αIIbβ3 priming and clustering by orally active and intravenous integrin antagonists
| Autor: | R. F. Connor, Shaker A. Mousa, Mary C. Stahle, Roy R. Hantgan, John H. Connor |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Blood Platelets
Male Models Molecular Pyrrolidines Platelet Function Tests Protein Conformation Amidines Administration Oral Eptifibatide Alpha (ethology) Platelet Glycoprotein GPIIb-IIIa Complex In Vitro Techniques Pharmacology Fibrinogen Binding Competitive Structure-Activity Relationship Reference Values medicine Disintegrin Humans Platelet Beta (finance) Alanine Dose-Response Relationship Drug biology Chemistry Fibrinogen binding Isoxazoles Hematology Tirofiban Platelet Activation Kinetics Biochemistry Injections Intravenous biology.protein Intercellular Signaling Peptides and Proteins Tyrosine Female Peptides Dimerization Platelet Aggregation Inhibitors Protein Binding medicine.drug |
| Zdroj: | Journal of Thrombosis and Haemostasis. 5:542-550 |
| ISSN: | 1538-7836 |
| DOI: | 10.1111/j.1538-7836.2007.02351.x |
| Popis: | Background Drugs that block platelet-platelet and platelet-fibrin interactions via the alpha(IIb)beta(3) (glycoprotein IIb/IIIa) receptor are used daily in patients undergoing percutaneous coronary interventions. Along with expected increases in spontaneous bleeding, clinical trials have revealed a surprising increase in thrombosis when these drugs are used without other anticoagulants. A better understanding of their mechanisms can minimize these risks. Objectives This study tested the hypothesis that interventions designed to block fibrinogen binding inevitably leave the alpha(IIb)beta(3) receptor in an activated state. It compared the effects on platelet function and alpha(IIb)beta(3) conformation of the orally active compounds orbofiban and roxifiban, the i.v. agents eptifibatide and tirofiban, and echistatin, an arginine-glycine-aspartate (RGD) disintegrin. Methods The integrin antagonist concentrations required to saturate platelets and to block platelet-platelet and platelet-fibrin interactions were determined by flow cytometry, aggregometry, and clot-based adhesion assays, respectively. Analytical ultracentrifugation measured each antagonist's effects on the solution structure of alpha(IIb)beta(3). Fluorescence anisotropy provided equilibrium and kinetic data for integrin:antagonist interactions. Results Both orally active drugs bound more tightly and inhibited platelet aggregation and adhesion to fibrin more effectively than echistatin. Analytical ultracentrifugation yielded this order for perturbing alpha(IIb)beta(3) conformation (priming) and promoting oligomerization (clustering): echistatin > eptifibatide > orbofiban > tirofiban > roxifiban. Roxifiban was also most effective at disrupting the rapidly forming/slowly dissociating alpha(IIb)beta(3):echistatin complex. Conclusions Our results suggest that the same molecular mechanisms that enable glycoprotein IIb/IIIa inhibitors to bind tightly to the alpha(IIb)beta(3) receptor and block fibrinogen binding contribute to their ability to perturb the resting integrin's conformation, thus limiting the safety and efficacy of both oral and i.v. integrin antagonists. |
| Databáze: | OpenAIRE |
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