Polyamine-Trypanothione Pathway: An Update

Abstract

In trypanosomatids, polyamine and trypanothione pathways can be considered as a whole unique metabolism, where most enzymes are essential for parasitic survival and infectivity. Leishmania parasites and all the other members of the Trypanosomatids family depend on polyamines for growth and survival: the enzymes involved in the synthesis and utilization of spermidine and trypanothione, i.e., arginase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, spermidine synthase and in particular trypanothione synthetase-amidase, trypanothione reductase and tryparedoxin-dependent peroxidase are promising targets for drug development. This review deals with recent structure-based studies on these enzymes, aimed at the discovery of inhibitors of this pathway.

Synthesis and Leishmanicidal Activity of Novel Urea, Thiourea, and Selenourea Derivatives of Diselenides

“…(30)(31)(32). Different inhibitors have been described in the literature, although so far none of them proceeded to the further step of drug development (33). With this purpose, hit compounds were screened at six different concentrations between 0.1 and 75 M. Mepacrine, a well-known TryR inhibitor, was used as a positive control (34) and dimethyl sulfoxide (DMSO) as a vehicle.…”

Biochemical and pathophysiological properties of polyamines

“…Ilari et al (2012) solved the crystal structure of Leishmania infantum trypanothione reductase (TR) in complex with Sb(III), Ag(I) and with auranofin, an anti-rheumatic organogold drug. Saccoliti et al (2017) solved the X-ray structure of trypanothione reductase (TR) from Leishmania in complex with the diaryl sulfide compound RDS 777 (6-(secbutoxy)-2-((3-chlorophenyl)thio)pyrimidin-4-amine), which impairs the parasite defense against the reactive oxygen species by inhibiting TR with high efficiency binding to the catalytic site (Saccoliti et al 2017;Ilari et al 2017). On the basis of the RDS 777-TR complex, Colotti et al (2020) designed and synthesized a new class of diaryl sulfide TR inhibitors able to compete for trypanothione binding to the enzyme and to kill the promastigote in the micromolar range.…”

2-Amino-1,3,4-thiadiazoles as prospective agents in trypanosomiasis and other parasitoses

“…A genetic feature of trypanosomatids is the lack of genes encoding glutathione reductase (GR) and thioredoxin reductase, the main enzymes in the redox systems of most living organisms (48,92). In trypanosomatids, T(SH) 2, T(SH) 2 -dependent antioxidant system (tryparedoxin TXN/tryparedoxin peroxidase system TXNPx) and TryR replace the antioxidant functions performed by glutathione (GSH), GSH-dependent antioxidant enzymes and glutathione reductase (GR) in most cells (90,91,93). T(SH) 2 provides the reduction potential to several redoxin proteins that control metabolic functions.…”