. The objective of this project is to characterize peptide mimics of the region(s) of the fibrinogen(Fg) receptor which bind peptides corresponding to the RGDX sequences of Fg, fibronectin(Fn), vitronectin(Vn) and von Willebrand factor(vWF) and the LGGAKQAGDV sequence of the gamma-chain of Fg for the purposes of understanding the interaction of Fg with its receptor and to provide a rationale for designing a new class of local, or systemic, platelet specific antithrombotic agents. This objective will be accomplished by using the molecular recognition hypothesis and the cDNA information for human Fg, Fn, Vn and vWF. This information will be used to direct the synthesis of peptides which are presumptive mimics of the fibrinogen binding region(s) of the Fg receptors. These presumptive peptide mimics of the Fg receptor are expected to be complementary with the peptides RGDS and LGGAKQAGDV and therefore, be able to bind Fg. This expectation will be tested by determining if these peptides can bind Fg in an ELISA. All of the peptides will be assayed to determine if they can inhibit platelet aggregation, Fg binding to platelets and clot retraction. Active peptides will also be characterized by affinity chromatography and equilibrium dialysis. Immunological techniques will be used to determine if the presumptive Fg receptor mimics have epitopes which are present on platelet Fg receptors, or other platelet plasma membrane proteins. The active peptides will be tested as inhibitors in a fibroblast attachment to Tn assay, and as modulators of development of amphibian embryos. The active peptides will also be tested as antithrombotic agents using artificial conduits and human umbilical cord arteries. Characterization of these peptides may provide a rationale for the design of a new class of antithrombotic agents: peptides which bind to Fg rather than compete with Fg for binding to its receptor.
