Targeting thrombin--rational drug design from natural mechanisms

It is difficult to overstate the medical importance of the serine protease thrombin. Thrombin is involved in many diverse processes, such as cell signaling and memory, but it is the crucial role that it plays in blood coagulation that commands the interest of the medical community. Thrombosis is the most common cause of death in the industrialized world and, whether through venous thromboembolism, myocardial infarction or stroke, ultimately involves the inappropriate activity of thrombin. The number and type of intrinsic and extrinsic natural mechanisms of targeting thrombin that have evolved validate thrombin as an important physiological target, and provide strategies to knock it out. The more we learn about the natural mechanisms that determine thrombin specificity the more likely we are to develop compounds that selectively alter thrombin activity. In this article, we review the natural mechanisms that regulate thrombin activity and novel approaches to inhibit thrombin based on these mechanisms.