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

抗凝治疗的终极目标是在不影响止血的情况下控制血栓形成。FXIIa （Hageman factor）的活性在病理生理条件下启动凝血的接触激活（内在）系统，在炎症状态下启动钾likrein-kinin系统。fxii缺陷小鼠被发现对动脉血栓形成、胶原蛋白和肾上腺素诱导的血栓栓塞和缺血性中风有保护作用。广泛的流行病学研究表明，与其他凝血丝氨酸蛋白酶不同，FXIIa的凝血活性与止血维持无关。靶向FXIIa也可能为对抗阿尔茨海默病中增加的血栓提供新的治疗机会。目前还没有发现选择性FXIIa抑制剂，目前使用的抗凝药物均有出血并发症。该学生项目的总体目标是开发我们现有的具有适度活性和选择性的FXIIa抑制剂系列之一，从而确定可能适合在血栓形成动物模型中进行评估的化合物。目前的化合物设计是基于模拟的FXIIa结构，学生将参与正在进行的x射线晶体学研究，其目的是结晶完全活化的FXIIa，以及与抑制剂的复合物。获得这样的结构将大大改进我们目前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.