Targeting Folate Metabolism in the Human Malaria Parasite Plasmodium falciparum

John      E. Hyde; Ingrid      B. Muller

Abstract

Human malaria parasites, in particular the most dangerous species, Plasmodium falciparum, are responsible for more than a million deaths per year, mainly of young African children, as well as causing enormous social and economic problems in endemic countries. In the absence of efficacious vaccines, the main weapon against malaria infections is intervention with drugs. Within the antimalarial drugs currently deployed clinically, the antifolates are amongst the oldest synthetic compounds, having been in use for over six decades and still of major importance today, despite widespread parasite resistance to this class of inhibitor. To date, only two enzymes of folate metabolism have ever been targeted in malaria chemotherapy and prophylaxis, dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS). The products of this pathway, reduced folate cofactors, are essential for DNA synthesis and the metabolism of certain amino acids. However, the de novo synthesis and interconversions of reduced folate derivatives involve a number of other enzymes that have not as yet been exploited as drug targets, despite the well established position of folate metabolism as a clinically validated point of intervention. Our current understanding of this area of metabolism in the parasite and its potential for providing novel targets for badly needed new antimalarial drugs are reviewed here.

Keywords: Antifolates, de novo folate synthesis, drug design, drug screening, folate salvage, inhibition, reduced folate interconversion, shikimate pathway, dihydrofolate reductase, prophylaxis