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.

Assigning function to active site residues of Schistosoma mansoni thioredoxin/glutathione reductase from analysis of transient state reductive half-reactions with variant forms of the enzyme

“…Given that praziquantel is the only effective treatment for schistosomiasis, there is an increasing concern that drug resistance may become more prevalent (Utzinger et al, 2009;Wang et al, 2012). More recently, pursuit of alternative antiparasitic drugs have been made possible by a more in-depth investigation of metabolic pathways specific to schistosomes and by direct study of TGR (Silvestri et al, 2018;Fata et al, 2021;Petukhova et al, 2023).…”

G6PDH as a key immunometabolic and redox trigger in arthropods

“…In mammals this system is completely separated, in the other hand some invertebrate such as Flatworm and Schistosoma mansoni has encoded only one single gene, thioredoxin glutathione reductase (TGR) (Alger and Wiliams, 2002;Salinas et al, 2004;Otero et al, 2010). In the last 10 years this enzyme complex has received more attention, Ross et al, 2012;Petukhova et al, 2023 showed that thioredoxin glutathione reductase enzyme can be a potential target against these invertebrate animals.…”

Unveiling potent inhibitors for schistosomiasis through ligand-based drug design, molecular docking, molecular dynamics simulations and pharmacokinetics predictions

“…Non-covalent inhibitors of SmTGR offer several advantages over covalent inhibitors, including reversibility, selectivity, reduced potential for toxicity, ease of optimization, and lower risk of drug resistance. These properties make them promising candidates for the development of novel therapeutic agents against schistosomiasis [ 32 ]. Therefore, a collection of compounds exhibiting phenotypic antischistosomal activities served as the initial foundation for devising inhibitors targeting SmTGR, presenting a logical and effective method for identifying promising candidate compounds with possible therapeutic benefits against schistosomiasis [ 18 ].…”