Integrin αIIbβ3: from discovery to efficacious therapeutic target.
Integrin αIIbβ3: from discovery to efficacious therapeutic target.
复制标题
DOI：
10.1161/circresaha.112.300570
复制
发表时间：
2013-04-12
影响因子：
20.1
通讯作者：
Plow EF
中科院分区：
文献类型：
--
作者：
Bledzka K;Smyth SS;Plow EF
从1882年对血小板的最初描述开始，血小板聚集和促成血栓形成的倾向是显而易见的。事实上，过度的血小板聚集与心肌梗塞和其他血栓性疾病有关，而血小板聚集减少的血小板无力症是一种出血综合征。在世纪的后半叶，许多研究者对血小板聚集的细胞和分子基础有了深入的了解。血小板上的主要膜蛋白整合素αIIbβ3通过从其静息状态快速转变为活化状态来介导这种反应，在活化状态下，整合素αIIbβ3作为可将血小板桥接在一起的配体的受体。单克隆抗体、天然产物和小肽均被证明可抑制αIIbβ3依赖性血小板聚集，这些抑制剂成为拮抗剂的先驱，通过临床前试验和大型患者试验治疗急性冠状动脉综合征，特别是在经皮冠状动脉介入治疗的背景下。三种这样的αIIbβ3拮抗剂，阿昔单抗，依替巴肽和替罗非班，获得了食品和药物管理局的批准。在过去的15年中，数百万患者接受了这些αIIbβ3拮抗剂的治疗，许多人的生命因其给药而得到挽救。随着出血增加的副作用和新型抗血栓药物的开发，αIIbβ3拮抗剂的使用正在减少。尽管如此，它们仍然被广泛用于预防经皮冠状动脉介入治疗期间的围手术期血栓形成。本文综述了αIIbβ3的生物学特性、拮抗剂的研究进展以及αIIbβ3拮抗剂的优缺点。
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.