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

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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.