ABSTRACT
Thrombin is a serine protease that plays critical roles in both blood clot formation and anticoagulation. In the penultimate step of the coagulation cascade, thrombin cleaves soluble fibrinogen to form insoluble fibrin. Most drug discovery efforts focus on thrombin inhibition as a means to prevent the serious consequences of thrombus formation in myocardial infarction and stroke. Thrombin consists of two polypeptides, an A chain of 36 residues and a 259- residue B chain, linked by a disulfide bond. The crystallographic structure of thrombin reveals a globular protein organized about two β barrels with the overall folding pattern of the chymotrypsin serine protease family. The use of arginine boronate esters as transition-state mimetics results in potent peptidyl thrombin inhibitors. X-ray crystallographic studies of Fibrinogen peptide A mimetic (FPAM) complexed with thrombin showed that the S1 subsite is occupied by the arginine guanidinium. A strategy to prepare highly selective thrombin inhibitors involves linkage of molecules capable of interacting at distinct subsites.
