Anticoagulatory Substances of Bloodsucking Animals: From Hirudin to Hirudin Mimetics

Abstract Bloodsucking animals contain substances in their saliva that specifically interfere with the blood clotting system. These substances are mainly low molecular weight proteins with a molecular mass of between 4 and 50 kDa. Some have become accessible in large quantities with the help of genetic engineering, and as a result their structures and structure—activity relationships have been studied and clinically tested. In the light of what is known about the mode of action of these natural products at the molecular level, new compounds with possible therapeutic effect can be derived. In the last ten years this approach has been tested with the proteinase inhibitor hirudin, obtained from medicinal leeches, and with the thrombin/hirudin complex. The serine protease thrombin plays a central role in the complex pathway of the blood clotting process and its pathophysiological effect finally results in thrombosis. The selectivity of the formation of complexes from hirudin and thrombin lies in the bivalent interaction of the inhibitor with the active site of the enzyme as well as with a substrate recognition site outside of the active site, the so‐called fibrin‐(ogen) binding site (FBS). The knowledge of this mode of action enabled the synthesis of bifunctional thrombin inhibitors based on hirudin peptides. Hirudin and hirudin mimetics in vivo have been shown to be highly potent anticoagulants for the treatment of arterial and venous thrombosis.