In vivo and in vitro auranofin activity against Trypanosoma cruzi: Possible new uses for an old drug

Silva, Marco Túlio Alves da; Silva, Alexandre de Almeida e; Portapilla, Gisele Bulhões; Lima, G.M.A.; Costa, Fernanda Cristina; Aníbal, Fernanda de Freitas; Thiemann, Otávio Henrique

doi:10.1016/j.exppara.2015.05.012

Cited by 29 publications

(14 citation statements)

References 32 publications

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“…Compounds with an IC 50 less or equal to 10 µM were selected. As a positive control, parasites were incubated only in culture medium with a 1% DMSO concentration, corresponding to the highest sample dilution of DMSO [ 34 , 35 , 36 ].…”

Section: Methodsmentioning

confidence: 99%

Trypanocidal Activity of Quinoxaline 1,4 Di-N-oxide Derivatives as Trypanothione Reductase Inhibitors

et al. 2017

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Chagas disease or American trypanosomiasis is a worldwide public health problem. In this work, we evaluated 26 new propyl and isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives as potential trypanocidal agents. Additionally, molecular docking and enzymatic assays on trypanothione reductase (TR) were performed to provide a basis for their potential mechanism of action. Seven compounds showed better trypanocidal activity on epimastigotes than the reference drugs, and only four displayed activity on trypomastigotes; T-085 was the lead compound with an IC50 = 59.9 and 73.02 µM on NINOA and INC-5 strain, respectively. An in silico analysis proposed compound T-085 as a potential TR inhibitor with better affinity than the natural substrate. Enzymatic analysis revealed that T-085 inhibits parasite TR non-competitively. Compound T-085 carries a carbonyl, a CF3, and an isopropyl carboxylate group at 2-, 3- and 7-position, respectively. These results suggest the chemical structure of this compound as a good starting point for the design and synthesis of novel trypanocidal derivatives with higher TR inhibitory potency and lower toxicity.

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Section: Methodsmentioning

confidence: 99%

Trypanocidal Activity of Quinoxaline 1,4 Di-N-oxide Derivatives as Trypanothione Reductase Inhibitors

et al. 2017

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“…The anti-inammatory gold compound Auranon for example was effective in parasite infection control due to thiol redox enzyme inhibition effects. 35,36 However, unlike the gold nanoparticles the metal- We have proposed gold nanoparticles design earlier for effective control of parasite infections. 37 KAunps profound efficacy against macrophage infested L. donovani strains was likely due to thiol redox enzyme inhibition and kaempferol inhibition of parasite pyrimidine biosynthesis pathways.…”

Section: Antileishmanial Activity and Cytotoxicitymentioning

confidence: 99%

Rapid synthesis for monodispersed gold nanoparticles in kaempferol and anti-leishmanial efficacy against wild and drug resistant strains

et al. 2017

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“…While the precise mechanism and molecular target(s) of Auranofin’s anti-inflammatory activity have not been established, in a number of human parasites Auranofin is believed to inhibit antioxidant pathways maintaining the intracellular redox environment by targeting thiol redox enzymes such as thioredoxin reductase, thioredoxin-glutathione reductase (TGR) or trypanothione reductase (Angelucci et al, 2009; Caroli et al, 2012; Ilari et al, 2012; Prast-Nielsen et al, 2011; Sannella et al, 2008). In addition to E. histolytica and Giardia , unicellular human parasites in which Auranofin induces oxidative stress include Trypanosoma cruzi (da Silva et al, 2015), Leishmania infantum (Ilari et al, 2012), Leishmania donovani (Sharlow et al, 2014) and Plasmodium falciparum (Caroli et al, 2012), as well as parasitic flatworms Schistosoma mansoni (Angelucci et al, 2009), Schistosoma japonicum (Song et al, 2012) and Taenia crassiceps (Martinez-Gonzalez et al, 2015). Also, Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis (Harbut et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

X-ray structures of thioredoxin and thioredoxin reductase from Entamoeba histolytica and prevailing hypothesis of the mechanism of Auranofin action

Parsonage

Sheng

Hirata

et al. 2016

Journal of Structural Biology

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The anti-arthritic gold-containing drug Auranofin is lethal to the protozoan intestinal parasite Entamoeba histolytica, the causative agent of human amebiasis, in both culture and animal models of the disease. A putative mechanism of Auranofin action proposes that monovalent gold, Au(I), released from the drug, can bind to the redox-active dithiol group of thioredoxin reductase (TrxR). Au(I) binding in the active site is expected to prevent electron transfer to the downstream substrate thioredoxin (Trx), thus interfering with redox homeostasis in the parasite. To clarify the molecular mechanism of Auranofin action in more detail, we determined a series of atomic resolution x-ray structures for E. histolytica thioredoxin (EhTrx) and thioredoxin reductase (EhTrxR), the latter with and without Auranofin. Only the disulfide-bonded form of the active site dithiol (Cys140-Cys143) was invariably observed in crystals of EhTrxR in spite of the addition of reductants in various crystallization trials, and no gold was found associated with these cysteines. Non-catalytic Cys286 was identified as the only site of modification, but further mutagenesis studies using the C286Q mutant demonstrated that this site was not responsible for inhibition of EhTrxR by Auranofin. Interestingly, we obtained both of the catalytically-relevant conformations of this bacterial-like, low molecular weight TrxR in crystals without requiring an engineered disulfide linkage between Cys mutants of TrxR and Trx (as was originally done with E. coli TrxR and Trx). We note that the –CXXC– catalytic motif, even if reduced, would likely not provide space sufficient to bind Au(I) by both cysteines of the dithiol group.

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In vivo and in vitro auranofin activity against Trypanosoma cruzi: Possible new uses for an old drug

Cited by 29 publications

References 32 publications

Trypanocidal Activity of Quinoxaline 1,4 Di-N-oxide Derivatives as Trypanothione Reductase Inhibitors

Trypanocidal Activity of Quinoxaline 1,4 Di-N-oxide Derivatives as Trypanothione Reductase Inhibitors

Rapid synthesis for monodispersed gold nanoparticles in kaempferol and anti-leishmanial efficacy against wild and drug resistant strains

X-ray structures of thioredoxin and thioredoxin reductase from Entamoeba histolytica and prevailing hypothesis of the mechanism of Auranofin action

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