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

• Published in: PLoS medicine 2007-06, Vol.4 (6), p.e206-e206
• Main Authors: Kuntz, Angela N, Davioud-Charvet, Elisabeth, Sayed, Ahmed A, Califf, Lindsay L, Dessolin, Jean, Arnér, Elias S J, Williams, David L
• Format: Article
• Language: English
• Subjects: Animals; Auranofin - pharmacology; Auranofin - therapeutic use; Biochemistry; Chemotherapy; Drug Design; Drug targeting; Drug therapy; Drugs and adverse drug reactions; Enzymes; Female; Genetic aspects; Health aspects; Infectious Diseases; Kinetics; Male; Medicin och hälsovetenskap; Medicine in Developing Countries; Methods; Mice; Mice, Inbred C57BL; Microbiology; Multienzyme Complexes - antagonists & inhibitors; Multienzyme Complexes - genetics; Multienzyme Complexes - metabolism; NADH, NADPH Oxidoreductases - antagonists & inhibitors; NADH, NADPH Oxidoreductases - genetics; NADH, NADPH Oxidoreductases - metabolism; Naphthoquinones - pharmacology; Naphthoquinones - therapeutic use; Oxidation-Reduction; Parasites; Potassium; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - metabolism; Reducing agents (Chemistry); RNA Interference; Schistosoma mansoni - drug effects; Schistosoma mansoni - enzymology; Schistosoma mansoni - growth & development; Schistosomiasis; Schistosomiasis mansoni - parasitology; Schistosomiasis mansoni - prevention & control; Schistosomicides - pharmacology; Schistosomicides - therapeutic use; Signal Transduction - drug effects; Tropical diseases; Worms
• ISSN: 1549-1676; 1549-1277; 1549-1676
• DOI: 10.1371/journal.pmed.0040206

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. 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. 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.