Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10751526 | Biochemical and Biophysical Research Communications | 2015 | 7 Pages |
Abstract
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 αIIbβ3 and reduced AktSer473 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 αIIbβ3 inhibition and PI3K signaling blockage, with a low bleeding risk.
Related Topics
Life Sciences
Biochemistry, Genetics and Molecular Biology
Biochemistry
Authors
Yahui Chen, Ying Wang, Zhouling Xie, Xin Ming, Zhiyu Li, Yi Kong,