Integrin αIIbβ3: from discovery to efficacious therapeutic target

Abstract

From the initial description of platelets in 1882, their propensity to aggregate and to contribute to thrombosis was apparent. Indeed, excessive platelet aggregation is associated with myocardial infarction and other thrombotic diseases whereas Glanzmann thrombasthenia, in which platelet aggregation is reduced, is a bleeding syndrome. Over the last half of the 20th century, many investigators have provided insights into the cellular and molecular basis for platelet aggregation. The major membrane protein on platelets, integrin αIIbβ3, mediates this response by rapidly transiting from its resting to an activated state in which it serves as a receptor for ligands that can bridge platelets together. Monoclonal antibodies, natural products, and small peptides were all shown to inhibit αIIbβ3 dependent platelet aggregation, and these inhibitors became the forerunners of antagonists that proceeded through preclinical testing and into large patient trials to treat acute coronary syndromes, particularly in the context of percutaneous coronary interventions. Three such αIIbβ3 antagonists, abciximab, eptifibatide, and tirofiban, received Food and Drug Administration approval. Over the past 15 years, millions of patients have been treated with these αIIbβ3 antagonists and many lives have been saved by their administration. With the side effect of increased bleeding and the development of new antithrombotic drugs, the use of αIIbβ3 antagonists is waning. Nevertheless, they are still widely used for the prevention of periprocedural thrombosis during percutaneous coronary interventions. This review focuses on the biology of αIIbβ3, the development of its antagonists, and some of the triumphs and shortcomings of αIIbβ3 antagonism.

Figure 1. Highlights of the chronology of key discoveries in αIIbβ3 receptor antagonists

FDA indicates Food and Drug Administration; PL^A1/PL^A2, platelet alloantigen 1, 2; KGD, lysine-glycine-aspartic acid sequence; and RGD, arginine-glycine-aspartic acid sequence.

Figure 2

A, Depiction of the domain organization of the αIIb and β3 subunits in an extended conformation. B, Pathway for activation of αIIbβ3. Inside-out signaling can be induced by different agonists, usually binding to a G-protein coupled receptor, which initiate signaling pathways that lead to the cytoplasmic tails of αIIbβ3. Inside-out signaling to activate the receptor begins with unclasping of the membrane proximal complex between the αIIb and β3 cytoplasmic tails. Talin and kindlin cooperate in this activation process. Their separation triggers dissociation of the transmembrane complex of the subunits. These changes then trigger a conformational switch in the integrin extracellular domain, resulting in its conversion from a bent conformation in its resting state to an extended conformation in which it becomes competent to bind soluble ligands. The subsequent outside-in signaling initiated by ligand binding is transmitted back to the cytoplasmic tails to trigger intracellular responses. Portions of this figure are adapted from reference . EGF indicates epidermal growth factor; MIDAS, metal ion–dependent adhesion site; and PSI, plexin-semaphorin-integrin.