A tryptophan derivative TD-26 attenuates thrombus formation by inhibiting both PI3K/Akt signaling and binding of fibrinogen to integrin αIIbβ3.
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 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 αIIbβ3 inhibition and PI3K signaling blockage, with a low bleeding risk.
School of Life Science & Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, PR China.
Yahui
Y
Chen
School of Life Science & Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, PR China.
Ying
Y
Wang
School of Pharmacy, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, PR China.
Zhouling
Z
Xie
Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Xin
X
Ming
School of Pharmacy, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, PR China. Electronic address: zhiyuli@263.net.
Zhiyu
Z
Li
School of Life Science & Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, PR China. Electronic address: yikong668@163.com.
Yi
Y
Kong
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000008:administration & dosage; D051379:Mice; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D011485:Protein Binding; D011655:Pulmonary Embolism / Q000188:drug therapy* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015996:Survival Rate; D016896:Treatment Outcome; D014364:Tryptophan / Q000008:administration & dosage* / Q000031:analogs & derivatives*
D005343:Fibrinolytic Agents; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014364:Tryptophan; D005340:Fibrinogen; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt
Integrin αIIbβ3; PI3K/Akt signaling; Platelet adhesion; Platelet aggregation