Recombinant Serpins for Coagulative Disorders

Inhibitors of proteolytic enzymes have multiple roles in limiting the molecular and cellular mechaninflammation, coagulation and thrombolysis which if not controlled would result in acute and chronicSpecifically, human neutrophil elastase and other neutrophil proteases are controlled by plasma protserine protease inhibitor (serpin) family of proteins. Inactivation or insufficient production of sethreatening diseases. Data from the study of low molecular weight heterocyclic inhibitors, recombinaanti-chymotrypsin, and the Pittsburgh mutant of alpha-1-1 protease inhibitor suggest that substationsingle amino acid (designated P1) in the serpin results in a marked increase in anti-thrombin activiincreases in bleeding disorders. The purpose of this project is to produce sufficient quantities ofpromising arginine variants of alpha-1 anti-chymotrypsin with potential activities against thrombinevaluate their inhibitory activities in vitro. The data generated will provide a better understandinserine protease inhibitors in homeostasis. In addition, several of the compounds to be tested in thiinhibitors could be considered for use in the treatment of various bleeding disorders, including exccoronary by-pass and transplant surgery, and disseminated intravascular coagulation.