Polyamine Metabolism for Drug Intervention in Trypanosomatids

Abstract

Neglected tropical diseases transmitted by trypanosomatids include three major human scourges that globally affect the world’s poorest people: African trypanosomiasis or sleeping sickness, American trypanosomiasis or Chagas disease and different types of leishmaniasis. Different metabolic pathways have been targeted to find antitrypanosomatid drugs, including polyamine metabolism. Since their discovery, the naturally occurring polyamines, putrescine, spermidine and spermine, have been considered important metabolites involved in cell growth. With a complex metabolism involving biosynthesis, catabolism and interconversion, the synthesis of putrescine and spermidine was targeted by thousands of compounds in an effort to produce cell growth blockade in tumor and infectious processes with limited success. However, the discovery of eflornithine (DFMO) as a curative drug against sleeping sickness encouraged researchers to develop new molecules against these diseases. Polyamine synthesis inhibitors have also provided insight into the peculiarities of this pathway between the host and the parasite, and also among different trypanosomatid species, thus allowing the search for new specific chemical entities aimed to treat these diseases and leading to the investigation of target-based scaffolds. The main molecular targets include the enzymes involved in polyamine biosynthesis (ornithine decarboxylase, S-adenosylmethionine decarboxylase and spermidine synthase), enzymes participating in their uptake from the environment, and the enzymes involved in the redox balance of the parasite. In this review, we summarize the research behind polyamine-based treatments, the current trends, and the main challenges in this field.

Targeting Trypanothione Metabolism in Trypanosomatids

“…Specific proteins and enzymes in the parasite that are essential for the viability of the parasite can be targeted to control the growth and proliferation of these parasites. Some of the druggable targets that have been more extensively studied are sterol biosynthesis, glycolysis, purine salvage pathway, DNA topoisomerases, folate metabolism, polyamine, and redox metabolism (Figure 1) [53][54][55][56]. Among these, redox metabolism and its relationship with oxidative stress are of particular interest due to the distinctive features of the redox-controlling system in trypanosomatids, which is based on trypanothione [57].…”

“…Glutathione is formed by the combination of glutamate, glycine, and cysteine in a reaction catalyzed by γ-glutamylcysteine synthetase and glutathione synthetase [61,65,77]. The polyamine spermidine has to be synthesized from its amino acid precursors, L-arginine and L-methionine [56,78], or otherwise internalized from the host by specific transporters [79]. In T. brucei and Leishmania, spermidine is derived from ornithine, which is formed from L-arginine due to the activity of arginase in Leishmania, but not in T. brucei and T. cruzi, which lack this enzymatic activity [80].…”