Targeting Trypanothione Reductase, a Key Enzyme in the Redox Trypanosomatid Metabolism, to Develop New Drugs against Leishmaniasis and Trypanosomiases

Abstract

The protozoans Leishmania and Trypanosoma, belonging to the same Trypanosomatidae family, are the causative agents of Leishmaniasis, Chagas disease, and human African trypanosomiasis. Overall, these infections affect millions of people worldwide, posing a serious health issue as well as socio-economical concern. Current treatments are inadequate, mainly due to poor efficacy, toxicity, and emerging resistance; therefore, there is an urgent need for new drugs. Among several molecular targets proposed, trypanothione reductase (TR) is of particular interest for its critical role in controlling the parasite's redox homeostasis and several classes of active compounds that inhibit TR have been proposed so far. This review provides a comprehensive overview of TR's structural characterization. In particular, we discuss all the structural features of TR relevant for drug discovery, with a focus on the recent advances made in the understanding of inhibitor binding. The reported cases show how, on the basis of the detailed structural information provided by the crystallographic analysis, it is possible to rationally modify molecular scaffolds to improve their properties.

Pseudoirreversible slow‐binding inhibition of trypanothione reductase by a protein–protein interaction disruptor

“…Trypanothione or N 1 ,N 8 ‐bis(glutathionyl)spermidine is a unique low MW molecule characteristic of trypanosomatids that replaces glutathione (GSH) as the main electron donor in the cell. It is made up of two molecules of GSH linked by a spermidine bridge (Battista, Colotti, Ilari, & Fiorillo, 2020). Trypanothione is necessary for many highly relevant cellular processes such as (i) protection of DNA from the damage generated by radicals (Awad, Henderson, Cerami, & Held, 1992); (ii) elimination of hydrogen peroxide, being much more efficient than other thiols present in trypanosomatids such as GSH, mono‐glutathionylspermidine and ovothiol A (Ariyanayagam & Fairlamb, 2001); (iii) detoxification of peroxynitrite (Thomson, Denicola, & Radi, 2003); (iv) reduction of protein and non‐protein disulfides (Ariyanayagam & Fairlamb, 2001); (v) synthesis of deoxyribonucleotides by ribonucleotide reductase (Dormeyer, Reckenfelderbäumer, Ludemann, & Krauth‐Siegel, 2001); (vi) resistance to chemotherapeutic agents (Baiocco, Colotti, Franceschini, & Ilari, 2009) and (vii) detoxification of methylglyoxal which, in almost all organisms, is detoxified by a system of GSH‐dependent glyoxalases I and II (Ariza et al, 2006; Irsch & Krauth‐Siegel, 2004).…”

“…Trypanothione, like glutathione, may exist in a reduced (T[SH] 2 ) or an oxidized (TS 2 ) form and it is maintained as T[SH] 2 by trypanothione reductase, an enzyme that fulfils the same function that glutathione reductase (now known as glutathione‐disulfide reductase) does in the systems based on GSH (Battista et al, 2020; Krauth‐Siegel & Comini, 2008). Trypanothione reductase (EC1.8.1.12) is a flavoenzyme that is responsible for reducing oxidized trypanothione and oxidized mono‐glutathionylspermidine using NADPH as an electron donor.…”

3-Methoxycarpachromene and Masticadienonic Acid as New Target Inhibitors from <em>Pistacia atlantica </em>Leaves against Trypanothione Reductase of Leishmania Parasites: In Vitro and In Silico Studies

“…It should be noted that trypanothione reductase structure is identical for all the characterised species of Trypanosomatidae (67% similarity of primary sequence from Trypanosomatidae, 82% identity between Leishmania spp. and >80% among Trypanosoma spp) [46]. So this result proves to be important in the treatment of all diseases linked to Trypanosomatidae species.…”

Epigallocathechin-O-3-Gallate Inhibits Trypanothione Reductase of Leishmania infantum, Causing Alterations in Redox Balance and Leading to Parasite Death

“…Other EGCG/TR interactions brought into light by this in silico analysis include: i) EGCG interaction with residues of the Z-site ( Figures 4B, C , blue circles), an hydrophobic cavity with interest for drug development owing to its accessibility by hydrophobic compounds with TR-inhibitory activity; and ii) EGCG docking near a hydrophobic wall formed by residues Leu17, Trp21 and Met113 ( Figure 4C , purple circles), which together form a target region for competitive inhibition by TR inhibitors ( Meiering et al., 2005 ; Baiocco et al., 2013 ; Colotti et al., 2013 ; Battista et al., 2020 ).…”