Malaria parasite purine transporters: Function determination & inhibitor identification
Frame, Ithiel James Llego
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Malaria is a disease that continues to affect hundreds of millions of people in tropical regions of the world every year. The parasite species Plasmodium falciparum and Plasmodium vivax cause the most virulent and prevalent malaria. Drug resistance to antimalarials persists thus new drugs need to be continually developed. Parasites lack a de novo purine biosynthesis pathway and meet their purine requirements through a salvage pathway using host-derived purines. Experimental evidence on the P. falciparum Equilibrative Nucleoside Transporter-1 (ENT1) show that most of the purine uptake into the parasite is through this transporter. Furthermore, parasites lacking ENT1 are only able to grow in culture when supplemented with supraphysiological concentrations of purines. Thus, many researchers have hypothesized that targeting purine transport through ENT1 may be a compelling and new antimalarial strategy.;Malaria parasites are predicted to have at least three other ENT proteins, however, and their functions have not been reported. Additionally, there are no reported small molecules that inhibit ENT1 activity.;In this work, we describe the purine transport properties of two homologous proteins: the P. falciparum and P. vivax ENT4. Substrate specificity and kinetic analysis show these transporters do transport purines, however we speculate that ENT4's role in parasite physiology is not as a redundant protein in the purine uptake pathway. We also describe a new method to identify PfENT1 inhibitors using a high throughput screen. The system is robust and we describe compounds revealed in our screen. We hope that our work will result in the development of new therapeutic leads for the treatment of malaria.