LX0702, a novel snake venom peptide derivative, inhibits thrombus formation via affecting the binding of fibrinogen with GPIIb/IIIa.
Based on the structure of AAP, a novel anti-thrombotic peptide from snake venom which we discovered in our previous study, more than 60 compounds were designed and synthesized. One of these termed as LX0702 exhibited stronger anti-platelet aggregation activity than AAP. This study aims to investigate the effects of LX0702 on anti-thrombotic formation and its underlying mechanism. We found that LX0702 inhibited platelet aggregation induced by ADP, thrombin and collagen in a dose dependent manner, with IC50 values of 49.90 ± 2.03, 50.65 ± 0.34 and 83.90 ± 2.06 μM, respectively. It also inhibited thrombus formation in the rat arterio-venous shunt model. In addition, the effect of LX0702 on hemostasis system was tested. Compared to control saline, bleeding time was not prolonged. Furthermore, the ELISA revealed that LX0702 inhibited fibrinogen binding with GPIIb/IIIa in a dose dependent manner with an IC50 value of 1.26 ± 0.13 μM. These findings clearly demonstrate that LX0702 has anti-platelet/anti-thrombotic effects without increased bleeding risk. Therefore it might be developed into an effective drug for the prevention or treatment of thrombotic diseases.
School of Life Science & Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: yikong668@163.com.
Yi
Y
Kong
School of Life Science & Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, PR China.
Ying
Y
Wang
School of Life Science & Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, PR China.
Wei
W
Yang
School of Pharmacy, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, PR China.
Zhouling
Z
Xie
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; School of Pharmacy, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, PR China. Electronic address: zhiyuli@263.net.
Zhiyu
Z
Li
D000818:Animals; D001760:Bleeding Time; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D005343:Fibrinolytic Agents; D008297:Male; D008813:Mice, Inbred ICR; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011817:Rabbits; D017207:Rats, Sprague-Dawley; D012910:Snake Venoms / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013927:Thrombosis / Q000517:prevention & control*; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology
D005343:Fibrinolytic Agents; C000605756:LX0702; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D012910:Snake Venoms; D013449:Sulfonamides; D014364:Tryptophan; D005340:Fibrinogen
Arterio-venous shunt; Bleeding risk; GPIIb/IIIa receptor; Platelet aggregation; Thrombosis