Tapparelli C, Metternich R, Ehrhardt C, Cook N S
Sandoz Pharma Ltd, Basel, Switzerland.
Trends Pharmacol Sci. 1993 Oct;14(10):366-76. doi: 10.1016/0165-6147(93)90095-2.
Thrombin is a multifunctional protein: in addition to its role in coagulation, thrombin has important biological effects on platelets, endothelial and smooth muscle cells, leukocytes, the heart and neurones. A detailed understanding of the structure of thrombin, of related serine proteases and of enzyme-inhibitor complexes has aided in the discovery of potent and selective new inhibitor molecules. Some of these novel thrombin inhibitors are active when administered orally and have shown remarkable efficacy as antithrombotic agents in animal models, offering a greater therapeutic potential than presently available drugs. This potential extends also to non-thrombotic indications where thrombin may be involved, namely inflammation, cancer and neurodegenerative diseases. The recent identification of specific thrombin receptors on different cells provides an alternative strategy for inhibiting thrombin's cellular actions, without necessarily compromising its role in haemostasis. In this review, Carlo Tapparelli and colleagues present a comprehensive update of these recent developments in the field of thrombin biology and pharmacology suggesting a new era of therapeutic drugs is on the horizon.
除了在凝血过程中发挥作用外，凝血酶对血小板、内皮细胞和平滑肌细胞、白细胞、心脏和神经元也具有重要的生物学效应。对凝血酶、相关丝氨酸蛋白酶以及酶 - 抑制剂复合物结构的详细了解，有助于发现强效且具选择性的新型抑制剂分子。其中一些新型凝血酶抑制剂口服给药时具有活性，并且在动物模型中作为抗血栓药物已显示出显著疗效，相较于目前可用的药物具有更大的治疗潜力。这种潜力还延伸至可能涉及凝血酶的非血栓形成适应症，即炎症、癌症和神经退行性疾病。最近在不同细胞上鉴定出特定的凝血酶受体，为抑制凝血酶的细胞作用提供了一种替代策略，而不一定会损害其在止血中的作用。在这篇综述中，卡洛·塔帕雷利及其同事全面更新了凝血酶生物学和药理学领域的这些最新进展，表明治疗药物的新时代即将到来。
