THROMBOSTATIN--A SELECTIVE ANTITHROMBIN

描述：(改编自调查人员摘要)目的 研究目的是开发一种高度选择性的蛋白水解酶抑制剂 A-凝血酶，阻止其与血小板受体相互作用，但 不干扰α-凝血酶裂解其他底物。的假说 这一建议是，缓激肽相关序列是一种 -凝血酶裂解某些生理底物。开发一种高度 选择性凝血酶抑制剂靶向克隆的凝血酶受体 细胞将具有预防动脉血栓形成的适用性，因为 血小板血栓。新一代选择性α-凝血酶抑制剂 需要开发，因为非特异的蛋白水解酶抑制剂 A-凝血酶，如水飞蓟素和水飞蓟素，与脑容量增加有关 大出血。该项目将创造一种新的选择性a-凝血酶 抑制剂。这些代理将是第二代的第一代 选择性阻断α-凝血酶S能力的凝血酶抑制剂 在不干扰其激活因子V的能力的情况下激活血小板 和VIII和凝血纤维蛋白原，这项提案的具体目标是 以下是： 1.RPPGF选择性抑制α-凝血酶的作用机制为 特色化的。将进行调查以确定RPPGF是否具有约束力 到表达克隆凝血酶受体的血小板和昆虫细胞。 此外，还将进行调查，以确定RPPGF是否与 蛋白C和蛋白S。 2.RPPGF抑制α-凝血酶的结构要求为 以开发一种新的类别的 选择性的a-凝血酶抑制剂。 3.将在兔身上进行动物实验，以确定 这些多肽在体内模型中预防动脉血栓形成的有效性。 这些拟议的调查将确定抑制的机制和 RPPGF及其聚集物作为选择性抗凝血剂的疗效观察这些 研究应该表征一类新的a-凝血酶抑制剂 这抑制了这种酶切割克隆的凝血酶受体的能力。 这些研究的重要性在于它们可以介绍一部小说 预防动脉血栓形成的药理学方法。

DESCRIPTION: (Adapted from investigator's abstract) The purpose of this investigation is to develop a highly selective proteolytic inhibitor of a-thrombin that prevents its interaction with platelet receptors but does not interfere wit a-thrombin cleaving other substrates. The hypothesis of this proposal is that bradykinin-related sequences are inhibitors of a -thrombin cleaving certain physiologic substrates. Developing a highly selective thrombin inhibitor directed to the cloned thrombin receptor on cells would have applicability to prevent arterial thrombosis due to platelet thrombus. A new generation of selective a-thrombin inhibitors needs to be developed since nonspecific proteolytic inhibitors of a-thrombin, e.g. hirudin and hirulog, are associated with increased cerebral hemorrhage. This project will create a new class of selective a-thrombin inhibitors. These agents will be the first of a second generation a-thrombin inhibitors that selectively block a-thrombin s ability to activate platelets without interfering with its ability to activate factor V and VIII and clot fibrinogen The specific aims of this proposal are as follows: 1. The mechanism of selective inhibition of a-thrombin by RPPGF will be characterized. Investigations will be performed to determine if RPPGF binds to platelets and insect cells which express the clone thrombin receptor. Further, investigations will be performed to determine if RPPGF binds to Protein C and Protein S. 2. The structural requirements for RPPGF to inhibit a-thrombin will be characterized with the aim towards the development of a novel class of selective, a-thrombin inhibitors. 3. Animal experiments will be performed in rabbits to determine the efficacy of these peptides to prevent arterial thrombosis in vivo models. These proposed investigations will determine the mechanism of inhibition and efficacy of using RPPGF and its congers as selective anti-thrombins. These investigations should characterize a new class of a-thrombin inhibitors which inhibit this enzyme's ability to cleave the cloned thrombin receptor. The importance of these studies is that they could introduce a novel pharmacologic approach to prevent arterial thrombosis.