MOLECULAR CHARACTERIZATION AND INHIBITION OF A PLASMODIUM-FALCIPARUM ASPARTIC HEMOGLOBINASE

Intraerythrocytic malaria parasites rapidly degrade virtually all of t he host cell hemoglobin. We have cloned the gene for an aspartic hemog lobinase that initiates the hemoglobin degradation pathway in Plasmodi um falciparum. It encodes a protein with 35% homology to human renin a nd cathepsin D, but has an unusually long pro-piece that includes a pu tative membrane spanning anchor. Immunolocalization studies place the enzyme in the digestive vacuole and throughout the hemoglobin ingestio n pathway, suggesting an unusual protein targeting route. A peptidomim etic inhibitor selectively blocks the aspartic hemoglobinase, prevents hemoglobin degradation and kills the organism. We conclude that Plasm odium hemoglobin catabolism is a prime target for antimalarial chemoth erapy and have identified a lead compound towards this goal.