Thioredoxin glutathione reductase from Schistosoma mansoni: an essential parasite enzyme and a key drug target.
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.


RESULTS
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 microM), 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.
Kuntz
Angela N
AN
Department of Biological Sciences, Illinois State University, Normal, Illinois, United States of America.
Davioud-Charvet
Elisabeth
E
Sayed
Ahmed A
AA
Califf
Lindsay L
LL
Dessolin
Jean
J
Arnér
Elias S J
ES
Williams
David L
DL
D000818:Animals; D001310:Auranofin / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D005260:Female; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology / Q000627:therapeutic use; D010084:Oxidation-Reduction; D034622:RNA Interference; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D012555:Schistosomiasis mansoni / Q000469:parasitology / Q000517:prevention & control*; D012556:Schistosomicides / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
D009097:Multienzyme Complexes; D009285:Naphthoquinones; D011994:Recombinant Proteins; D012556:Schistosomicides; D001310:Auranofin; C005503:naphthazarin; D009247:NADH, NADPH Oxidoreductases; C466433:thioredoxin glutathione reductase