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Reversible conformational changes induced in glycoprotein IIb-IIIa by a
potent and selective peptidomimetic inhibitor
WC Kouns, D Kirchhofer, P Hadvary, A Edenhofer, T Weller, G Pfenninger, HR Baumgartner, LK Jennings and B Steiner
Pharma Division, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Platelet glycoprotein (GP) IIb-IIIa inhibitors may become useful
antithrombotic agents. Ro 43-5054 is a low molecular weight, noncyclic,
peptidomimetic inhibitor that is three orders of magnitude more potent than
RGDS in inhibiting fibrinogen binding to purified GPIIb-IIIa and in
preventing platelet aggregation. Comparisons of RGDS and Ro 43-5054 in cell
adhesion assays showed that, in contrast to RGDS, Ro 43-5054 was highly
selective GPIIb-IIIa inhibitor. Effects of RGDV and Ro 43- 5054 on the
conformation and activation state of GPIIb-IIIa were also examined. RGDV
and Ro 43-5054 induced conformational changes in purified inactive
GPIIb-IIIa as determined by binding of the monoclonal antibody D3GP3 (D3).
These conformational alterations were not reversed after inhibitor removal,
as indicated by the continued exposure of the D3 epitope and a newly
acquired ability to bind fibrinogen. Similarly, RGDV and Ro 43-5054 induced
conformational changes in GPIIb-IIIa on the intact platelet. However, after
removal of the inhibitors, exposure of the D3 epitope was fully reversed
and the platelets did not aggregate in the absence of agonist. Thus, while
RGD(X) peptides and Ro 43-5054 transformed purified inactive GPIIb-IIIa
into an irreversibly activated conformer, the effects of these inhibitors
were reversible on the intact platelet. This suggests that factors present
in the platelet membrane or cytoplasm may regulate in part the ability of
the complex to shift between active and inactive conformers.
Volume 80,
Issue 10,
pp. 2539-2547,
11/15/1992
Copyright © 1992 by The American Society of Hematology
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