Suppression of arterial thrombosis without affecting hemostatic parameters with a cell-penetrating PAR1 pepducin.
Suppression of arterial thrombosis without affecting hemostatic parameters with a cell-penetrating PAR1 pepducin.
复制标题
DOI：
10.1161/circulationaha.112.091918
复制
发表时间：
2012-07-03
期刊：
影响因子：
37.8
通讯作者：
Kuliopulos A
中科院分区：
文献类型：
--
作者：
Zhang P;Gruber A;Kasuda S;Kimmelstiel C;O'Callaghan K;Cox DH;Bohm A;Baleja JD;Covic L;Kuliopulos A
凝血酶依赖性血小板活化在经皮冠状动脉介入治疗（PCI）中升高，并可能导致动脉血栓形成，随后发生心肌坏死。鉴于急性冠状动脉综合征（ACS）患者的不良反应发生率较高，因此仍需要开发靶向血小板活化而不过度影响止血的新疗法。凝血酶受体PAR 1最近成为ACS患者治疗干预的一个有前途的新靶点。我们报告了一种具有优化药代动力学特性的一流细胞内PAR 1抑制剂的开发，用于ACS患者PCI期间。PZ-128是PAR 1的细胞穿透性“肽蛋白”抑制剂，其靶向血小板内表面上的受体-G蛋白界面。PZ-128的结构非常类似于PAR 1第三胞内环的相应质膜区域的预测关闭状态。PZ-128起效迅速，可抑制豚鼠和狒狒的PAR 1聚集和动脉血栓形成，并与口服氯吡格雷有强烈协同作用。血小板功能在24小时内完全恢复。重要的是，PZ-128对灵长类动物或PCI患者血液中的出血或凝血参数没有影响。基于在非人灵长类动物中未观察到止血不良反应的有效性数据，我们预计PZ-128的快速起效血小板抑制作用和可逆性非常适合PCI的急性介入治疗，并可能成为PAR 1长效小分子抑制剂的替代药物。
Thrombin-dependent platelet activation is heightened in the setting of percutaneous coronary intervention (PCI) and may cause arterial thrombosis with consequent myocardial necrosis. Given the high incidence of adverse effects in patients with acute coronary syndromes (ACS), there remains an unmet need for the development of new therapeutics that target platelet activation without unduly affecting hemostasis. The thrombin receptor, PAR1, has recently emerged as a promising new target for therapeutic intervention in ACS patients. We report the development of a first-in-class intracellular PAR1 inhibitor with optimized pharmacokinetic properties for use during PCI in ACS patients. PZ-128 is a cell-penetrating ‘pepducin’ inhibitor of PAR1 which targets the receptor-G protein interface on the inside surface of platelets. The structure of PZ-128 closely resembles the predicted off-state of the corresponding juxtamembrane region of the third intracellular loop of PAR1. The onset of action of PZ-128 was rapid and suppressed PAR1 aggregation and arterial thrombosis in guinea pigs and baboons and strongly synergized with oral clopidogrel. There was full recovery of platelet function by 24 h. Importantly, PZ-128 had no effect on bleeding or coagulation parameters in primates or in blood from PCI patients. Based on the efficacy data in non-human primates with no noted adverse effects on hemostasis, we anticipate that the rapid onset of platelet inhibition and reversible properties of PZ-128 are well suited to the acute interventional setting of PCI and may provide an alternative to long-acting small molecule inhibitors of PAR1.