Inhibition of fibrinogen binding to human platelets by the tetrapeptide glycyl-L-prolyl-L-arginyl-L-proline.

The role of fibrinogen as a cofactor in platelet aggregation is mediated by its binding to platelet receptors that are induced by stimuli such as ADP. In the present study, we demonstrate that the tetrapeptide glycyl-L-prolyl-L-arginyl-L-proline inhibits the interaction of fibrinogen with its platelet receptor. The primary effect of the peptide was on the extent rather than on the rate of fibrinogen binding. Significant inhibition occurred at a 1:1 molar ratio of peptide to fibrinogen and reached maximal levels at 100:1 ratio. The inhibition was dependent upon fibrinogen concentration and occurred in the presence of calcium or magnesium. The peptide inhibited the binding of fibrinogen to platelets with exposed receptors, suggesting that it interfered directly with the ligand-receptor interaction. Fibrinogen binding supported by epinephrine and thrombin as well as ADP was inhibited by the peptide. Fibrinogen-dependent aggregation of washed platelets by ADP was abolished by a 30-fold molar excess of the peptide. The tetrapeptide is an analog of the amino-terminal sequence of the alpha-chain of fibrin and has been shown to inhibit fibrin polymerization [Laudano, A. P. & Doolittle, R. F. (1978) Proc. Natl. Acad. Sci. USA 75, 3085-3089]. A peptide corresponding to the natural sequence, glycyl-L-prolyl-L-arginyl-L-valyl-L-valine, was also capable of inhibiting fibrinogen binding to the platelet. These results suggest that common structural features within fibrinogen may serve a dual function by permitting the molecule to participate in both platelet aggregation and fibrin formation.