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.
Highlights
Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi
30% of the infected patients progress to chronic Chagas cardiomyopathy (CCC) which manifests as diffuse heart fibrosis and hypertrophy, complex electrical abnormalities and arrhythmias, thromboembolic events, and congestive heart failure [3, 8]
We systematically review the in vivo preclinical evidence on the relevance of trypanothione reductase (TR) inhibitors in Chagas disease
Summary
Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. Chagas disease is associated with poverty and is endemic in Central and South American countries. While vector-borne transmission, intake of contaminated foods, and congenital transmission are the main forms of T. cruzi infection in endemic countries [3,4,5], autochthonous iatrogenic cases secondary to blood transfusion, organ transplant from infected donors, and Oxidative Medicine and Cellular Longevity congenital transmission are the most frequent infection pathways in nonendemic regions [3, 5]. Chagas disease is a life-threatening illness associated with at least 50,000 deaths/year worldwide, especially due to sudden cardiac death (60%), heart failure (25%), and stroke (15%) [6]. The course of infection includes neural (autonomic neuropathy) and digestive disorders (mega syndromes), chronic Chagas cardiomyopathy (CCC) is the most severe and incapacitating clinical form of the disease [3, 7]. CCC is associated with a higher mortality hazard ratio (2.48) than noninfectious cardiomyopathies [9, 11]
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