A tryptophan derivative TD-26 attenuates thrombus formation by inhibiting both PI3K/Akt signaling and binding of fibrinogen to integrin alpha IIb beta 3

作者：Chen, Yahui; Wang, Ying; Xie, Zhouling; Ming, Xin; Li, Zhiyu; Kong, Yi^*

来源：Biochemical and Biophysical Research Communications, 2015, 465(3): 516-522.

DOI：10.1016/j.bbrc.2015.08.051

• Platelet aggregation
• Platelet adhesion
• Integrin alpha IIb beta 3
• PI3K/Akt signaling

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.

• 出版日期2015-9-25
• 单位中国药科大学