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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Thioredoxin glutathione reductase from Schistosoma mansoni: An essential parasite enzyme and a key drug target
PLoS Medicine, Volume 4, No. 6, Year 2007
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Description
Background: Schistosomiasis - infection with helminth parasites in the genus Schistosoma, including S. mansoni - is a widespread, devastating tropical disease affecting more than 200 million people. No vaccine is available, and praziquantel, the only drug extensively utilized, is currently administered more than 100 million people yearly. Because praziquantel resistance may develop it is essential to identify novel drug targets. Our goal was to investigate the potential of a unique, selenium-containing parasite enzyme thioredoxin glutathione reductase (TGR) as a drug target. Methods and Findings: Using RNA interference we found that TGR is essential for parasite survival; after silencing of TGR expression, in vitro parasites died within 4 d. We also found that auranofin is an efficient inhibitor of pure TGR (Ki = 10 nM), able to kill parasites rapidly in culture at physiological concentrations (5 μM), and able to partially cure infected mice (worm burden reductions of ∼60%). Furthermore, two previously used antischistosomal compounds inhibited TGR activity, suggesting that TGR is a key target during therapy with those compounds. Conclusions: Collectively, our results indicate that parasite TGR meets all the major criteria to be a key target for antischistosomal chemotherapy. To our knowledge this is the first validation of a Schistosoma drug target using a convergence of both genetic and biochemical approaches. © 2007 Kuntz et al.
Authors & Co-Authors
Davioud-Charvet, Elisabeth
Germany, Heidelberg
Universität Heidelberg
France, Paris
Cnrs Centre National de la Recherche Scientifique
Sayed, Ahmed Abdel Aziz
United States, Chicago
Illinois State University
Arnér, Elias S.J.
Sweden, Stockholm
Karolinska Institutet
Williams, David Lee
United States, Chicago
Illinois State University
Statistics
Citations: 310
Authors: 4
Affiliations: 5
Identifiers
Doi:
10.1371/journal.pmed.0040206
ISSN:
15491277
Research Areas
Cancer
Genetics And Genomics
Infectious Diseases