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Abstract
Parasitic flatworms cause serious infectious diseases that affect humans and livestock in vast regions of the world, yet there are few effective drugs to treat them. Thioredoxin glutathione reductase (TGR) is an essential enzyme for redox homeostasis in flatworm parasites and a promising pharmacological target. We purified to homogeneity and characterized the TGR from the tapeworm Mesocestoides vogae (syn. M. corti). This purification revealed absence of conventional TR and GR. The glutathione reductase activity of the purified TGR exhibits a hysteretic behavior typical of flatworm TGRs. Consistently, M. vogae genome analysis revealed the presence of a selenocysteine-containing TGR and absence of conventional TR and GR. M. vogae thioredoxin and glutathione reductase activities were inhibited by 3,4-bis(phenylsulfonyl)-1,2,5-oxadiazole N2-oxide (VL16E), an oxadiazole N-oxide previously identified as an inhibitor of fluke and tapeworm TGRs. Finally, we show that mice experimentally infected with M. vogae tetrathyridia and treated with either praziquantel, the reference drug for flatworm infections, or VL16E exhibited a 28% reduction of intraperitoneal larvae numbers compared to vehicle treated mice. Our results show that oxadiazole N-oxide is a promising chemotype in vivo and highlights the convenience of M. vogae as a model for rapid assessment of tapeworm infections in vivo.
Highlights
Parasitic flatworms from two main classes, Cestoda and Trematoda, cause chronic human and livestock infections and are a major cause of disability, mortality and significant economic losses in most developing countries [1,2]
The deduced amino acid sequence indicates that M. vogae Thioredoxin glutathione reductase (TGR) contains an N-terminal glutaredoxin domain fused to a conventional thioredoxin reductase, similar to what has been observed for all other TGRs
The redox systems of several parasitic flatworms are unique in that conventional thioredoxin reductase (TR) and glutathione reductase (GR) have been replaced by TGR
Summary
Parasitic flatworms from two main classes, Cestoda (or tapeworms) and Trematoda (or flukes), cause chronic human and livestock infections and are a major cause of disability, mortality and significant economic losses in most developing countries [1,2]. A unique aspect of flatworm biochemistry is that these parasites are entirely dependent on the enzyme thioredoxin glutathione reductase (TGR, EC 1.8.1.B1) for the control of redox homeostasis and other essential processes. Corti) [21,22], a rodent cestode parasite that does not infect humans has been proposed as an important in vitro-in vivo model to test and study cestocidal and anthelmintic drugs [23,24,25], due to its rapid mouse infection and its close relationship to cestodes of medical relevance, such as those from Echinococcus or Taenia genera. We used M. vogae as a cestode experimental infection model to assess the efficacy of the previously identified TGR inhibitor VL16E. Our results highlight that M. vogae is a good model for flatworm parasite redox metabolism and provides further evidence that is a convenient model to examine cestocidal drugs in vivo.
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