PLASMODIUM FALCIPARUM ASPARTIC PROTEINASE INHIBITOR DEVELOPMENT

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The goal of the proposed research project is to understand at a molecular level and to inhibit the function of the aspartic hemoglobinase that initiates hemoglobin degradation in the human malaria parasite, Plasmodium falciparum. This organism causes disease in several hundred million people, death in millions of children each year, and is of concern to over one million travelers per year in this country alone. The parasite grows by catabolizing host erythrocyte hemoglobin and using the resulting amino acids as major nutrient source. We have shown that the initial enzyme in the catabolic pathway is an aspartic protease that makes a single cleavage to unravel the hemoglobin molecule, exposing it for further, efficient proteolysis. We have found a selective peptidomimetic inhibitor that blocks hemoglobinase action and kills P. falciparum parasites in culture. This protease appears to be a valid drug target. We now propose to examine in greater detail the properties of the enzyme and its interaction with inhibitors, using the tools of recombinant enzyme overexpression, molecular modeling, crystallography, and site-directed mutagenesis. Our goal is to better understand the structure and function of this important enzyme, as well as to improve the potency and selectivity of protease inhibition. The expertise of the other project groups in protein expression, molecular interactions and ultrastructural localization will be an enormous asset to this endeavor. It is expected that the proposed experiments will lead to the development of a serious drug candidate for the prophylaxis and treatment of malaria.