Synthesis of Anticoagulant Sulfoproteins from Hematophagous Organisms

Abstract

Blood-feeding arthropods (such as ticks, mosquitoes and leeches) produce potent anticoagulant proteins in their saliva to facilitate access to their blood meal. These compounds interfere with the coagulation cascade - a series of enzymes which regulate the process of blood clotting - particularly the central protease thrombin. Undesired blood clotting is implicated in several serious human diseases, including stroke. Stroke is the fifth leading cause of death and single leading cause of permanent disability in developed countries such as Australia. However, very few treatment options exist for stroke and other diseases that involve unwanted formation of blood clots, and those that are approved show poor efficacy and serious side-effects. This thesis describes the synthesis of salivary proteins from a range of blood-feeding organisms including mosquitoes (Chapters 2 and 6), ticks (Chapters 3-6) and flies (Chapter 6) and their evaluation as potential therapeutic leads for the development of new treatment options for clot-based diseases such as stroke. Particularly, this thesis focuses on the role of the post-translational modification of tyrosine sulfation (the enzymatic addition of a sulfate group to the phenolic oxygen of tyrosine side chains after the translation of the target protein on the ribosome) and its role in modulating the anticoagulant properties of the above salivary proteins.