Summary
Naturally-occurring fibrinogen receptor antagonists and platelet aggregation inhibitors
that are found in snake venom (disintegrins) and leeches share many common features,
including an RGD sequence, high cysteine content, and low molecular weight. There
are, however, significant selectivity and potency differences. We compared the effect
of three proteins on platelet function: albolabrin, a 7.5 kDa disintegrin, eristostatin,
a 5.4 kDa disintegrin in which part of the disintegrin domain is deleted, and decorsin,
a 4.5 kDa non-disintegrin derived from the leech Macrobdella decora, which has very little sequence similarity with either disintegrin. Decorsin was
about two times less potent than albolabrin and six times less potent than eristostatin
in inhibiting ADP- induced human platelet aggregation. It had a different pattern
of interaction with glycoprotein IIb/IIIa as compared to the two disintegrins. Decorsin
bound with a low affinity to resting platelets (409 nM) and to ADP-activated platelets
(270 nM), and with high affinity to thrombin- activated platelets (74 nM). At concentrations
up to 685 nM, it did not cause expression of a ligand-induced binding site epitope
on the (β3 subunit of the GPIIb/IIIa complex. It did not significantly inhibit isolated GPIIb/IIIa
binding to immobilized von Willebrand Factor. At low doses (1.5-3.0 μg/mouse), decorsin
protected mice against death from pulmonary thromboembolism, showing an effect similar
to eristostatin. This suggested that decorsin is a much more potent inhibitor of platelet
aggregation in vivo than in vitro, and it may have potential as an antiplatelet drug.
