Elucidation of the role of Plasmodium falciparum folate transporters in antifolates transport and implication on drug design

PROJECT SUMMARY Antifolates (drugs that target enzymes the folic acid biosynthesis pathway) are widely used to treat a number of infectious disease, including malaria. Although drug resistance is spreading, antifolate drug combination Sulfadoxine-Pyrimethamine (SP) remains the safest and most efficient treatment option for preventive treatment of malaria in pregnant women and in infants. Developing alternative treatment options is therefore crucial. SP resistance is mainly caused by mutations in the folate enzymes. This has been addressed with the development of P218 clinical candidate, which is equally efficient on SP-sensitive and SP-resistant parasite. Yet, growing evidence from our group and others shows that folate transporters may play an important role in antifolate sensitivity and resistance. Understanding (anti)folate transport therefore appears crucial for the development of novel potent drug candidates. Plasmodium falciparum possesses only two folate transporters, PfFT1 and PfFT2, which function have not been yet characterized. This project proposes to investigate PfFT1 and PfFT2 function using a series of biochemical assays. Their natural substrate scope will be identified, and their ability to transport a series of antifolate drugs will be assessed. The determinants of (anti)folate-transporter recognition will be investigated and used to construct a structure-relationship activity model. The knowledge generated from this project will be valuable to guide the development of new antifolate drug candidates with improved transport properties.