High-throughput screening against thioredoxin glutathione reductase identifies novel inhibitors with potential therapeutic value for schistosomiasis

Infectious Diseases of Poverty
Ting LiMing-wei Wang

Abstract

Schistosomiasis, a parasitic disease also known as bilharzia and snail fever, is caused by different species of flatworms, such as Schistosoma mansoni (S. mansoni). Thioredoxin glutathione reductase (TGR) from S. mansoni (SmTGR) is a well-characterized drug target for schistosomiasis, yet no anti-SmTGR compounds have reached clinical trials, suggesting that therapeutic development against schistosomiasis might benefit from additional scaffolds targeting this enzyme. A high-throughput screening (HTS) assay in vitro against SmTGR was developed and applied to a diverse compound library. SmTGR activity was quantified with ThioGlo®, a reagent that fluoresces upon binding to the free sulfhydryl groups of the reaction product GSH (reduced glutathione). We implemented an HTS effort against 59,360 synthetic compounds. In the primary screening, initial hits (928 or 1.56 %) showing greater than 90 % inhibition on SmTGR activity at a final concentration of 10 μM for each compound were identified. Further tests were carried out to confirm the effects of these hits and to explore the concentration-dependent response characteristics. As a result, 74 of them (0.12 %) representing 17 chemical scaffolds were confirmed and showed a great concentr...Continue Reading

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Citations

Nov 22, 2015·Nucleic Acids Research·Bjoern-Oliver GohlkeRobert Preissner
Mar 1, 2016·Free Radical Biology & Medicine·Narciso CoutoJill Barber
May 31, 2016·Parasitology International·Timir TripathiBanchob Sripa
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Jan 29, 2019·PLoS Neglected Tropical Diseases·Sören FrahmClarissa Prazeres da Costa
May 20, 2016·Apoptosis : an International Journal on Programmed Cell Death·Hongzhi WangLeilei Fu
Dec 15, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Audronė MarozienėNarimantas Čėnas
Jun 29, 2018·Infectious Diseases of Poverty·Hong-Bo WengMing-Wei Wang
Dec 19, 2018·Pharmaceutical Research·Helen W HernandezSean Ekins
Jan 13, 2021·ACS Infectious Diseases·Kimberley M ZornConor R Caffrey
Jan 23, 2021·RSC Medicinal Chemistry·Godwin Akpeko DziwornuKelly Chibale
Jun 18, 2021·Frontiers in Immunology·José T Moreira-FilhoCarolina H Andrade
Mar 12, 2020·ACS Infectious Diseases·Timir Tripathi, Purna B Chetri

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Methods Mentioned

BETA
fluorescence

Software Mentioned

AMRESCO
GraphPad Prism®

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