INHIBITORS OF THE EXTRINSIC BLOOD COAGULATION PATHWAY

DISSEMINATED INTRAVASCULAR COAGULATION (DIC) IS A DISEASE PROCESS ASSOCIATED WITH SEPTICEMIA CANCER, AND VIREMIA THAT KILLS OVER 107,000 INDIVIDUALS EACH YEAR IN THE U. S.. THIS SERIOUS INTERMEDIARY MECHANISM OF DISEASE OCCURS WHEN THERE IS EXCESSIVE AND WIDESPREAD ACTIVATION OF THE BLOOD COAGULATION IN THE ABSENCE OF ACUTE FOCAL BLOOD VESSEL DAMAGE. IN PHASE I, WE WILL DEVELOP NEW PEPTIDYL INHIBITORS OF THE INITIATION OF THE EXTRINSIC PATHWAY THROUGH THE USE OF MOLECULAR MODELING AND SYNTHETIC PEPTIDE TECHNIQUES. SYNTHETIC PEPTIDES WILL MIMIC UNIQUE SURFACE ACCESSIBLE REGIONS OF FACTOR VIIA, AS DETERMINED BY SEQUENCE AND STRUCTURE ANALYSIS. A STRUCTURE OF THE CATALYTIC DOMAIN OF VIIA WILL BE DEVELOPED USING HOMOLOGIES TO SERINE PROTEASES WITH KNOWN STRUCTURES. PEPTIDES WILL BE STUDIED IN ASSAYS SPECIFIC FOR THE INITIATION EVENTS OF THE EXTRINSIC PATHWAY, THE FORMATION OF THE CATALYTICALLY ACTIVE BINARY COMPLEX OF TISSUE FACTOR WITH VIIA AND THE ACTIVATION OF FACTOR X. IN PHASE II, WE INTEND TO DEVELOP THERAPEUTIC MOLECULES BASED ON THE ACTIVE PEPTIDES DISCOVERED IN PHASE I. MOLECULAR MODELING AND PEPTIDOMIMETIC TECHNIQUES WILL BE USED TO DESIGN ACTIVE, STABLE INHIBITORS OF THE EXTRINSIC COAGULATION PATHWAY AND, HENCE, DIC.