Relevance of Trypanothione Reductase Inhibitors on Trypanosoma cruzi Infection: A Systematic Review, Meta‐Analysis, and In Silico Integrated Approach

Abstract

Due to the rudimentary antioxidant defenses in Trypanosoma cruzi, disruptors of redox balance are promising candidates for new antitrypanosomal drugs. We developed an integrated model based on systematic review, meta-analyses, and molecular modeling to evaluate the effect of trypanothione reductase (TR) inhibitors in T. cruzi infections. Our findings indicated that the TR inhibitors analyzed were effective in reducing parasitemia and mortality due to Trypanosoma cruzi infection in animal models. The most investigated drugs (clomipramine and thioridazine) showed no beneficial effects on the occurrence of infection-related electrocardiographic abnormalities or the affinity and density of cardiac β-adrenergic receptors. The affinity between the tested ligands and the active site of TR was confirmed by molecular docking. However, the molecular affinity score was unable to explain TR inhibition and T. cruzi death in vitro or the antiparasitic potential of these drugs when tested in preclinical models of T. cruzi infection. The divergence of in silico, in vitro, and in vivo findings indicated that the anti-T. cruzi effects of the analyzed drugs were not restricted to TR inhibition. As in vivo studies on TR inhibitors are still scarce and exhibit methodological limitations, mechanistic and highly controlled studies are required to improve the quality of evidence.

Current trends in the pharmacological management of Chagas disease

“…Its beneficial action was initially associated to the inhibition of trypanothione reductase (TR), a unique enzyme that interacts with Flavin-adenine dinucleotide (FAD) and reduces nicotinamide adenine dinucleotide phosphate (NADPH), which is essential to parasite survival (Fauro et al, 2013; Benson et al, 1992). However, this hypothesis diverges from studies showing that the trypanocide effect would only be achieved by almost total inhibition of the TR, what is not obtained with this drug (Krieger et al, 2002; Mendonça et al, 2018). Sertraline is also indicated for the treatment of depression and anxiety, and its use in CD in vitro experiments showed efficacy against intracellular and bloodstream forms, with low cytotoxicity to mammalian cells (Ferreira et al, 2018).…”

Caracterización molecular de aislados de Trypanosoma cruzi de triatominos recolectados en los municipios del Estado de Hidalgo, México

“…En este contexto, resalta el TcI como el linaje más abundante en el continente Americano, el cual puede estar asociado con los ciclos silvestres y domésticos de la enfermedad (Zingales et al, 2018). Por otro lado, estudios contemporáneos que analizaron la resistencia o sensibilidad de diferentes cepas de T. cruzi a los fármacos más comunes, sugieren que una proporción importante de los parásitos de los diferentes linajes de T. cruzi presentan cierta resistencia a los fármacos comúnmente empleados para tratar la infección (Mendonça et al, 2018). Sin embargo, en aislados de T. cruzi de la región norte de Sudamérica, se han observado ciertas diferencias en la resistencia a los fármacos.…”

Could pre-infection exercise training improve the efficacy of specific antiparasitic chemotherapy for Chagas disease?

“…It is associated with extensive inflammatory processes, oxidative damage, cardiomyocytolysis, necrosis, progressive heart fibrosis, electromechanical insufficiency, heart failure and death (Bern, 2015; Pérez-Molina and Molina, 2018). Chagas disease is the leading cause of nonischemic cardiomyopathy and the third highest indication for heart transplantation in Latin America (Mendonça et al ., 2018; Nogueira et al ., 2018). Chronic Chagas cardiomyopathy (CCC) is associated with a worse prognosis and 2.48-times greater risk of death than noninfectious cardiomyopathies (Freitas et al ., 2005; Nogueira et al ., 2018).…”

“…After more than four decades, benznidazole (Bz) is still the first-line drug for the etiological treatment of T. cruzi infection (Urbina, 2010; Nogueira et al ., 2018). However, this drug has high toxicity and low cure rates (10–20%) after the parasites have spread and established quiescent amastigote reservoirs in multiple tissues (Urbina, 2010; Mendonça et al ., 2018). As the prospect of new drugs for the treatment of T. cruzi infection is not promising, supporting drugs (e.g.…”

“…As the prospect of new drugs for the treatment of T. cruzi infection is not promising, supporting drugs (e.g. antiarrhythmic, anti-inflammatory and antioxidant drugs) (Santos et al ., 2015; Novaes et al ., 2016 a ; Mendonça et al ., 2018) and non-pharmacological strategies (e.g. exercise training) (Novaes et al ., 2016 b , 2017; Lucchetti et al ., 2017) have been proposed to increase host resistance against T. cruzi .…”