The anti‐platelet approach targeting the fibrinogen ligand of the GPIIb/IIIa receptor

Abstract

Activation of the platelet surface receptor GPIIb/IIIa is the final pathway of platelet aggregation, regardless of the initiating stimulus. RGD analogues, peptidomimetics and monoclonal antibodies to GPIIb/IIIa have been developed targeting the blockage of the receptor and inhibition of the fibrinogen binding. However, the intrinsic activating effect of GPIIb/IIIa blockers is widely discussed as one potential contributing factor for the disappointing outcome of trials with GPIIb/IIIa inhibitors. An alternative method for thrombus prevention could be the use of specific fibrinogen blockers since they will act at the final step of the platelet aggregation and are expected to leave the receptor unaffected. To achieve this target the design of the fibrinogen ligands could be based on (i) sequences derived from GPIIb/IIIa ligand binding sites, and (ii) sequences complementary to RGD and/or to fibrinogen gamma-chain. The available information, which could be used as a starting point for developing potent fibrinogen ligands, is reviewed.

RGD peptides induce relaxation of pulmonary arteries and airwaysviaβ3‐integrins

“…Even more important could be novel therapeutic options that arise from the relaxant property of soluble RGD peptides in PAs because the RGD peptide is also effective during hypoxia and in vivo . Together with the known RGD‐dependent inhibition of platelet aggregation (47, 48), angiogenesis (49, 50), and pulmonary T‐cell proliferation (51), the relaxing effect of RGD may be helpful for pulmonary hypertension and asthma therapy. In fact, RGD peptides were recently reported to inhibit airway smooth muscle remodeling in an animal model of allergic asthma (26).…”

Antiaggregatory and proangiogenic effects of a novel recombinant human dual specificity anti‐integrin antibody

“…Substances combining both antithrombotic and proangiogenic properties, a double effect with a significant theoretical benefit in microthrombotic lesions with insufficient collateral angiogenesis, such as in chronic leg ulcers, are not yet available. Fibrinogen binds to its activated receptor GPIIb-GPIIIa in part through an RGD or RGD-like sequence [3], and the three clinically used GPIIb-GPIIIa blockers eptifibatide, tirofiban and abciximab inhibit the RGD-driven ligand-receptor interaction by steric hindrance, an allosteric effect on the RGD binding region, or both [4,22]. The Fab fragments used in this study were selected by using washed platelets from normal and Fig.…”

“…Fibrinogen binds to its activated receptor GPIIb–GPIIIa in part through an RGD or RGD‐like sequence [3], and the three clinically used GPIIb–GPIIIa blockers eptifibatide, tirofiban and abciximab inhibit the RGD‐driven ligand–receptor interaction by steric hindrance, an allosteric effect on the RGD binding region, or both [4,22]. The Fab fragments used in this study were selected by using washed platelets from normal and thrombasthenic individuals, with final selection via immobilized GPIIb–GPIIIa [16].…”

“…A variety of natural (e.g. disintegrins) and synthetic compounds mimicking GPIIb and GPIIIa sequences have been described [3]. Only a few, the Fab fragment of the chimeric monoclonal antibody (mAb) 7E3 abciximab, the non-peptide tirofiban, and the synthetic cyclic hexapeptide eptifibatide, have reached clinical use [4].…”

Matrix biology meets toxinology

“…Together with the Cterminal sequence of the disintegrin, this amino acid sequence within the integrin-binding loop determines their integrin-binding specificity. Structural docking models (Xiong et al, 2002) propose that the common aspartate residue of the integrin-binding loop interacts with the vWF A-domain of the integrin β subunit, whereas the residual two residues of the tripeptide sequence specify the integrin α subunit, which is recognized by the disintegrin (Calvete et al, 2009a,b): RGD blocks the platelet integrin αIIbβ3 (Tsikaris, 2004), along with the even more selective KGD-sequence, as well as the integrins αVβ3, αVβ1, α5β1 (along with the sequences WGD, VGD and MGD) and α8β1; MLD-containing disintegrins block the immunologically relevant integrins α4β1, α4β7, the integrin α9β1, and the lamininbinding integrins α3β1, α6β1, and α7β1 (Sanz et al, 2006), whereas the KTS/RTS-sequences are selectively found in α1β1 integrininhibiting disintegrins (Brown et al, 2009;Calvete et al, 2007;Eble et al, 2003). Interestingly, non-RGD-disintegrins are only found in combination with RGD-containing disintegrins in venoms, providing Fig.…”