Su Xing-li, Su Wen, He Zhi-long, Ming Xin, Kong Yi
*Division of Biopharmaceutical Science, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China; †Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina, Chapel Hill, NC; and ‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
J Cardiovasc Pharmacol. 2015 Sep;66(3):254-60. doi: 10.1097/FJC.0000000000000269.
Centipede has been prescribed for the treatment of cardiovascular diseases in Asian countries for several hundred years. Previously, a new antiplatelet tripeptide SQL (H-Ser-Gln-Leu-OH) was isolated and characterized from centipede. In this study, we investigated its antithrombotic activities in vivo and underlying mechanism. It was found that SQL inhibited platelet aggregation induced by adenosine diphosphate, thrombin, epinephrine, and collagen and attenuated thrombus formation in both the ferric chloride-induced arterial thrombosis model and arteriovenous shunt thrombosis model in rats. It did not prolong the bleeding time in mice even at the dose of 10 mg/kg that showed potent antithrombosis effects. Molecular docking revealed that SQL binds PI3Kβ with the binding free energy of -24.341 kcal/mol, which is close to that of cocrystallized ligand (-24.220 kcal/mol). Additionally, SQL displayed inhibition on the late (180 seconds) but did not influence the early (60 seconds) Akt Ser473 phosphorylation in the immunoblot assay. These results suggest that SQL inhibits thrombus formation in vivo and that SQL inhibits PI3K-mediated signaling or even the PI3K itself in platelets. This study may help elucidate the mechanism for centipede treating cardiovascular diseases.
在亚洲国家，蜈蚣被用于治疗心血管疾病已有数百年历史。此前，从蜈蚣中分离并鉴定出一种新的抗血小板三肽SQL（H-Ser-Gln-Leu-OH）。在本研究中，我们研究了其体内抗血栓形成活性及潜在机制。结果发现，SQL可抑制二磷酸腺苷、凝血酶、肾上腺素和胶原诱导的血小板聚集，并减轻大鼠在氯化铁诱导的动脉血栓形成模型和动静脉分流血栓形成模型中的血栓形成。即使在显示出强效抗血栓形成作用的10 mg/kg剂量下，SQL也不会延长小鼠的出血时间。分子对接显示，SQL以-24.341 kcal/mol的结合自由能与PI3Kβ结合，这与共结晶配体的结合自由能（-24.220 kcal/mol）相近。此外，在免疫印迹分析中，SQL对晚期（180秒）Akt Ser473磷酸化有抑制作用，但对早期（60秒）无影响。这些结果表明，SQL在体内可抑制血栓形成，且SQL可抑制血小板中PI3K介导的信号传导甚至PI3K本身。本研究可能有助于阐明蜈蚣治疗心血管疾病的机制。
