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Comparative specificity of platelet alpha(IIb)beta(3) integrin antagonists.
G Thibault1, P Tardif, G Lapalme
1Laboratoire de biologie cellulaire de l'hypertension, Institut de recherches cliniques de Montréal and Université de Montréal, Montréal, Canada. thibaug@ircm.qc.ca
The Journal of Pharmacology and Experimental Therapeutics
|February 22, 2001
Summary
RGD peptidomimetics are specific to alpha(IIb)beta(3) integrins, crucial for preventing arterial thrombi. Cyclic RGD peptides, however, also interact with alpha(v) integrins, suggesting broader RGD-dependent integrin binding.
Area of Science:
- Pharmacology
- Integrin Biology
- Cardiovascular Research
Background:
- Platelet alpha(IIb)beta(3) integrin antagonists are developed to prevent arterial thrombi.
- The specificity of these antagonists on other arginine-glycine-aspartic acid (RGD)-dependent integrins is not well-established.
- Some cyclic RGD peptides can interact with alpha(v)beta(3) integrin.
Purpose of the Study:
- To evaluate the specificity of various RGD compounds on different integrins.
- To compare the potency of RGD compounds on platelets and fibroblasts.
- To determine if RGD peptidomimetics and cyclic RGD peptides exhibit differential integrin binding.
Main Methods:
- Utilized a novel pharmacological assay based on SDS-stable interaction between (125)I-echistatin and RGD-dependent integrins.
- Assessed RGD compound specificity on integrins from rat cardiac fibroblasts and human skin fibroblasts.
- Compared the potency of RGD compounds on basal and thrombin-activated human and rat platelets.
Main Results:
- RGD peptidomimetics (L-734,217, lamifiban, Ro 44-3888, SR 121566A, BIBU-52, XV459) showed no interaction with alpha(v)beta(3), alpha(8)beta(1) on rat fibroblasts, or alpha(v)beta(3), alpha(v)beta(1) on human fibroblasts.
- Cyclic RGD peptides exhibited potency (3-80 microM) on rat and human integrins with an alpha(v) subunit.
- All tested RGD compounds inhibited human platelet aggregation (IC(50) 0.6-530 nM), with increased potency upon thrombin activation.
- Eptifibatide, DMP728, and XJ735 were potent on rat platelets (IC(50) ~0.1-1.5 microM).
Conclusions:
- RGD peptidomimetics demonstrate specificity limited to the alpha(IIb)beta(3) integrin.
- Cyclic RGD peptides can interact with additional RGD-dependent integrins, particularly those involving the alpha(v) subunit.
- Findings highlight differential integrin binding profiles between RGD peptidomimetics and cyclic RGD peptides.