Malaria Parasite Physiology and Mechanisms of Nucleoside and Drug Transport
Malaria is a major public health problem affecting large areas of the world. About 600,000 people, mostly children and pregnant woman, die each year due to malaria. Malaria is caused by unicellular parasites from the Plasmodium species that grow inside erythrocytes. Plasmodium falciparum causes the most lethal form of malaria. Plasmodium spp. parasites are purine auxotrophs and require an exogenous source of purines to survive. They import purine precursors from the host erythrocyte via equilibrative nucleoside transporters (ENTs). Knockout of PfENT1 is lethal at purine concentrations found in human plasma. This suggests that PfENT1 inhibitors might kill parasites and represent a novel target for antimalarial drug development. We seek to characterize the purine nucleoside transporters and identify inhibitors as potential antimalarial drugs.
We have developed a yeast-based high throughput screen to identify PfENT1 inhibitors. We screened a 65,000 compound library and identified 171 hits. The nine best hits block PfENT1 and kill P. falciparum parasites in culture. We are characterizing the hits and exploring the SAR for the compounds to identify more potent derivatives. Additional work is focused on testing the hits against P. vivax ENT1 and in a mouse malaria model. In addition, in collaboration with GSK, they used our assay to screen their 1.8 million compound library. They have given us six of the best hits to develop as novel antimalarial drugs. We are currently in the hit-to-lead medicinal chemistry process to improve the potency and physicochemical properties of the hits. We are also investigating the molecular basis of their interaction with PfENT1 and the mechanism of their parasitocidal activity.
For additional information see Einstein News Release: Einstein Scientists Develop Novel Technique for Finding Drugs to Combat Malaria