Potent Inhibitors of Thioredoxin Glutathione Reductase: Grail of Anti-Schistosome Drug within Reach?

Tripathi, Timir; Chetri, Purna B

doi:10.1021/acsinfecdis.0c00072

Cited by 5 publications

(2 citation statements)

References 11 publications

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“…The unusual approach exhibited by Schistosoma to limit oxidative damage has resulted in heavy reliance on a single enzyme to survive inside the host. Efforts to inhibit helminthic TGRs have identified numerous molecules that slow or halt activity. − The mode of inhibition for some of these molecules has been established by X-ray crystal structures, , while the mode of action for others either is proposed by docking or remain unknown . Despite its established importance, Schistosoma TGR has hitherto had no comprehensive transient-state analysis reported.…”

Section: Conclusive Remarksmentioning

confidence: 99%

Descriptive Analysis of Transient-State Observations for Thioredoxin/Glutathione Reductase (Sec597Cys) from Schistosoma mansoni

et al. 2023

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Thioredoxin/glutathione reductase from Schistosoma mansoni (SmTGR) catalyzes the reduction of both oxidized thioredoxin and glutathione with electrons from reduced nicotinamide adenine dinucleotide phosphate (NADPH). SmTGR is a drug target for the treatment of Schistosomiasis, an infection caused by Schistosoma platyhelminths residing in the blood vessels of the host. Schistosoma spp. are reliant on TGR enzymes as they lack catalase and so use reduced thioredoxin and glutathione to regenerate peroxiredoxins consumed in the detoxification of reactive oxygen species. SmTGR is a flavin adenine dinucleotide (FAD)-dependent enzyme, and we have used the flavin as a spectrophotometric reporter to observe the movement of electrons within the enzyme. The data show that NADPH fractionally reduces the active site flavin with an observed rate constant estimated in this study to be ∼3000 s −1 . The flavin then reoxidizes by passing electrons at a similar rate to the proximal Cys159−Cys154 disulfide pair. The dissociation of NADP + occurs with a rate of ∼180 s −1 , which induces the deprotonation of Cys159, and this coincides with the accumulation of an intense FAD-thiolate charge transfer band. It is proposed that the electrons then pass to the Cys596−Cys597 disulfide pair of the associated subunit in the dimer with a net rate constant of ∼2 s −1 . (Note: Cys597 is Sec597 in wild-type (WT) SmTGR.) From this position, the electrons can be passed to oxidized thioredoxin or further into the protein to reduce the Cys28− Cys31 disulfide pair of the originating subunit of the dimer. From the Cys28−Cys31 center, electrons can then pass to oxidized glutathione that has a binding site directly adjacent.

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Section: Conclusive Remarksmentioning

confidence: 99%

Descriptive Analysis of Transient-State Observations for Thioredoxin/Glutathione Reductase (Sec597Cys) from Schistosoma mansoni

et al. 2023

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“…Regarding the mechanism of action of PLUM on S. mansoni , its effect is attributed to the generation of reactive oxygen species (ROS) via NAD(P)H: quinone oxidoreductase 1 and the increase in H 2 O 2 , interfering in enzymes and proteins of the S. mansoni , reducing the glutathione reserve by the oxidation of GSH to GSSG, and resulting in lipid peroxidation and protein disorganization, thus affecting the worm’s ability to protect itself from free radicals, resulting in its death [ 63 , 65 , 86 , 87 ]. Furthermore, PLUM has an inhibitory activity on thioredoxin glutathione reductase (TGR), an enzyme that contains selenium and is essential for the survival of S. mansoni in the definitive host, being a promising target for drugs, since it is specific to the parasite and absent in its host [ 65 , 88 , 89 ].…”

Section: Resultsmentioning

confidence: 99%

Plumbagin: A Promising In Vivo Antiparasitic Candidate against Schistosoma mansoni and In Silico Pharmacokinetic Properties (ADMET)

Silva,

França,

Santos

et al. 2023

Biomedicines

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Schistosomiasis, a potentially fatal chronic disease whose etiological agents are blood trematode worms of the genus Schistosoma spp., is one of the most prevalent and debilitating neglected diseases. The treatment of schistosomiasis depends exclusively on praziquantel (PZQ), a drug that has been used since the 1970s and that already has reports of reduced therapeutic efficacy, related with the development of Schistosoma-resistant or -tolerant strains. Therefore, the search for new therapeutic alternatives is an urgent need. Plumbagin (PLUM), a naphthoquinone isolated from the roots of plants of the genus Plumbago, has aroused interest in research due to its antiparasitic properties against protozoa and helminths. Here, we evaluated the in vivo schistosomicidal potential of PLUM against Schistosoma mansoni and the in silico pharmacokinetic parameters. ADMET parameters and oral bioavailability were evaluated using the PkCSM and SwissADME platforms, respectively. The study was carried out with five groups of infected mice and divided as follows: an untreated control group, a control group treated with PZQ, and three groups treated orally with 8, 16, or 32 mg/kg of PLUM. After treatment, the Kato–Katz technique was performed to evaluate a quantity of eggs in the feces (EPG). The animals were euthanized for worm recovery, intestine samples were collected to evaluate the oviposition pattern, the load of eggs was determined on the hepatic and intestinal tissues and for the histopathological and histomorphometric evaluation of tissue and hepatic granulomas. PLUM reduced EPG by 65.27, 70.52, and 82.49%, reduced the total worm load by 46.7, 55.25, and 72.4%, and the female worm load by 44.01, 52.76, and 71.16%, for doses of 8, 16, and 32 mg/kg, respectively. PLUM also significantly reduced the number of immature eggs and increased the number of dead eggs in the oogram. A reduction of 36.11, 46.46, and 64.14% in eggs in the hepatic tissue, and 57.22, 65.18, and 80.5% in the intestinal tissue were also observed at doses of 8, 16, and 32 mg/kg, respectively. At all doses, PLUM demonstrated an effect on the histopathological and histomorphometric parameters of the hepatic granuloma, with a reduction of 41.11, 48.47, and 70.55% in the numerical density of the granulomas and 49.56, 57.63, and 71.21% in the volume, respectively. PLUM presented itself as a promising in vivo antiparasitic candidate against S. mansoni, acting not only on parasitological parameters but also on hepatic granuloma. Furthermore, in silico, PLUM showed good predictive pharmacokinetic profiles by ADMET.

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Functional expression, localization, and biochemical characterization of thioredoxin glutathione reductase from air-breathing magur catfish, Clarias magur

Koner

Nag

Kalita

et al. 2023

International Journal of Biological Macromolecules

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Potent Inhibitors of Thioredoxin Glutathione Reductase: Grail of Anti-Schistosome Drug within Reach?

Cited by 5 publications

References 11 publications

Descriptive Analysis of Transient-State Observations for Thioredoxin/Glutathione Reductase (Sec597Cys) from Schistosoma mansoni

Descriptive Analysis of Transient-State Observations for Thioredoxin/Glutathione Reductase (Sec597Cys) from Schistosoma mansoni

Plumbagin: A Promising In Vivo Antiparasitic Candidate against Schistosoma mansoni and In Silico Pharmacokinetic Properties (ADMET)

Functional expression, localization, and biochemical characterization of thioredoxin glutathione reductase from air-breathing magur catfish, Clarias magur

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