PEPTIDE INHIBITORS OF THE PLATELET ADHESION RECEPTOR

血小板的粘附和聚集是血液中的一个关键事件

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.