Chen Meimei, Ye Xiaohui, Ming Xin, Chen Yahui, Wang Ying, Su Xingli, Su Wen, Kong Yi
School of Life Science &Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, PR China.
Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Sci Rep. 2015 Jun 2;5:10846. doi: 10.1038/srep10846.
Snake venom is a natural substance that contains numerous bioactive proteins and peptides, nearly all of which have been identified over the last several decades. In this study, we subjected snake venom to enzymatic hydrolysis to identify previously unreported bioactive peptides. The novel peptide ACH-11 with the sequence LTFPRIVFVLG was identified with both FXa inhibition and anti-platelet aggregation activities. ACH-11 inhibited the catalytic function of FXa towards its substrate S-2222 via a mixed model with a Ki value of 9.02 μM and inhibited platelet aggregation induced by ADP and U46619 in a dose-dependent manner. Furthermore, ACH-11 exhibited potent antithrombotic activity in vivo. It reduced paralysis and death in an acute pulmonary thrombosis model by 90% and attenuated thrombosis weight in an arterio-venous shunt thrombosis model by 57.91%, both at a dose of 3 mg/kg. Additionally, a tail cutting bleeding time assay revealed that ACH-11 did not prolong bleeding time in mice at a dose of 3 mg/kg. Together, our results reveal that ACH-11 is a novel antithrombotic peptide exhibiting both FXa inhibition and anti-platelet aggregation activities, with a low bleeding risk. We believe that it could be a candidate or lead compound for new antithrombotic drug development.
蛇毒是一种天然物质，含有众多生物活性蛋白质和肽类，在过去几十年里几乎所有这些成分都已被鉴定出来。在本研究中，我们对蛇毒进行酶解，以鉴定此前未报道的生物活性肽。鉴定出了具有LTFPRIVFVLG序列的新型肽ACH-11，它具有抑制凝血因子Xa（FXa）和抗血小板聚集活性。ACH-11通过混合模型抑制FXa对其底物S-2222的催化功能，抑制常数（Ki）值为9.02 μM，并以剂量依赖性方式抑制由二磷酸腺苷（ADP）和U46619诱导的血小板聚集。此外，ACH-11在体内表现出强大的抗血栓活性。在急性肺血栓形成模型中，它以3 mg/kg的剂量使瘫痪和死亡减少了90%；在动静脉分流血栓形成模型中，它使血栓重量减轻了57.91%。另外，断尾出血时间试验表明，3 mg/kg剂量的ACH-11不会延长小鼠的出血时间。总之，我们的结果表明，ACH-11是一种新型抗血栓肽，兼具抑制FXa和抗血小板聚集活性，且出血风险较低。我们认为它可能是新型抗血栓药物开发的候选物或先导化合物。
