Research Article: Thioredoxin Glutathione Reductase from Schistosoma mansoni: An Essential Parasite Enzyme and a Key Drug Target

Date Published: June 19, 2007

Publisher: Public Library of Science

Author(s): Angela N Kuntz, Elisabeth Davioud-Charvet, Ahmed A Sayed, Lindsay L Califf, Jean Dessolin, Elias S. J Arnér, David L Williams, Alex Loukas

Abstract: BackgroundSchistosomiasis—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 FindingsUsing 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.ConclusionsCollectively, 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.

Partial Text: Schistosomiasis (also known as bilharzia)—infection with the helminth parasites in the genus Schistosoma—remains an important infection in many tropical areas, especially Africa. More than 200 million people have schistosomiasis, with 20 million exhibiting severe symptoms. Recent analyses suggest that the morbidity due to schistosomiasis is grossly underestimated [1], resulting in an estimated 280,000 deaths annually in sub-Saharan Africa alone [2]. Since the mid-1980s praziquantel (Figure S1) has been the drug of choice for schistosomiasis; effectively it is currently the only choice available. Artemether has shown promise as a new drug for schistosomiasis, targeting larval parasites more effectively than praziquantel, which is primarily effective against adult parasites [3]. However, the use of artemether for schistosomiasis should be restricted so that its use as an antimalarial compound is not put at risk from the development of possible drug resistance in the malaria parasite. With the exception of the artemisinin-based drugs, no new drugs have been introduced for schistosomiasis after praziquantel, and prior drugs have ceased to be produced or are ineffective [4]. Furthermore, resistance to oxamniquine, which is effective against S. mansoni, has been reported [5], thereby reducing its potential usefulness. Research for new antischistosome drugs is limited by the difficulty of working with the parasite and the low priority the pharmaceutical industry generally places on tropical diseases. Currently more than 100 million people are being treated for schistosomiasis with praziquantel [2]; they are rapidly reinfected and must be retreated on an annual or semiannual basis. If praziquantel-resistant parasites develop, treatment for schistosomiasis will be in a crisis state.

In this study we have demonstrated that TGR is an essential protein for the survival of S. mansoni and that it meets all the major criteria of an important target for antischistosomal chemotherapy development. Silencing of TGR expression by RNAi lead to rapid parasite death, and auranofin, a specific chemical inhibitor of TGR, provides partial parasitological cures of infected mice. We have screened a number of TGR inhibitors and identified potential lead compounds for novel drug development. Furthermore, we demonstrated that TGR was likely a key target of some earlier therapies.



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