Optimisation of coagulation factor XIIa inhibitors as potential anticoagulants devoid of bleeding side effects

抗凝治疗的圣杯是在不影响止血的情况下控制血栓形成。FXIIa(Hageman因子)的活性在病理生理条件下启动凝血的接触激活(内在)系统，在炎症条件下启动激肽释放酶-激动素系统。FXII基因缺陷的小鼠被发现可以预防动脉血栓形成、胶原和肾上腺素诱导的血栓栓塞症和缺血性中风。广泛的流行病学研究表明，与其他凝固性丝氨酸蛋白酶不同，FXIIa凝血活性与维持止血无关。靶向FXIIa还可以在对抗阿尔茨海默病血栓增加的治疗方面提供新的治疗机会。目前尚无已知的选择性FXIIa抑制剂，目前使用的所有抗凝药物都有出血并发症。学生项目的总体目标是开发我们目前的FXIIa抑制剂系列之一，具有适度的活性和选择性，以确定潜在适合在血栓形成动物模型中进行评估的化合物。目前，化合物设计是基于模拟的FXIIa结构，学生将参加正在进行的X射线结晶学研究，目的是使完全激活的FXIIa以及与抑制剂的络合物结晶。获得这样的结构将极大地改进我们目前的基于结构的设计方法。

The holy grail of anticoagulant therapy is to control thrombosis without compromising haemostasis. The activity of FXIIa (Hageman factor) initiates the contact activation (intrinsic) system of coagulation under pathophysiological conditions, as well as the kallikrein-kinin system in inflammation. FXII-deficient mice were found to be protected against arterial thrombosis, collagen- and epinephrine-induced thromboembolism, and ischaemic stroke. Extensive epidemiologic studies show that unlike other coagulation serine proteases, FXIIa coagulation activity is not implicated in the maintenance of haemostasis. Targeting FXIIa could also present novel therapeutic opportunities in combating increase thrombosis in Alzheimer's disease. At present no selective FXIIa inhibitors are known and all currently used anticoagulation drugs have bleeding complications. The overall aim of the student project is to develop one of the series of our current FXIIa inhibitors with modest activity and selectivity to the point where compounds potentially suitable for evaluation in animal models of thrombosis have been identified. Currently compound design is based on modelled FXIIa structures and the student will participate in on-going X-ray crystallography studies whose aim is to crystallise fully activated FXIIa, as well as complexes with inhibitors. Obtaining such structures will significantly improve our current structure-based design methods.