Abstract
Trypanosoma cruzi is the aetiologic agent of Chagas disease, which affects people in the Americas and worldwide. The parasite has a complex life cycle that alternates among mammalian hosts and insect vectors. During its life cycle, T. cruzi passes through different environments and faces nutrient shortages. It has been established that amino acids, such as proline, histidine, alanine, and glutamate, are crucial to T. cruzi survival. Recently, we described that T. cruzi can biosynthesize glutamine from glutamate and/or obtain it from the extracellular environment, and the role of glutamine in energetic metabolism and metacyclogenesis was demonstrated. In this study, we analysed the effect of glutamine analogues on the parasite life cycle. Here, we show that glutamine analogues impair cell proliferation, the developmental cycle during the infection of mammalian host cells and metacyclogenesis. Taken together, these results show that glutamine is an important metabolite for T. cruzi survival and suggest that glutamine analogues can be used as scaffolds for the development of new trypanocidal drugs. These data also reinforce the supposition that glutamine metabolism is an unexplored possible therapeutic target.
Highlights
Chagas disease (CD) is caused by the flagellate protist Trypanosoma cruzi and affects approximately8 million people worldwide [1], with some 25 million further people at risk of infection
We showed that the biosynthesis and uptake of Gln are developmentally regulated according to Gln availability in the extracellular environment and cell demand
We evaluated the impact of the Gln analogues acivicin (ACV), azaserine (AZA) and 2,4-diaminopentanedioic acid (DPA, Figure 1) on the cell biology and life cycle of T. cruzi according to the hypothesis that they will preferentially interfere with enzymes that recognize Gln as a substrate, product or allosteric modulator
Summary
8 million people worldwide [1], with some 25 million further people at risk of infection It is endemic in the Americas where the vector transmission occurs [2]. The CD treatment available nowadays is based in two drugs discovered many years ago: nifurtimox and beznidazole. The effect of these drugs is controversial, depending on the stage of disease, age and immune response of patient and the susceptibility of the T. cruzi genotype, cause many side effects and the treatment required a prolonged course. The insect vectors become infected during the blood meal, when they ingest the non-replicative, infective trypomastigotes present in the host bloodstream. The trypomastigotes differentiate into the replicative epimastigotes, which colonize the Molecules 2020, 25, 1628; doi:10.3390/molecules25071628 www.mdpi.com/journal/molecules
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