The Inhibition of Thioredoxin Glutathione Reductase in Schistosoma mansoni
Session Number
A04
Advisor(s)
David Williams, Rush University Medical Center
Location
B-101
Start Date
28-4-2016 8:50 AM
End Date
28-4-2016 9:10 AM
Abstract
Schistosoma mansoni is a parasitic flatworm that is a causative agent of the disease schistosomiasis. Schistosomiasis plagues many third-world countries and is considered by the CDC to be a neglected tropical disease. Currently there is only one treatment: praziquantel. Praziquantel has many limitations, which necessitates discovery of a new treatment. The enzyme thioredoxin glutathione reductase (TGR) has been identified as vital to worm survival and been identified as a potential drug target. A screen of 350,000 compounds found 10,000 that inhibited TGR, and of these 2,000 were screened against thioredoxin reductase, glutathione reductase, and mammalian cells. Following up on this study, 42 compounds were obtained and screened using a TGR-enzyme assay. Of these 42, 5 were found to have a half maximal inhibitory concentration (IC50) lower than 10 micromolar (μM), the threshold set for a compound to be suitable for drug development. These five were sent to other labs for further study. In a second follow-up study an additional five compounds that were obtained and screened using the same assay; three of these were found to have an IC50 of less than 10 μM. Other work being done on these compounds includes testing for activity against live worms and structural studies to identify the binding site of the inhibitors.
The Inhibition of Thioredoxin Glutathione Reductase in Schistosoma mansoni
B-101
Schistosoma mansoni is a parasitic flatworm that is a causative agent of the disease schistosomiasis. Schistosomiasis plagues many third-world countries and is considered by the CDC to be a neglected tropical disease. Currently there is only one treatment: praziquantel. Praziquantel has many limitations, which necessitates discovery of a new treatment. The enzyme thioredoxin glutathione reductase (TGR) has been identified as vital to worm survival and been identified as a potential drug target. A screen of 350,000 compounds found 10,000 that inhibited TGR, and of these 2,000 were screened against thioredoxin reductase, glutathione reductase, and mammalian cells. Following up on this study, 42 compounds were obtained and screened using a TGR-enzyme assay. Of these 42, 5 were found to have a half maximal inhibitory concentration (IC50) lower than 10 micromolar (μM), the threshold set for a compound to be suitable for drug development. These five were sent to other labs for further study. In a second follow-up study an additional five compounds that were obtained and screened using the same assay; three of these were found to have an IC50 of less than 10 μM. Other work being done on these compounds includes testing for activity against live worms and structural studies to identify the binding site of the inhibitors.