Disagregin is a fibrinogen receptor antagonist lacking the Arg-Gly-Asp sequence from the tick, Ornithodoros moubata.

A platelet aggregation inhibitor was identified in the salivary gland of the tick Ornithodoros moubata and isolated by gel filtration and reverse phase high pressure liquid chromatography. The purified inhibitor is a approximately 6-kDa protein, which we have named disagregin. It inhibits ADP-stimulated platelet aggregation in plasma with an IC50 = 104 +/- 17 nM. Disagregin also inhibits platelet aggregation induced by other agonists, including collagen, epinephrine, platelet-activating factor, thrombin, and the thrombin receptor peptide SFLLRNPNDKYEPF. It does not, however, affect platelet shape change induced by these agonists or thrombin-induced dense granule release. Disagregin inhibits platelet aggregation by binding to the platelet fibrinogen receptor. 125I-Disagregin forms a specific complex with both subunits of the fibrinogen receptor, glycoproteins IIb and IIIa, in the presence of a chemical cross-linker. It binds to unstimulated platelets with a Kd = 42.5 +/- 7.5 nM (23,800 +/- 1600 sites/platelet) and to ADP-stimulated platelets with Kd = 39.4 +/- 6.6 nM (24,050 +/- 1500 sites/platelet). Unlabeled disagregin and the snake venom disintegrin echistatin both compete for this binding. Disagregin also completely blocks platelet adhesion to fibrinogen while partially inhibiting platelet adhesion to fibronectin and having little effect on platelet adhesion to collagen. Disagregin had no effect on the adhesion of human umbilical cord vein endothelial cells to fibrinogen or vitronectin. These cells lack the glycoprotein IIb-IIIa complex; therefore, this result is consistent with the ability of disagregin to bind selectively to platelet glycoproteins IIb and IIIa. Sequence analysis of disagregin revealed 60 residues composing a unique protein. Unlike other fibrinogen antagonists it does not contain the Arg-Gly-Asp cell recognition sequence or a conservative substitution, and it has no structural homology with the Arg-Gly-Asp-containing snake venom disintegrins. Thus, disagregin is unique both in structure and function and may serve as a useful tool for the design of therapeutically useful antithrombotic agents.