First non-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo

Abstract Only one drug, praziquantel, is available for treating schistosomiasis, a disease affecting more than 200 million people. Laboratory studies have shown that schistosome worms can develop resistance to praziquantel and low cure rates from mass drug administration programs suggest that resistance is evolving in the field. Previous studies have identified thioredoxin glutathione reductase (TGR), a selenoprotein, as essential for schistosome survival, and therefore, a target for much-needed new therapeutics for schistosomiasis. Compounds targeting TGR identified to date are irreversible and/or covalent inhibitors. Both potassium antimonial tartrate and oltipraz inhibit TGR and were used clinically for schistosomiasis treatment but their use was discontinued due to unacceptable side effects. These findings highlight the importance of the development of non-covalent, metabolically stable, and druglike TGR inhibitors. To identify TGR inhibitors for clinical use, small molecule fragments obtained by X-ray crystallography screening were ligated and partially optimized as first-in-class non-covalent inhibitors of TGR. A first cryo-EM structure of TGR demonstrated that these inhibitors bind at a secondary site preventing the NADPH oxidation steps. These compounds display schistosomicidal activity against different parasite-life cycle stages reaching the nanomolar range. Most importantly, novel druglike and orally bioavailable TGR inhibitors demonstrated efficacy against schistosome infections in mice, meeting the criteria for lead progression indicated by WHO and significantly outperformed praziquantel against juvenile worms. These findings open a new avenue for the development of therapeutics for the treatment of schistosomiasis.