Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The Netherlands.
Int J Mol Sci. 2021 Mar 25;22(7):3366. doi: 10.3390/ijms22073366.
The integrin αIIbβ3 is the most abundant integrin on platelets. Upon platelet activation, the integrin changes its conformation (inside-out signalling) and outside-in signalling takes place leading to platelet spreading, platelet aggregation and thrombus formation. Bloodsucking parasites such as mosquitoes, leeches and ticks express anticoagulant and antiplatelet proteins, which represent major sources of lead compounds for the development of useful therapeutic agents for the treatment of haemostatic disorders or cardiovascular diseases. In addition to hematophagous parasites, snakes also possess anticoagulant and antiplatelet proteins in their salivary glands. Two snake venom proteins have been developed into two antiplatelet drugs that are currently used in the clinic. The group of proteins discussed in this review are disintegrins, low molecular weight integrin-binding cysteine-rich proteins, found in snakes, ticks, leeches, worms and horseflies. Finally, we highlight various oral antagonists, which have been tested in clinical trials but were discontinued due to an increase in mortality. No new αIIbβ3 inhibitors are developed since the approval of current platelet antagonists, and structure-function analysis of exogenous disintegrins could help find platelet antagonists with fewer adverse side effects.
整合素αIIbβ3 是血小板上最丰富的整合素。血小板激活后，整合素改变其构象（内信号），发生外信号转导，导致血小板伸展、血小板聚集和血栓形成。吸血寄生虫，如蚊子、水蛭和蜱，表达抗凝和抗血小板蛋白，这些蛋白是开发用于治疗止血紊乱或心血管疾病的有用治疗剂的主要先导化合物来源。除了吸血寄生虫外，蛇类的唾液腺中也存在抗凝和抗血小板蛋白。两种蛇毒蛋白已被开发成两种抗血小板药物，目前正在临床使用。本综述讨论的蛋白组为蛇、蜱、水蛭、蠕虫和马蝇中存在的小分子量整合素结合半胱氨酸富含蛋白——去整合素。最后，我们强调了各种已在临床试验中测试但因死亡率增加而被停用的口服拮抗剂。自当前血小板拮抗剂获得批准以来，尚未开发出新的 αIIbβ3 抑制剂，对外源性去整合素的结构-功能分析有助于寻找具有较少不良反应的血小板拮抗剂。
