Parasite, Compartments, and Molecules: Trick versus Treatment on Chagas Disease

Abstract

Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic to Latin America, standing out as a socioeconomic problem for low-income tropical populations. Such disease affects millions of people worldwide and emerges in nonendemic areas due to migration and climate changes. The current chemotherapy is restricted to two nitroderivatives (benznidazole and nifurtimox), which is unsatisfactory due to limited efficacy (particularly in chronic phase) and adverse side effects. T. cruzi life cycle is complex, including invertebrate and vertebrate hosts and three developmental forms (epimastigotes, trypomastigotes, and amastigotes). In this chapter, we will discuss promising cellular and molecular targets present in the vertebrate-dwelling forms of the parasite (trypomastigotes and amastigotes). Among the cellular targets, the mitochondrion is the most frequently studied; while among the molecular ones, we highlight squalene synthase, C14α-sterol demethylase, and cysteine proteases. In this scenario, proteomics becomes a valuable tool for the identification of other molecular targets, and some previously identified candidates will be also discussed. Multidisciplinary studies are needed to identify novel key molecules in T. cruzi in order to increase trypanocidal activity and reduce mammalian toxicity, ensuring the development of novel drugs for Chagas disease.

Is the mitochondrion a promising drug target in trypanosomatids?

“…1). (6,7,8,9) Despite this promising scenario, mitochondrial phenotypes are commonly observed only by electron microscopy, with few reports assessing the real impact of these compounds in the organelle physiology.…”

Perspectives for a new drug candidate for Chagas disease therapy

“…CD therapy is based on two old antiparasitic drugs that are in clinical use for at least half a century: nifurtimox (Nif)(5-nitrofurane, Bayer 2502; Bayer, Germany) and benznidazole (Bz) (2-nitroimidazole; Pharmaceutical Laboratory of the State of Pernambuco [LAFEPE], Brazil, ELEA/Mundo Sano, Argentina). 9 Both present low efficacies especially in the later chronic stage, are contraindicated during pregnancy, cause severe side effects leading to high drop-out rates (treatment discontinuation ≈ 20%), and are inactive against parasite strains naturally resistant to both nitroderivatives. 9 In fact, T. cruzi display high genetic diversity with multiple strains belonging to seven discrete type units (DTUs) and that result in different naturally resistance profile and distinct drug efficacy.…”

“… 9 Both present low efficacies especially in the later chronic stage, are contraindicated during pregnancy, cause severe side effects leading to high drop-out rates (treatment discontinuation ≈ 20%), and are inactive against parasite strains naturally resistant to both nitroderivatives. 9 In fact, T. cruzi display high genetic diversity with multiple strains belonging to seven discrete type units (DTUs) and that result in different naturally resistance profile and distinct drug efficacy. 10 , 11 Also, the recent pandemic Coronavirus disease 2019 (COVID-19) brought additional concerns adding a potential worsen prognostic for the chagasic carriers, impacting the most vulnerable populations who need public policies for health services.…”

“…However, despite the large amount of pre-clinical studies screening different classes of natural products and synthetic compounds, only few drugs moved to clinical trials, which included repurposing studies with two anti-fungi triazoles inhibitors of the sterol 14a-demethylase (CYP51): Posaconazole (POSA) and E1224, the later a prodrug of fosravuconazole, an antifungal discovered by Eisai Ltd (Japan). 9 Although showing very promising in in vitro and in vivo assays, both CYP51 inhibitors fail to sustain efficacy in clinical trials. 13 , 14 , 18 The discrepancy of pre-clinical and clinical outcomes of both azoles raised several concerns regarding the lack of translation of pre-clinical ( in vitro and in vivo ) and clinical trials.…”

Review on Experimental Treatment Strategies Against Trypanosoma cruzi

“…Organelles: Kp: kinetoplast, f: flagellum, fp: flagellar pocket, mt: mitochondrion, nu: nucleus, ER: endoplasmic reticulum, Go: golgi apparatus, Ac: acidocalcisomes, Gl: glycosomes, Ap: autophagosomes. The drawing is based on data from Benaim et al and Vannier-Santos et al163,228…”