In trypanosomatids, redox homeostasis is centered on trypanothione (N1,N8-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.
Keywords: Chagas’ disease, glutamate-cysteine ligase, glutathione, polyamine uptake, trypanothione, trypanothione reductase,
Rights & PermissionsPrintExport