Purine and Pyrimidine Pathways as Antimalarial Targets

Abstract

Malaria continues to plague the endemic regions of sub-Saharan Africa and Southeast Asia. With the current development of artemisinin resistance and a risk of failure of the current first line therapies, there is a growing need for novel antimalarials. Purine and pyrimidine metabolism in Plasmodium is distinctly different from the human host, making these pathways valid targets for the development of novel antimalarials. Targeting key enzymes in these pathways with transition state analogs has provided high affinity inhibitors. Transition state mimicry can also provide selectivity for the parasite enzymes over the homologous enzymes of the human host. Resistance of Plasmodium parasites to current antimalarials will be compared to resistance development induced by transition state analogs inhibitors, a feature that may contribute to decreased resistance development. Tight binding and specificity of transition state analog inhibitors provide important features for novel antimalaria therapy with low toxicity and prevention of antibiotic resistance.