
Laboratory of Blood and Vascular Biology, Rockefeller University, New York, NY 10065, USA.

Abstract

We previously reported on a novel compound (Compound 1; RUC-1) identified by high-throughput screening that inhibits human alphaIIbbeta3. RUC-1 did not inhibit alphaVbeta3, suggesting that it interacts with alphaIIb, 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 alphaIIb 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 alphaIIbbeta3 receptor composed of human alphaIIb and murine beta3, but not a hybrid receptor composed of murine alphaIIb and human beta3. 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 halphaIIb/mbeta3 receptors. Collectively, these data support RUC-1's specificity for alphaIIb, provide new insights into the alphaIIb binding pocket, and establish RUC-1's antithrombotic effects in vivo.

PMID:
19414864
PMCID:
PMC2710948
DOI:
10.1182/blood-2008-08-169243
[Indexed for MEDLINE]
Free PMC Article

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