Identification of Thioredoxin Glutathione Reductase Inhibitors That Kill Cestode and Trematode Parasites

Fabiana Ross,Mariana Boiani,Hugo Cerecetto,Vadim N Gladyshev,Carlos Carmona,Williams Porcal,Tatiana Basika,Paola Hernández,Mariana Bonilla,Gloria V López,Gabriela Maggioli,Gustavo Salinas,Martín Fló,Mercedes González,Luis Eduardo Soares Netto

doi:10.1371/journal.pone.0035033

Fabiana Ross, Mariana Boiani + Show 13 more

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https://doi.org/10.1371/journal.pone.0035033

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Abstract

Parasitic flatworms are responsible for serious infectious diseases that affect humans as well as livestock animals in vast regions of the world. Yet, the drug armamentarium available for treatment of these infections is limited: praziquantel is the single drug currently available for 200 million people infected with Schistosoma spp. and there is justified concern about emergence of drug resistance. Thioredoxin glutathione reductase (TGR) is an essential core enzyme for redox homeostasis in flatworm parasites. In this work, we searched for flatworm TGR inhibitors testing compounds belonging to various families known to inhibit thioredoxin reductase or TGR and also additional electrophilic compounds. Several furoxans and one thiadiazole potently inhibited TGRs from both classes of parasitic flatworms: cestoda (tapeworms) and trematoda (flukes), while several benzofuroxans and a quinoxaline moderately inhibited TGRs. Remarkably, five active compounds from diverse families possessed a phenylsulfonyl group, strongly suggesting that this moiety is a new pharmacophore. The most active inhibitors were further characterized and displayed slow and nearly irreversible binding to TGR. These compounds efficiently killed Echinococcus granulosus larval worms and Fasciola hepatica newly excysted juveniles in vitro at a 20 µM concentration. Our results support the concept that the redox metabolism of flatworm parasites is precarious and particularly susceptible to destabilization, show that furoxans can be used to target both flukes and tapeworms, and identified phenylsulfonyl as a new drug-hit moiety for both classes of flatworm parasites.

Highlights

Flatworm infections are a major cause of human disability and mortality in many developing countries, and remains as one of the most important challenges for medicine in the 21st century [1,2]
Cystic echinococcosis or cystic hydatid disease caused by the larval stage of the dog tapeworm Echinococcus granulosus, the most widespread zoonosis caused by a cestode, remains a serious threat to human health
The rationale to screen the compounds using the TR assay was that both thioredoxin and glutathione reductase activities are dependent on the TR module of Thioredoxin glutathione reductase (TGR), and its inhibition leads to ablation of all thiol-disulfide oxidoreductase activities of TGR

Summary

Introduction

Flatworm infections are a major cause of human disability and mortality in many developing countries, and remains as one of the most important challenges for medicine in the 21st century [1,2]. Many flatworms parasitize livestock and cause economically important diseases. Cystic echinococcosis or cystic hydatid disease caused by the larval stage of the dog tapeworm Echinococcus granulosus, the most widespread zoonosis caused by a cestode, remains a serious threat to human health. Control programs of cystic echinococcosis are based on repeated anthelmintic treatment of dogs with praziquantel [5]. Praziquantel is the single effective drug for schistosomiasis treatment, the main chronic disease caused by flatworms, infecting 200 million people in tropical regions. A rational targetbased approach to the discovery of drug candidates holds promise to accelerate the process

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