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With a focus on learning, we employ a range of strategies to support innovation, collaboration across centers, and university-wide discussion and decision-making


Fourth Annual Grant Winners 2003-2004

Maria A. Hernandez, Ph.D., HPD College of Pharmacy

Dean William Hardigan – HPD College of Pharmacy

Title: Synthesis and Biochemical Testing of Novel Protease Inhibitors as Anticoagulants


The present proposal outlines the synthesis and biochemical testing of 10 novel inhibitors of serine proteases of Trypsin-like specificity. Lead compounds synthesized under the previous tenure of the President’s Faculty Scholarship Award serve as the basis for a new application for this class of inhibitors, mainly their potential as anticoagulants. Compounds synthesized under this proposal will be evaluated for their inhibitory activity toward trypsin, thrombin, Factor Xa, and other commercially available coagulation enzymes. Optimization of the side chains required for inhibitory potency will be pursued using Modde 5.0 software, a windows program for the generation and evaluation of statistical experimental designs. Chem3D software will also be used to optimize the chemical properties needed for enzyme inhibition. The best inhibitors will be used in further assays of prothrombin time, which will measure their effectiveness as anticoagulants. The blood coagulation system consists of a number of inactive enzymes (zymogens) that are activated in a cascade of enzymatic reactions. The final step in coagulation is the formation of the fibrin clot from fibrinogen, by the action of the protease thrombin, which in turn is generated from prothrombin by the action of factor Xa. The intrinsic and extrinsic systems of the blood coagulation pathway converge with the activation of factor X and involve a number of other enzymes. All the blood coagulation enzymes are serine proteases of trypsin-like specificity; however, they have much more complex structures and are more specific than trypsin. Intravascular clotting is a major health problem in the United States, and research in this area is needed to afford suitable alternatives to existing anticoagulant therapies. Publishing of this work in peer-reviewed journals and further funding for continuation of work will be sought.