Vol. 296, Issue 3, 690-696, March 2001

Comparative Specificity of Platelet _IIb3 Integrin Antagonists

Gaétan Thibault, Patrick Tardif and Geneviève Lapalme

Laboratoire de biologie cellulaire de l'hypertension, Institut de recherches cliniques de Montréal and Université de Montréal, Montréal, Canada

Several platelet _IIb3 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 _v3 integrin. We used a novel pharmacological assay, based on SDS-stable interaction between ¹²⁵I-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 _v3 and ₈₁ on rat fibroblasts or with _v3 and _v1 on human fibroblasts. Cyclic RGD peptides showed some potency (3-80 µM) on rat and human integrins with an _v subunit. We also compared the potency of these compounds on platelets. All RGD compounds demonstrated IC₅₀ between 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 _IIb3 integrin, whereas cyclic RGD peptides can also interact with other RGD-dependent integrins, particularly those of the _v subunit family.