1. Trypanothione Metabolism as Drug Target for Trypanosomatids
María Dolores Piñeyro, Diego Arias, Adriana Parodi-Talice, Sergio Guerrero, Carlos Robello Curr Pharm Des. 2021;27(15):1834-1846. doi: 10.2174/1381612826666201211115329.
Chagas Disease, African sleeping sickness, and leishmaniasis are neglected diseases caused by pathogenic trypanosomatid parasites, which have a considerable impact on morbidity and mortality in poor countries. The available drugs used as treatment have high toxicity, limited access, and can cause parasite drug resistance. Long-term treatments, added to their high toxicity, result in patients that give up therapy. Trypanosomatids presents a unique trypanothione based redox system, which is responsible for maintaining the redox balance. Therefore, inhibition of these essential and exclusive parasite's metabolic pathways, absent from the mammalian host, could lead to the development of more efficient and safe drugs. The system contains different redox cascades, where trypanothione and tryparedoxins play together a central role in transferring reduced power to different enzymes, such as 2-Cys peroxiredoxins, non-selenium glutathione peroxidases, ascorbate peroxidases, glutaredoxins and methionine sulfoxide reductases, through NADPH as a source of electrons. There is sufficient evidence that this complex system is essential for parasite survival and infection. In this review, we explore what is known in terms of essentiality, kinetic and structural data, and the development of inhibitors of enzymes from this trypanothione-based redox system. The recent advances and limitations in the development of lead inhibitory compounds targeting these enzymes have been discussed. The combination of molecular biology, bioinformatics, genomics, and structural biology is fundamental since the knowledge of unique features of the trypanothione-dependent system will provide tools for rational drug design in order to develop better treatments for these diseases.
2. Polyamine-trypanothione pathway: an update
Andrea Ilari, Annarita Fiorillo, Ilaria Genovese, Gianni Colotti Future Med Chem. 2017 Jan;9(1):61-77. doi: 10.4155/fmc-2016-0180. Epub 2016 Dec 13.
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.
3. The trypanothione system
Luise R Krauth-Siegel, Marcelo A Comini, Tanja Schlecker Subcell Biochem. 2007;44:231-51. doi: 10.1007/978-1-4020-6051-9_11.
Trypanosomes and Leishmania, the causative agents of severe tropical diseases, employ 2-Cys-peroxiredoxins together with cysteine-homologues of glutathione peroxidases and ascorbate-dependent peroxidases for the detoxification of hydroperoxides. All three types of peroxidases gain their reducing equivalents from the parasite-specific dithiol trypanothione [bis(glutathionyl)spermidine]. Based on their primary structure and cellular localization, the trypanosomatid 2-Cys-peroxiredoxins are subdivided into two families that occur in the mitochondrion and cytosol of the parasites. In Trypanosoma brucei, the cytosolic 2-Cys-peroxiredoxin, as well as the glutathione peroxidase-type enzyme, is essential for cell viability. Despite overlapping substrate specificities and subcellular localizations, the two types of peroxidases can obviously not substitute for each other which suggests distinct cell-physiological roles.
