With 214 million cases and up to 0.6 million deaths occurring worldwide annually, malaria remains a major public health problem and threat to the economic development of countries in tropical and subtropical regions of the world (WHO, 2015). Although efforts to mitigate this problem have decreased malaria mortality rates by 60%, malaria continues to affect approximately 40% of the world’s population, killing mostly pregnant women and children. With increasing signs of resistance to ACT, the main anti-malarial treatment, efforts to establish new targets for drug development within the malaria parasite are of increasing importance.
Malaria is caused by infection with Plasmodium species parasites. Of the five Plasmodium species that can infect humans, P. falciparum is the most lethal. Plasmodium parasites are obligate intracellular purine auxotrophs. The dependence of Plasmodium on importing purines from its host makes it vulnerable to inhibitors of the purine transport and salvage pathways. PfENT1 (plasmodium falciparum equilibrative nucleoside transporter) is the main pathway for purine transport into the parasite and is therefore a promising drug target. pfent1 knockout parasites are not viable at physiological purine levels, however, they can be cultured at supra-physiological purine levels. This suggests the existence of an unknown secondary pathway for purine uptake. This pathway has been previously identified as an AMP pathway however it remains to be characterized.
I aim to gain new insight into the P. falciparum purine salvage transporters and pathways. I will conduct transport studies to characterize the pathway for AMP import into P. falciparum. I will also use hit-to-lead medicinal chemistry to optimize our top-hit PfENT1 inhibitors. Finally, I will characterize the effects of PfENT1 single nucleotide polymorphisms (SNPs) on purine import and known PfENT1 inhibitors.
