PEPTIDE INHIBITORS OF THE PLATELET ADHESION RECEPTOR

血小板粘附受体的肽抑制剂

• 批准号: 3354656
• 负责人: MICHAEL D PIERSCHBACHER
• 金额: $ 24.27万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 1991-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3354656
• 关键词: HeLa cells; adhesions; arginine; aspartate; binding proteins; blood coagulation; blood proteins; chemical models; chemical structure function; computer simulation; conformation; fibrinogen; genetic manipulation; glycine; high performance liquid chromatography; human tissue; laboratory mouse; membrane activity; model design /development; molecular cloning; nuclear magnetic resonance spectroscopy; peptide analog; peptide chemical synthesis; platelet aggregation; platelet aggregation inhibitors; protein engineering; protein metabolism; protein sequence; radiotracer; receptor; receptor binding; synthetic peptide; thrombosis; tissue /cell culture

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.

血小板的黏附和聚集是血液中的关键事件 凝血。它是由与之相互作用的黏附蛋白介导的 血小板表面的受体。受体与一种 共同识别结构，精氨酸-甘氨酸-天冬氨酸 (RGD)三肽序列，在黏附蛋白中，包括 纤维蛋白原、纤维连接蛋白、玻璃体连接蛋白和血管性血友病因子 (VWF)。其中的两种，纤维连接蛋白和玻璃体连接蛋白，也起到了调节作用。 大多数类型的有核细胞的粘附性。另一方面， 纤维蛋白原和vWF则不起作用。这种区别认识是 这是通过一系列黏附受体完成的。成纤维细胞 对纤维连接蛋白中的RGD序列有不同的受体 Vitronectin，而在血小板中是一个共同的受体(GPIIb/IIIa) 结合纤维连接蛋白、玻璃体连接蛋白、纤维蛋白原和vWF。短的，线性的 含有RGD序列的多肽抑制每一个的功能 其中一个受体。 这里提出的工作的目的是设计能够 会选择性地抑制血小板受体的功能。至 获得这样的多肽，我们将合成多肽类似物和 监测它们与不同受体的结合，选择变化 这增加了多肽的特异性和亲和力 血小板受体。我们还将进一步探索我们的 观察到一种天然的肽，睾丸特异的碱性蛋白，是 更有效地被血小板受体结合比 其他受体。我们将合成这种多肽，并将其用作 对血小板具有选择性的RGD结构的原型 受体。通过这些方法产生的活性多肽将是 使用计算机技术进行建模，旨在预测其 构象。我们将检查这些模型的正确性 使用核磁共振。这些信息将用于设计更多 精制类似物，既表现出选择性，又表现出高亲和力 与血小板表面的相互作用。 通过这些方法产生的多肽可能成为一种新的 一类可预防血栓形成的凝血调节剂 血栓形成。