Comparative Specificity of Platelet αIIbβ3 Integrin Antagonists
- Laboratoire de biologie cellulaire de l'hypertension, Institut de recherches cliniques de Montréal and Université de Montréal, Montréal, Canada
Abstract
Several platelet αIIbβ3 integrin antagonists have been designed as preventive agents against the formation of arterial thrombi. Although the potency of these compounds in inhibiting platelet aggregation is in the nanomolar range, their specificity on other integrins that can bind ligands through an arginine-glycine-aspartic acid (RGD) motif is far from being well established. For instance, some cyclic RGD peptides can also interact with αvβ3 integrin. We used a novel pharmacological assay, based on SDS-stable interaction between125I-echistatin and RGD-dependent integrins, to evaluate the specificity of several RGD compounds on integrins present on rat cardiac fibroblasts and human skin fibroblasts. None of the RGD peptidomimetics tested (L-734,217, lamifiban, Ro 44-3888, SR 121566A, BIBU-52, XV459) could interact with either αvβ3 and α8β1on rat fibroblasts or with αvβ3 and αvβ1 on human fibroblasts. Cyclic RGD peptides showed some potency (3–80 μM) on rat and human integrins with an αv subunit. We also compared the potency of these compounds on platelets. All RGD compounds demonstrated IC50between 0.6 and 530 nM on basal human platelets. Activation of the receptor with thrombin resulted in a 2- to 60-fold increase in potency, with L-734,217 and BIBU-52 showing the largest difference. On basal and thrombin-activated rat platelets, only eptifibatide, DMP728, and XJ735 could displace 125I-echistatin (IC50 ≈ 0.1–1.5 μM). These results indicate that RGD peptidomimetics have a specificity limited to αIIbβ3 integrin, whereas cyclic RGD peptides can also interact with other RGD-dependent integrins, particularly those of the αv subunit family.
Footnotes
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Send reprint requests to: Gaétan Thibault, Ph.D., Laboratoire de biologie cellulaire de l'hypertension, Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, Québec, Canada H2W 1R7. E-mail:thibaug{at}ircm.qc.ca
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This work was supported by grants to G.T. from the National Sciences and Engineering Research Council of Canada and the Medical Research Council of Canada. P.T. received a summer studentship award from the National Sciences and Engineering Research Council of Canada.
- Abbreviations:
- RGD
- arginine-glycine-aspartic acid
- PAGE
- polyacrylamide gel electrophoresis
- NP-40
- Nonidet P-40
- SR 121787
- ethyl 3-[N-[4-[4-[amino[(ethoxycarbonyl)imino]methyl]phenyl]-1,3-thiazol-2-yl]-N-[1-[(ethoxycarbonyl)methyl]piperid-4-yl]amino]propionate
- BIBU-52
- 3-pyrrolidineacetic acid:5[[[4′-(aminoimino-methyl)-[1,1′-biphenyl]4-yl]oxy]methyl]2-oxo-(3S-trans)
- DMP728
- cyclo[d-2-aminobutyryl-N-methyl-l-arginyl-glycyl-l-aspartyl)-3-aminomethylbenzoic acid]
- L-734,217
- [3(R)-[2-(piperidin-4-yl)ethyl]-2-oxopiperidinyl]acetyl-3(R)-methyl-β-alanine
- Ro 44-3888
- [Z]-(S)-[[1-[2-[[4-(aminoiminomethyl)benzoyl]amino]-1-oxopropyl]-4-piperidinyl]oxy]-acetic acid
- SC-54701A
- (3S)-3-[[4-[[4-aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoic acid
- SR121566A
- 3-[N-[4-[4-(aminoiminomethyl)phenyl]-1,3-thiazol-2-yl]-N-[1-(carboxymethyl)piperid-4-yl]amino]propionic acid
- XJ735
- cyclo[l-alanyl-l-arginyl-glycyl-l-aspartyl)-3-aminomethylbenzoic acid]
- XV459
- N3-[2-{3-(4-formamidino-phenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(1-butyloxycarbonyl)-2,3-(S)-diaminopropionic acid
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- Received August 24, 2000.
- Accepted November 7, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
