Glutamine Analogues Impair Cell Proliferation, the Intracellular Cycle and Metacyclogenesis in Trypanosoma cruzi

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.

Identification of Potential Druggable Targets and Structure-Based Virtual Screening for Drug-like Molecules against the Shrimp Pathogen Enterocytozoon hepatopenaei

“…DON interacts with Phe373 and Cys399 and covalently binds to the active site of glutaminase [ 25 ]. Potent inhibitors of the CTP synthase enzymes of Plasmodium sp., Trypanosoma sp., and Toxoplasma sp., includingα-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid, glutamate γ-semialdehyde, azaserine, and 2,4-diaminopentanedioic acid, have been identified and reported in previous studies [ 22 , 26 , 27 ].…”

“…The complete protein information of EHP was retrieved from the UniProt Knowledgebase and subjected to a functional enrichment analysis for identifying the candidate proteins that are involved in major metabolic pathways, using the online tools in DAVID for a KEGG enrichment analysis. The protein targets were finally selected using an approach similar to that used in earlier studies [ 61 , 62 ], which involved a thorough review of the literature published on microsporidians [ 17 , 22 , 26 , 37 , 38 , 45 ].The amino acid sequences of the five druggable protein targets of EHP, including AQP, CTP synthase, MetAP, DHFR, and TK, were retrieved from the UniProt Knowledgebase ( accessed on 5 January 2022). The three-dimensional structures of all the five proteins were generated using AlphaFold 2 [ 63 ].…”

Synergistic effect and ultrastructural changes in Trypanosoma cruzi caused by isoobtusilactone A in short exposure of time

“…Citral, a terpenoid constituent of the essential oil of Cymbopogon citratus , was capable of inhibiting metacyclogenesis in 54% at 30 μg/mL [ 65 ]. Souza et al [ 66 ] showed that glutamine analogues inhibited the differentiation process at concentrations close to 6 μM for 144 h of treatment. Likewise, a calpain inhibitor, at a concentration of 50 μM in a 96-hour treatment also inhibited differentiation by almost 50% [ 67 ], which represents a longer exposure time than that used in the present study.…”