THROMBOSTATIN--A SELECTIVE ANTITHROMBIN

描述：（改编自研究者摘要） 研究是开发一种高选择性的蛋白水解抑制剂， a-凝血酶，阻止其与血小板受体的相互作用， 不干扰α-凝血酶裂解其它底物。 的假设 这一提议是缓激肽相关序列是一种抑制剂， - 凝血酶裂解某些生理底物。 发展一个高度 针对克隆的凝血酶受体的选择性凝血酶抑制剂， 细胞将具有防止动脉血栓形成的适用性， 血小板血栓 新一代选择性α-凝血酶抑制剂 需要开发，因为非特异性蛋白水解抑制剂， α-凝血酶，例如水蛭素和水蛭素，与脑血管病的增加有关。 出血 该项目将创造一种新的选择性α-凝血酶 抑制剂的 这些特工将是第二代特工 选择性阻断α-凝血酶的能力的α-凝血酶抑制剂， 激活血小板而不干扰其激活因子V的能力 本建议的具体目的是， 如下所示： 1. RPPGF选择性抑制α-凝血酶的机制将是 表征了 将进行研究以确定RPPGF是否结合 表达克隆凝血酶受体的血小板和昆虫细胞。 此外，将进行研究以确定RPPGF是否与 蛋白质C和蛋白质S 2. RPPGF抑制α-凝血酶的结构要求如下： 其特点是旨在发展一个新的阶级， 选择性α-凝血酶抑制剂。 3. 将在兔子中进行动物实验以确定 这些肽在体内模型中预防动脉血栓形成的功效。 这些拟议的研究将确定抑制机制， RPPGF及其康格斯作为选择性抗凝血酶的疗效。 这些 研究应表征一类新的α-凝血酶抑制剂 抑制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引入一部小说 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.