A tryptophan derivative TD-26 attenuates thrombus formation by inhibiting both PI3K/Akt signaling and binding of fibrinogen to integrin αIIbβ3
A tryptophan derivative TD-26 attenuates thrombus formation by inhibiting both PI3K/Akt signaling and binding of fibrinogen to integrin αIIbβ3
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DOI：
10.1016/j.bbrc.2015.08.051
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发表时间：
2015-09-25
影响因子：
3.1
通讯作者：
Kong, Yi
中科院分区：
文献类型：
--
作者：
Chen, Yahui;Wang, Ying;Kong, Yi
血栓性疾病的发病率和死亡率在世界范围内迅速增加。然而，现有的抗血栓药物与副作用有关，特别是出血并发症。因此，仍然需要开发更有效和更安全的抗血栓形成剂。本研究发现了一种新的色氨酸衍生物TD-26，它对血小板聚集有很强的抑制作用，而不会引起明显的出血危险。TD-26在体外抑制ADP、凝血酶、U46619和胶原诱导的血小板聚集，在体外抑制ADP诱导的血小板聚集。机制研究表明，TD-26抑制血小板粘附到纤维蛋白原包被的表面，阻断纤维蛋白原与整合素α IIb β 3的结合，并减少血小板磷脂酰肌醇3-激酶（PI 3 K）信号转导中Akt（ser 473）的磷酸化。此外，TD-26在体内表现出有效的抗血栓形成活性。在动物模型中，它使急性肺血栓形成小鼠的死亡率降低90%，血栓重量减轻60.3%，剂量均为3 mg/kg。TD-26对小鼠出血时间无明显延长作用。总而言之，我们的结果表明TD-26是一种新型抗血栓化合物，具有整合素α IIb β 3抑制作用和PI 3 K信号传导阻滞作用，且出血风险低。(C)2015 Elsevier Inc. All rights reserved.
The incidence and mortality of thrombotic disorders are rapidly increasing worldwide. The existing antithrombotic drugs, however, are associated with side effects, especially bleeding complications. Therefore, there remains a need for the development of more effective and safer antithrombotic agents. In this study, we discovered a new synthetic tryptophan derivative TD-26, producing potent inhibitory effect on platelet aggregation while without causing obvious bleeding risk. It has been shown that TD-26 inhibited platelet aggregation induced by ADP, thrombin, U46619 and collagen in vitro and suppressed the platelet aggregation induced by ADP ex vivo. Mechanism studies indicated that TD-26 inhibited platelet adhesion to fibrinogen-coated surfaces, blocked the binding of fibrinogen to integrin alpha IIb beta 3 and reduced Akt(ser473) phosphorylation in platelet phosphatidylinositol 3-kinase (PI3K) signaling. Furthermore, TD-26 exhibited potent antithrombotic activity in vivo. In animal models, it decreased death of mice with acute pulmonary thrombosis by 90% and attenuated thrombosis weight by 60.3%, both at a dose of 3 mg/kg. Additionally, TD-26 did not obviously prolong bleeding time in mice. Taken together, our results reveal that TD-26 is a novel antithrombotic compound exhibiting both integrin alpha IIb beta 3 inhibition and PI3K signaling blockage, with a low bleeding risk. (C) 2015 Elsevier Inc. All rights reserved.