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

Abstract

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. 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 a 100:1 ratio. The inhibition was dependent on fibrinogen concentration and occurred in the presence of Ca or Mg. 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 inhibits fibrin polymerization. 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. Common structural features within fibrinogen may serve a dual function by permitting the molecule to participate in both platelet aggregation and fibrin formation.