Structural and therapeutic insights from the species specificity and in vivo antithrombotic activity of a novel αIIb-specific αIIbβ3 antagonist

Robert Blue, M. Anna Kowalska, Jessica Hirsch, Marta Murcia, Christin A. Janczak, Amanda Harrington, Marketa Jirouskova, Jihong Li, Rudy Fuentes, Michael A. Thornton, Marta Filizola, Mortimer Poncz, Barry S. Coller

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

We previously reported on a novel compound (Compound 1; RUC-1) identified by high-throughput screening that inhibits human αIIbβ3. RUC-1 did not inhibit αVβ3, suggesting that it interacts with αIIb, 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 αIIb 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 αIIbβ3 receptor composed of human αIIb and murine β3, but not a hybrid receptor composed of murine αIIb 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 hαIIb/mβ3 receptors. Collectively, these data support RUC-1's specificity for αIIb, provide new insights into the αIIb binding pocket, and establish RUC-1's antithrombotic effects in vivo.

Original languageEnglish
Pages (from-to)195-201
Number of pages7
JournalBlood
Volume114
Issue number1
DOIs
StatePublished - 2009

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