Quantitative High-Throughput Screen Identifies Inhibitors of the Schistosoma mansoni Redox Cascade

@article{Simeonov2008QuantitativeHS,
  title={Quantitative High-Throughput Screen Identifies Inhibitors of the Schistosoma mansoni Redox Cascade},
  author={Anton Simeonov and Ajit Jadhav and Ahmed A. Sayed and Yuhong Wang and Michael E. Nelson and Craig J. Thomas and James Inglese and David L. Williams and Christopher P. Austin},
  journal={PLoS Neglected Tropical Diseases},
  year={2008},
  volume={2}
}
Schistosomiasis is a tropical disease associated with high morbidity and mortality, currently affecting over 200 million people worldwide. Praziquantel is the only drug used to treat the disease, and with its increased use the probability of developing drug resistance has grown significantly. The Schistosoma parasites can survive for up to decades in the human host due in part to a unique set of antioxidant enzymes that continuously degrade the reactive oxygen species produced by the host's… 

Figures and Tables from this paper

A 1,536-well-based kinetic HTS assay for inhibitors of Schistosoma mansoni thioredoxin glutathione reductase.
TLDR
The development of a highly miniaturized and robust screening assay for TGR is presented, based on the Ellman reagent [5,5'-dithiobis(2-nitrobenzoic acid) (DTNB)] and utilizes a high-speed absorbance kinetic read to minimize the effect of dust, absorbance interference, and meniscus variation.
Characterization of lead compounds targeting the selenoprotein thioredoxin glutathione reductase for treatment of schistosomiasis.
TLDR
This effort has identified several active compound series that may serve as the basis for the development of new schistosomicidal compounds.
Identification of oxadiazoles as new drug leads for the control of schistosomiasis
TLDR
Treatment of schistosome-infected mice with 4-phenyl-1,2,5-oxadiazole-3-carbonitrile-2-oxide led to marked reductions in worm burdens from treatments against multiple parasite stages and egg-associated pathologies, and protective effects exceed benchmark activity criteria set by the World Health Organization for lead compound development forschistosomiasis.
Cheminformatics Models for Inhibitors of Schistosoma mansoni Thioredoxin Glutathione Reductase
TLDR
It is shown that a combined approach of machine learning and other cheminformatics approaches such as substructure comparison and molecular docking is efficient to prioritise molecules from large molecular datasets.
The redox biology of schistosome parasites and applications for drug development.
TLDR
The redox biology of schistosomes is discussed and their potential use as drug targets is reviewed and it is hoped that compounds targeting parasite antioxidant responses will become clinically relevant drugs in the near future.
Targeting thioredoxin glutathione reductase as a potential antischistosomal drug target.
Inhibition of Schistosoma mansoni Thioredoxin-glutathione Reductase by Auranofin
TLDR
It is proposed that Sec mediates the transfer of gold from its ligands in AF to the redox-active Cys couples of TGR, and can be mimicked by an external source of selenium (benzeneselenol).
Redox-active antiparasitic drugs.
TLDR
The unique metabolic pathways along with redox enzymes of unicellular and multicellular parasites could be utilized to promote ROS-mediated toxicity and help researchers around the world in designing novel drugs in the future.
Identification of Thioredoxin Glutathione Reductase Inhibitors That Kill Cestode and Trematode Parasites
TLDR
The results support the concept that the redox metabolism of flatworm parasites is precarious and particularly susceptible to destabilization, show that furoxans can be used to target both flukes and tapeworms, and identify phenylsulfonyl as a new drug-hit moiety for both classes of Flatworm parasites.
Characterization of the Methionine Sulfoxide Reductases of Schistosoma mansoni
TLDR
Using real-time polymerase-chain reaction (RT-PCR), both proteins were found to be expressed in all stages of the parasite's life cycle, with the highest level of expression of both proteins in the egg stage, the first description of MsrB proteins from a parasite.
...
...

References

SHOWING 1-10 OF 46 REFERENCES
Thioredoxin Glutathione Reductase from Schistosoma mansoni: An Essential Parasite Enzyme and a Key Drug Target
TLDR
Investigating the potential of a unique, selenium-containing parasite enzyme thioredoxin glutathione reductase (TGR) as a drug target indicates that parasite TGR meets all the major criteria to be a key target for antischistosomal chemotherapy.
Redox Balance Mechanisms in Schistosoma mansoni Rely on Peroxiredoxins and Albumin and Implicate Peroxiredoxins as Novel Drug Targets*
TLDR
This study highlights Prx proteins as essential parasite proteins and potential new targets for anti-schistosome drug development and albumin as a novel, sacrificial oxidant scavenging protein in parasite redox regulation.
In Vitro and In Vivo Activities of Synthetic Trioxolanes against Major Human Schistosome Species
TLDR
The results, along with the low toxicity, metabolic stability, and good pharmacokinetic properties of the OZs, indicate the potential for the development of novel broad-spectrum antischistosomal OZ drug candidates.
Biochemical Characterization of 2-Cys Peroxiredoxins from Schistosoma mansoni*
TLDR
The ability of schistosome peroxiredoxins to use alternative electron donors, and their variable resistance to overoxidation may reflect their presence in different cellular sites and emphasizes the significant differences in overall redox balance mechanisms between the parasite and its mammalian host.
Artemisinins for schistosomiasis and beyond.
TLDR
The effect of artemisinin-based combination therapy on young children co-infected with Plasmodium sp and Schistosoma haematobium is described, and the promising activity of art Artemisinins against intestinal and liver flukes in vivo, as well as against cancer cells is reviewed.
Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide
TLDR
Results strongly suggest that the ATO anticancer activity is by means of a Trx system-mediated apoptosis, and blocking cancer cell DNA replication and repair and induction of oxidative stress by the inhibition of both Trx and GSH systems are suggested as cancer chemotherapeutic strategies.
Drug-resistant schistosomiasis: resistance to praziquantel and oxamniquine induced in Schistosoma mansoni in mice is drug specific.
TLDR
The results indicate that S. mansoni subjected to drug pressure may develop resistance to schistosomicidal drugs over the course of relatively few passages, but that cross-resistance between PZQ and OX does not occur.
A high-throughput screen for aggregation-based inhibition in a large compound library.
TLDR
Three key results emerge from this study: first, detergent-dependent identification of aggregate- based inhibition is feasible on the large scale, second, 95% of the actives obtained in this screen are aggregate-based inhibitors, and third, aggregate-Based inhibition is correlated with steep dose-response curves, although not absolutely.
...
...