Structure-guided approach to identify a novel class of anti-leishmaniasis diaryl sulfide compounds targeting the trypanothione metabolism

Colotti, Gianni; Saccoliti, Francesco; Gramiccia, Marina; Muccio, Trentina Di; Prakash, Jay; Yadav, Sunita; Dubey, Vikash Kumar; Vistoli, Giulio; Battista, Theo; Mocci, Stefano; Fiorillo, Annarita; Bibi, Aasia; Madia, Valentina Noemi; Messore, Antonella; Costi, Roberta; Santo, Roberto Di; Ilari, Andrea

doi:10.1007/s00726-019-02731-4

Cited by 17 publications

(9 citation statements)

References 43 publications

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“…Recombinant L. donovani trypanothione reductase (LdTryR) 47 was kindly provided by Dr. Neena Goyal, The CSIR-Central Drug Research Institute, Lucknow, India. An enzyme inhibition assay was performed spectrophotometrically 58 . The enzyme inhibition kinetics were determined in an assay mixture (40 mM HEPES, 1 mM EDTA at pH 7.5) containing LdTryR and the substrate trypanothione disulphide T(S) 2 (Sigma-Aldrich) at varying concentrations (25, 50, 100 and 200 µM), where β-sitosterol CCL as an inhibitor was added at concentrations of 0, 3.75, 7.5, and 15 µg/ml.…”

Section: Measurement Of Non-protein Thiols In β-Sitosterol CCL -Treatmentioning

confidence: 99%

Bioassay-based Corchorus capsularis L. leaf-derived β-sitosterol exerts antileishmanial effects against Leishmania donovani by targeting trypanothione reductase

Pramanik

Chakraborti

Bagchi

et al. 2020

Sci Rep

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Leishmaniasis, a major neglected tropical disease, affects millions of individuals worldwide. Among the various clinical forms, visceral leishmaniasis (VL) is the deadliest. Current antileishmanial drugs exhibit toxicity- and resistance-related issues. Therefore, advanced chemotherapeutic alternatives are in demand, and currently, plant sources are considered preferable choices. Our previous report has shown that the chloroform extract of Corchorus capsularis L. leaves exhibits a significant effect against Leishmania donovani promastigotes. In the current study, bioassay-guided fractionation results for Corchorus capsularis L. leaf-derived β-sitosterol (β-sitosterolCCL) were observed by spectroscopic analysis (FTIR, 1H NMR, 13C NMR and GC–MS). The inhibitory efficacy of this β-sitosterolCCL against L. donovani promastigotes was measured (IC50 = 17.7 ± 0.43 µg/ml). β-SitosterolCCL significantly disrupts the redox balance via intracellular ROS production, which triggers various apoptotic events, such as structural alteration, increased storage of lipid bodies, mitochondrial membrane depolarization, externalization of phosphatidylserine and non-protein thiol depletion, in promastigotes. Additionally, the antileishmanial activity of β-sitosterolCCL was validated by enzyme inhibition and an in silico study in which β-sitosterolCCL was found to inhibit Leishmania donovani trypanothione reductase (LdTryR). Overall, β-sitosterolCCL appears to be a novel inhibitor of LdTryR and might represent a successful approach for treatment of VL in the future.

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Section: Measurement Of Non-protein Thiols In β-Sitosterol CCL -Treatmentioning

confidence: 99%

Bioassay-based Corchorus capsularis L. leaf-derived β-sitosterol exerts antileishmanial effects against Leishmania donovani by targeting trypanothione reductase

Pramanik

Chakraborti

Bagchi

et al. 2020

Sci Rep

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“…Various chemical structures were reported with TR inhibitor activity and leishmaniacidal activity to the literature: Ag(0) nanoparticles encapsulated by ferritin molecules [89], Cu(II) diketonates [90], oxabicyclo[3.3.1]nonanones [73], azole-based compounds -e. pyrrole [91], β-carboline-quinazolinone hybrid [92], phenothiazine and phenoxazine derived chloroacetamides [93], selenocyanates and diselenide compounds [94,95], iminodibenzyl derivatives with ethylenediamine, ethanolamine and diethylenetriamine and their copper(II) complexes [96], diaryl sulfide derivatives [97], ammonium trichloro [1,2-ethanediolato-O,O′]-tellurat [98], all-hydrocarbon stapled peptides [99] chalcone derivatives [100], thiophene derivatives [101], imidazole-phenyl-thiazole compounds [102], isothiocyanate derivatives [103], (phenylthio)pyrimidin-4-amine derivatives [104], ferrocenylquinoline derivatives [105], triazole-phenyl-thiazoles derivatives [106], fluorene derivatives [107], adamantan derivatives, and their gold complexes [108] and natural products [109,110] (Figure 6).…”

Section: Trypanothione Reductase (Tr Tryr Trypanothione-disulfide Red...mentioning

confidence: 99%

Toward New Antileishmanial Compounds: Molecular Targets for Leishmaniasis Treatment

Istanbullu¹,

Bayraktar²

2022

Leishmaniasis - General Aspects of a Stigmatized Disease

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The leishmaniases are a group of diseases caused by protozoan parasites—Leishmania sp. Leishmaniasis is classified among the 20 neglected diseases by WHO. Although the disease has been known for more than 120 years, the number of drugs used for the treatment is still limited to 5–6. The first-line drugs against leishmaniasis are pentavalent antimonials, which were introduced to the treatment 70 years ago—despite all their side effects. Molecular targets are becoming increasingly important for efficacy and selectivity in postgenomic drug research studies. In this chapter, we have discussed potential therapeutic targets of antileishmanial drug discovery such as pteridine reductase (PTR1), trypanothione reductase (TR), N-myristoyltransferase (NMT), trypanothione synthetase (TryS), IU-nucleoside hydrolase, and topoisomerases, enzymes and their inhibitors reported in the literature.

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“…The other two molecules interact with the NADPH-binding site and are discussed later. Based on the structural information, a series of new derivatives have been synthesized, one of which has a higher activity on parasite cultures (IC50 11 µM) and is able to decrease the reduced-T(SH) 2 concentration in cell [25]. However, this new compound is less effective in TR inhibition (K i 12 µM) and docking studies suggest that it prefers the second outermost binding site, indicating that it likely has other intracellular targets besides TR.…”

Section: Catalytic Sitementioning

confidence: 99%

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

et al. 2020

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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.

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Structure-guided approach to identify a novel class of anti-leishmaniasis diaryl sulfide compounds targeting the trypanothione metabolism

Cited by 17 publications

References 43 publications

Bioassay-based Corchorus capsularis L. leaf-derived β-sitosterol exerts antileishmanial effects against Leishmania donovani by targeting trypanothione reductase

Bioassay-based Corchorus capsularis L. leaf-derived β-sitosterol exerts antileishmanial effects against Leishmania donovani by targeting trypanothione reductase

Toward New Antileishmanial Compounds: Molecular Targets for Leishmaniasis Treatment

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

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