Structural insights into the enzymes of the trypanothione pathway: targets for antileishmaniasis drugs (original) (raw)
Related papers
Molecules, 2020
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,...
According to World Health Organization (WHO), trypanosomiasis and leishmaniasis are the most challenging among the neglected tropical diseases. Comparative studies between Leishmania spp and Trypanosoma cruzi have been conducted aiming to find a broad spectrum antiprotozoal agent acting against both parasites. Among the potential molecular target, Trypanothione reductase (TR) is considered an ideal enzyme since it is involved in the unique thiol-based metabolism observed in the Trypanosomatidae family and is a validated target for the search of antitrypanosomatidae drugs. In this review we intend to describe the currently available therapy to treat trypanosomatidae diseases and to highlight important aspects of trypanothione reductase as a target for the search of new and selective inhibitors, such as tricyclic, diphenylsulfide, bicyclic and heterocyclic, polyamine, natural product, N-oxide and nitroheterocyclic, aryl β- aminocarbonyl and α,β-unsaturated carbonyl derivatives
European Journal of Biochemistry, 1995
Trypanothione reductase was purified to homogeneity from Leishmania donovani promastigotes transfected with the expression plasmid pTEX-LdTR. The physical, spectral and kinetic properties were found to be similar to those obtained from other pathogenic trypanosomatids. The substrates trypanothione disulfide and NADPH exhibit Michaelis-Menten saturation kinetics with K,,, values of 36 pM and 9 pM, respectively, the former yielding a k,,,lK, of 5.0X lo6 M-' s?. Like other trypanothione reductases, the leishmania enzyme is unable to use glutathione disulfide as substrate.
In-silico Screening and Identification of Novel Trypanothione Reductase Inhibitor from Leishmania
Journal of Pharmaceutical Research International, 2022
The negative effects of leishmanicidal medications are numerous, and drug resistance to all of them has been observed. As a result, new medication development and the identification of novel therapeutic targets are critical. Leishmania major trypanothione reductase (Lm-TR), a NADPH-dependent flavoprotein oxidoreductase critical for thiol metabolism, is required for parasite viability. Since it lowers trypanothione, a chemical required by Leishmania's tryparedoxin/tryparedoxin peroxidase system to neutralise hydrogen peroxide (H2O2) produced by host macrophages during infection, this enzyme is essential for parasite survival in the host. Because it is not found in the mammalian host, this enzyme is a promising target for novel anti-leishmania medicines. A three-dimensional model of Lm-TR was created using I-TASSER server. Virtual screening of about 5000 sigma aldrich compounds, acquired from the ZINC database, was carried out using Autodock vina tool. Top ten compounds were tabu...
The trypanothione system and its implications in the therapy of trypanosomatid diseases
International Journal of Medical Microbiology, 2012
Biosynthesis and the use of trypanothione, a redox metabolite of parasitic trypanosomatids, are reviewed here with special emphasis on the development of trypanocidal drugs. This metabolic system is unique to and essential for the protozoal parasites. Selective inhibition of key elements of trypanothione metabolism, therefore, promises eradication of the parasites without affecting the host. Considering the metabolic importance and drugability of system components, inhibition of the enzymes for regeneration and de novo synthesis of trypanothione is rated as the most promising approach, while related peroxidases and redoxins are disregarded as targets because of limited chances to achieve selective inhibition. The organizational need to exploit the accumulating knowledge of trypanosomatid metabolism for medical practice is briefly addressed.
Thiol Metabolism of the Trypanosomatids as Potential Drug Targets
International Union of Biochemistry and Molecular Biology Life, 2002
Trypanosomatids produce significant amounts of four major low molecular mass thiols, trypanothione, glutathionylspermidine, glutathione, and ovothiol A. Of these, only glutathione is present in cells of the host. All four low molecular mass thiols are directly or indirectly maintained in a reduced state by trypanothione reductase. Available evidence, from gene disruption studies, indicate that this is an essential enzyme. Attempts to exploit trypanothione reductase as a chemotherapeutic target lead to the design of competitive and irreversible inhibitors of the enzyme. A promising route involves the design of redox cyclers interacting specifically with trypanothione reductase as subversive substrates. Progress in studies on the biosynthesis of ovothiol A is summarized. IUBMB Life, 53: 243-248, 2002
Biotechnology Advances, 2012
Parasitic trypanosomatids (Kinetoplastida) are the causative agents of devastating and hard-to-treat diseases such as African sleeping sickness, Chagas disease and various forms of Leishmaniasis. Altogether they affect N 30 Million patients, account for half a million fatalities p.a. and cause substantial economical problems in the Third World due to human morbidity and life stock losses. The design of efficacious and safe drugs is expected from inhibition of metabolic pathways that are unique and essential to the parasite and absent in the host. In this respect, the trypanothione system first detected in the insect-pathogenic trypanosomatid Crithidia fasciculata qualified as an attractive drug target area. The existence of the system in pathogenic relatives was established by homology cloning and PCR. The vital importance of the system was verified in Trypanosoma brucei by dsRNA technology or knock-out in other trypanosomatids, respectively, and is explained by its pivotal role in the parasite's antioxidant defense and DNA synthesis. The key system component is the bisglutathionyl derivative of spermidine, trypanothione. It is the proximal reductant of tryparedoxin which substitutes for thioredoxin-, glutaredoxin-and glutathione-dependent reactions. Heterologous expression, functional characterization and crystallization of recombinant system components finally enable structurebased rational inhibitor design.