PEPTIDE INHIBITORS OF THE PLATELET ADHESION RECEPTOR

血小板的粘附和聚集是血液中的关键事件 凝血 它是由粘附蛋白介导的， 血小板表面的受体。 受体结合到一个 共同识别结构，甘氨酸-天冬氨酸 (RGD)三肽序列，在粘附蛋白，包括 纤维蛋白原、纤连蛋白、玻连蛋白和血管性血友病因子 （vWF）。 其中两个，纤维连接蛋白和玻连蛋白，也介导 大多数类型的有核细胞的粘附。 另一方面，在一项研究中， 纤维蛋白原和vWF则没有。 这种差异化的认知是 通过粘附受体家族完成。 成纤维 在纤连蛋白中具有不同的RGD序列受体， 玻连蛋白，而在血小板中的共同受体（gpIIb/IIIa） 结合纤连蛋白、玻连蛋白、纤维蛋白原和vWF。 短的线性 含有RGD序列的肽抑制每一个的功能， 其中一个受体。 本文提出的工作的目的是设计肽， 会选择性地抑制血小板受体的功能 到 为了获得这样的肽，我们将合成肽类似物， 监测它们与不同受体的结合， 这增加了肽的特异性和亲和力， 血小板受体 我们还将进一步探讨我们的 观察到一种天然肽，睾丸特异性碱性蛋白， 与血小板受体的结合比 其他受体。 我们将合成这种肽并将其用作 对血小板有选择性的RGD结构的原型 受体的 通过这些方法产生的活性肽将是 使用计算机技术建模， 构象 模型的正确性将被检验 使用NMR。 这些信息将用于设计更多 显示出选择性和高亲和力的精制类似物 与血小板表面的相互作用。 通过这些方法产生的肽可以成为一种新的 一类可用于预防血栓形成的凝血调节剂 血栓形成

Adhesion and aggregation of platelets is a key event in blood clotting. It is mediated by adhesive proteins that interact with receptors at the platelet surface. The receptors bind to a common recognition structure, an arginine-glycine-aspartic acid (RGD) tripeptide sequence, in the adhesion proteins which include fibrinogen , fibronectin, vitronectin and von Willebrand factor (vWF). Two of these, fibronectin and vitronectin, also mediate adhesion of most types of nucleated cells. On the other hand, fibrinogen and vWF do not. This differential recognition is accomplished through a family of adhesion receptors. Fibroblasts have distinct receptors for the RGD sequence in fibronectin and vitronectin, whereas in platelets a common receptor (gpIIb/IIIa) binds fibronectin, vitronectin, fibrinogen and vWF. Short, linear peptides containing the RGD sequence inhibit the function of each one of the receptors. The purpose of the work proposed here is to design peptides that would selectively inhibit the function of the platelet receptor. To obtain such peptides, we will synthesize peptide analogues and monitor their binding to different receptors selecting for changes that increase and specificity and affinity of the peptide toward the platelet receptor. We will also explore further our observation that a natural peptide, testis-specific basic protein, is bound much more efficiently by the platelet receptor than the other receptors. We will synthesize this peptide and use it as a prototype for an RGD structure that is selective for he platelet receptor. Active peptides generated by these approaches will be modeled using computer techniques designed to predict their conformation. The correctness of the models will be examined using NMR. This information will be used in designing more refined analogues that display both selectivity and a high affinity interaction with the platelet surface. The peptides produced by these approaches could become a new class of modulators of blood clotting useful in preventing thrombosis.