Key Proteins in the Polyamine-Trypanothione Pathway as Drug Targets Against Trypanosoma cruzi

Abstract

In trypanosomatids, redox homeostasis is centered on trypanothione (N(1),N(8)-bis(glutathionyl)spermidine, T(SH)2), a low molecular weight thiol that is distinctive for this taxonomic family and not present in the mammalian host. Thus, the study of the metabolism of T(SH)2 is interesting as a potential therapeutic target. In this review, we summarize the existing evidence about the metabolism of thiols in Trypanosoma cruzi, focused on those proteins that can be considered the best candidates for selective therapy. Herein, we examine the biosynthetic pathway of T(SH)2, identifying three key points that are susceptible to attack pharmacologically: the activity of the trypanothione reductase (TR), the function of glutamate-cysteine ligase (GCL) and polyamine transport in T. cruzi. TR has been widely studied and is a good example for the development of the medicinal chemistry of antichagasic compounds. Conversely, GCL and the polyamine uptake system are high flow points in the reductive metabolism of the parasite. However, very little is known at the molecular level about these two systems. Therefore, their potential as targets for drug development is discussed, and it is suggested that research should focus on the production of alternative drugs for Chagas' disease treatment.

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

“…The catalysis of NADPH-dependent reduction of trypanothione disulfide to T(SH) 2 is performed by trypanothione reductase (TR), enzyme that has been proposed as a molecular target, based on the specific inhibition of antioxidant defenses of the parasite [37,38]. The central role of trypanothione makes other enzymes that influence its production also interesting drug targets such as trypanothione synthetase, ornithine decarboxylase (ODC), S-adenosylmethionine (AdoMet) decarboxylase, γ-glutamylcysteine synthetase as well as polyamine transporters [39,40].…”

“…Polyamines are also relevant for controlling differentiation, including T. cruzi metacyclogenesis [81]. Thus, the enzymes involved in polyamine and TSH metabolism provide important drug targets for potential anti-T. cruzi therapy [40].…”

Molecular insights into trypanothione reductase‐inhibitor interaction: A structure‐based review

“…The main difference between the parasite and host substrate occurs at glycyl carboxylate groups of glutathione, which are linked to a spermidine unit by an amide bridge in T(S) 2 and are free in GSSG (Figure ). The crucial role of TR in the parasite survival through catalytic metabolism, and its absenteeism from the mammalian host projects the enzyme an extremely prominent target for developing drugs against parasitic infections . More specifically, an enzyme active site (the catalytic site) in which trypanothione binds (Figure ), can be an excellent drug target for controlling activity of TR in parasites.…”

Structural insights into the novel inhibition mechanism ofTrypanosoma cruzispermidine synthase

“…While nifurtimox and benznidazole are currently used for the treatment of Chagas disease, these drugs exhibit limited and varied efficacy and cause adverse effects (Bern et al, 2007). The polyamine-trypanothione pathway has been the focus of recent study as a drug target of trypanosomes and leishmanias (Maya et al, 2014;Colotti et al, 2013). Trypanothione [N 1 ,N 8 -bis(glutathionyl)spermidine] is an essential metabolite found in trypanosomes and leishmania but not in mammals (Fairlamb et al, 1985) that protects against oxidative stress (Flohé et al, 1999;Krauth-Siegel & Comini, 2008;Manta et al, 2013).…”