Evaluation of Small Molecule Inhibitors of Hemoglobin Transport as Antimalarials

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DESCRIPTION (provided by applicant): We've developed a new model for the internalization and transport of hemoglobin from host erythrocyte cytosol to the digestive vacuole (DV) in intraerythrocytic Plasmodium falciparum malaria parasites. The examination of serial sections by electron microscopy of malaria infected erythrocytes (IRBC) revealed that cytostomes extend to and fuse with the parasite digestive vacuole (DV), thereby delivering hemoglobin to the parasite. This process was dependent on actin dynamics, as agents that stabilize actin filaments prevented the delivery of hemoglobin to the DV. Furthermore, we demonstrated that the delivery of hemoglobin to the DV was an obligate process, as inhibition of this process inhibited parasite development and caused parasite death. More recently, using a specific small molecule GTPase inhibitor, we disrupted the cytostome morphology and prevented hemoglobin transport to the DV, resulting in the arrest of parasite development. Our new discoveries reveal that the inhibition of hemoglobin delivery to the DV is lethal to P. falciparum parasites and as a result validated this process as a new target for antimalarial therapy. We seek to capitalize on our observations to develop an in vitro assay to monitor hemoglobin transport to the DV (as a read out) and use it to screen a small molecule library for compounds that inhibit this process and parasite development. Validation experiments in vitro of positive hits from the small molecule screen will be performed prior to moving into in vivo testing down the road. Perturbing the hemoglobin transport system represents a unique approach for developing antimalarials. Given the urgent need for new drug targets and antimalarials and the millions of people worldwide afflicted by malaria, the potential impact of this project is very high. PUBLIC HEALTH RELEVANCE: Inhibitors of digestive vacuole hemoglobin proteases are being evaluated as antimalarials. Reports indicate great functional redundancy in these proteases and it appears that therapy would need to inhibit many different proteases. We believe the upstream cytostomal hemoglobin transport system may be a better target. Novel targeting of a unique process that occurs in Plasmodium falciparum infected erythrocytes and not in host cells could lead to entirely new antimalarial chemotypes that act by novel mechanisms untroubled by cross resistance to existing therapeutics. If inhibitors are identified then we will have a rational target, obtained by a rational process, which can be developed into a drug discovery program for a serious health problem.