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首页> 外文期刊>Journal of Medicinal Chemistry >Targeting the GPIbα Binding Site of Thrombin To Simultaneously Induce Dual Anticoagulant and Antiplatelet Effects
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Targeting the GPIbα Binding Site of Thrombin To Simultaneously Induce Dual Anticoagulant and Antiplatelet Effects

机译：靶向凝血酶的GPIbα结合位点，同时诱导双重抗凝和抗血小板作用

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摘要

Exosite 2 of human thrombin contributes to two opposing pathways, the anticoagulant pathway and the platelet aggregation pathway. We reasoned that an exosite 2 directed allosteric thrombin inhibitor should simultaneously induce anticoagulant and antiplatelet effects. To assess this, we synthesized SbO4L based on the sulfated tyrosine-containing sequence of GPIbα. SbO4L was synthesized in three simple steps in high yield and found to be a highly selective, direct inhibitor of thrombin. Michelis?Menten kinetic studies indicated a noncompetitive mechanism of inhibition. Competitive inhibition studies suggested ideal competition with heparin and glycoprotein Ibα, as predicted. Studies with site-directed mutants of thrombin indicated that SbO4L binds to Arg233, Lys235, and Lys236 of exosite 2. SbO4L prevented thrombin-mediated platelet activation and aggregation as expected on the basis of competition with GPIbα. SbO4L presents a novel paradigm of simultaneous dual anticoagulant and antiplatelet effects achieved through the GPIbα binding site of thrombin.
机译：人凝血酶的异位点2参与两个相反的途径，即抗凝剂途径和血小板聚集途径。我们认为外位2定向变构凝血酶抑制剂应同时诱导抗凝和抗血小板作用。为了评估这一点，我们基于GPIbα的含硫酸酪氨酸序列合成了SbO4L。 SbO4L可以通过三个简单步骤以高收率合成，并且是凝血酶的高度选择性直接抑制剂。 Michelis？Menten动力学研究表明抑制作用是非竞争性的。竞争性抑制研究表明，与预期的肝素和糖蛋白Ibα理想竞争。用凝血酶的定点突变体进行的研究表明，SbO4L与异位点2的Arg233，Lys235和Lys236结合。根据与GPIbα的竞争，SbO4L可以防止凝血酶介导的血小板活化和聚集。 SbO4L提出了通过凝血酶的GPIbα结合位点实现的同时双重抗凝和抗血小板作用的新型范例。

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