The broad, long-term goal of the RCDA candidate's research is to understand the biochemical determinants that allow for selective chemotherapy against malarial parasites. Previously, the PI identified 5-identified 5-fluoroorotate as a potent antimalarial agent that is selective in culture and curative in animal models of malaria. Recently, he showed that treatment of infected erythrocytes with nanomolar amounts of 5-fluoroorotate resulted in selective and efficient activation of 5-fluoroorotate to fluorinated nucleotides and near complete inactivation of thymidylate synthase. During the RCDA period, the PI will identify the enzymatic mechanisms which account for species-selective activation of 5-fluoroorotate to fluorinated nucleotides in malarial parasites and the PI will determine why malarial thymidylate synthase is so vulnerable to 5-fluoroorotate treatment. Finally, the consequences of thymidylate synthase inactivation will be evaluated by monitoring steady-stat levels of 2'-deoxyribonucleotides, by studying DNA fragmentation, and by determining clonal viability of 5- fluoroorotate-treated malarial parasites.
