Targeting the polyamine biosynthetic pathway in parasitic protozoa

Malaria, trypanosomiasis, and leishmaniasis are life-threatening parasitic diseases for which safe and more effective medicines are urgently needed. The polyamine biosynthetic pathway in protozoan pathogens is a validated target for the development of drugs, as demonstrated by the current use of a-difluoromethylornithine (DFMO) to treat patients diagnosed with human African trypanosomias (HAT). These parasites have evolved novel polyamine metabolic pathways that are considerably different from those of the human host. For example, trypanosomes contain a novel spermidine/glutathione conjugate termed trypanothione, and uniquely in these parasites S -adenosylmethionine decarboxylase (AdoMetDC) is activated by heterodimer formation with a catalytically dead homologue. In Plasmodium parasites, AdoMetDC and ODC are fused as a bifunctional protein. Trypanosoma cruzi lacks ODC and relies on polyamine transporters. In this chapter, we discuss these differences and highlight additional aspects of these organisms that could be exploited as potential therapeutic strategies, including differences in protein turnover rates and polyamine transport, the latter of which could be used for delivery of cytotoxic compounds.