Research ArticleCardiovascular Disease

Structure-Guided Design of a High-Affinity Platelet Integrin αIIbβ3 Receptor Antagonist That Disrupts Mg2+ Binding to the MIDAS

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Science Translational Medicine  14 Mar 2012:
Vol. 4, Issue 125, pp. 125ra32
DOI: 10.1126/scitranslmed.3003576

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Free-Flowing Blood

The αIIbβ3 integrin receptor, found on the surface of platelets, is central to the aggregation of platelets. This coagulation stops bleeding but, if unchecked, contributes to thrombosis, heart attacks, and some forms of stroke. Currently, there are three approved medications that block the integrin receptor and inhibit thrombosis, but they require intravenous administration and have the side effect of causing low platelet counts in some patients. The current study builds on previous research in which high-throughput screening identified a small molecule that could inhibit the receptor by binding to the αIIb subunit. An improved version of that compound, called RUC-2, also binds the αIIb subunit but, in addition, binds to the β3 subunit in an unprecedented way that prevents the binding of a vital Mg2+ ion to its usual site, preventing ligand binding and platelet aggregation. RUC-2 differs from drugs that were developed for oral therapy but failed during development as a result of increased mortality and low platelet counts. Unlike these drugs, RUC-2 does not induce the structural changes in the β3 subunit that may contribute to these adverse effects. RUC-2 could, therefore, have significant advantages over existing drugs, although this still needs to be tested directly in patients.

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