Protein Conformation and Enzymology Lab, Department of Biosciences, Jamia Millia Islamia (A Central University), Jamia Nagar, New Delhi, 110025, India.
J Thromb Thrombolysis. 2012 Aug;34(2):251-9. doi: 10.1007/s11239-012-0712-z.
An elevated prothrombotic state is a major risk factor for venous thromboembolism, atrial fibrillation and cardiac strokes. The regulation of various coagulation cascade proteases plays an important role in determining a prothrombotic state. Clinically used anticoagulants are inhibitor of enzymes that are involved in the coagulation pathway, primarily thrombin and factor Xa. The conformational activation of antithrombin by heparin is a critical step in the inhibition of factor Xa by antithrombin. Despite heparin being the most potent physiological activator which enhances the otherwise very lethargic antithrombin inhibition of factor Xa by approximately 1,000-fold, the conventional heparin therapy poses serious complications because of heparin's polyanionic nature and its cross-reactivity. A number of attempts have been carried out in designing alternative non-heparin based conformational activators of antithrombin for factor Xa inhibition. Studies have demonstrated appreciable activation of antithrombin by small organic molecules, but not much is known about the specificity and effects of these molecules on structure and stability. It is assumed that these activators of antithrombin perform their function by binding to heparin binding site. A recently identified cavity which links the heparin binding site to the strand 2A for antithrombin activation also seems to be an ideal target apart the heparin binding site of antithrombin. There are opportunities in discovering more activators from naturally available organic scaffolds and also for modifying such scaffolds for designing better conformational activators with minimum associated complications. This review summarizes the current literature on the mainstay anticoagulants and non-heparin based antithrombin conformation modulators.
高凝状态是静脉血栓栓塞、心房颤动和中风的主要危险因素。各种凝血级联蛋白酶的调节在确定高凝状态中起着重要作用。临床上使用的抗凝剂是参与凝血途径的酶的抑制剂，主要是凝血酶和因子 Xa。肝素对抗凝血酶的构象激活是抗凝血酶抑制因子 Xa 的关键步骤。尽管肝素是最有效的生理激活剂，可将抗凝血酶对因子 Xa 的抑制作用增强约 1000 倍，但由于肝素的多阴离子性质及其交叉反应性，传统的肝素治疗会引起严重的并发症。已经进行了许多尝试来设计替代的非肝素基构象抗凝血酶激活剂来抑制因子 Xa。研究表明，小分子可显著激活抗凝血酶，但对于这些分子对结构和稳定性的特异性和影响知之甚少。据推测，这些抗凝血酶激活剂通过与肝素结合位点结合来发挥作用。最近发现的一个连接抗凝血酶肝素结合位点和 2A 链的腔隙似乎也是肝素结合位点之外的理想靶点。在从天然存在的有机支架中发现更多的激活剂以及修饰这些支架以设计具有最小相关并发症的更好构象激活剂方面，存在着机会。本综述总结了关于主要抗凝剂和非肝素基构象抗凝血酶调节剂的当前文献。
