Characterization of Lead Compounds Targeting the Selenoprotein Thioredoxin Glutathione Reductase for Treatment of Schistosomiasis

Abstract

Schistosomiasis is a widespread human parasitic disease currently affecting over 200 million people. Chemotherapy for schistosomiasis relies exclusively on praziquantel. Although significant advances have been made in recent years to reduce the incidence and intensity of schistosome infections, these gains will be at risk should drug-resistant parasites evolve. Thioredoxin glutathione reductase (TGR) is a selenoprotein of the parasite essential for the survival of schistosomes in the mammalian host. Several high-throughput screening campaigns have identified inhibitors of Schistosoma mansoni TGR. Follow up analyses of select active compounds form the basis of the present study. We identified eight compounds effective against ex vivo worms. Compounds 1–5 are active against all major species and development stages. The ability of these compounds to target immature worms is especially critical because praziquantel is poorly active against this stage. Compounds 1–5, 7, and 8 displayed schistosomicidal activity even after only 1 h incubation with the worms. Compounds 1–4 meet or exceed standards set by the World Health Organization for leads for schistosomiasis therapy activity. The mechanism of TGR inhibition was studied further with wild-type and mutant TGR proteins. Compounds 4–6 were found to induce an nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in TGR, leading to the production of superoxide and hydrogen peroxide. Collectively, this effort has identified several active compound series that may serve as the basis for the development of new schistosomicidal compounds.

Single oral fixed-dose praziquantel-miltefosine nanocombination for effective control of experimental schistosomiasis mansoni

“…Taking these concerns into consideration and given the modern resources of drug development, synthesis of PZQ derivatives [8], discovery of alternative lead compounds [9,10], natural products [11,12] and repurposing of existing drugs [13,14] are effective approaches for the introduction of new antischistosomal agents. Recently, we demonstrated that miltefosine (MFS), a membrane active alkylphosphocholine, is a promising repurposing candidate against schistosomiasis [13,15].…”

To inhibit TrxR1 is to inactivate STAT3–Inhibition of TrxR1 enzymatic function by STAT3 small molecule inhibitors

“…These inhibitors may be especially reactive with TrxR1 due to its crucial and highly nucleophilic selenocysteine (Sec) residue in the active site of the enzyme [ 15 , 23 ]. Stattic was furthermore recently found to target the TrxR1 orthologue of Schistosoma mansoni , again likely by binding directly to its Sec residue [ 24 ]. In addition, a potent inhibitor of TrxR1, Auranofin, which is clinically approved for treatment of rheumatoid arthritis and currently in trials for anticancer treatment, was also shown to potently inhibit Interleukin-6 dependent JAK1/STAT3 phosphorylation [ 25 ].…”

Schistosomiasis Drug Discovery in the Era of Automation and Artificial Intelligence

“…A recent work selected the most active chemotypes from HTS plus analogues and re-tested against the enzyme. Ninety-seven had SmTGR inhibitory activity confirmed, and five of them killed S. japonicum, S. haematobium and S. mansoni (with LD 50 ≤ 10 µM) adult worms, and all other development stages of S. mansoni (138). SmTGR has also been recently explored under the fragmentbased drug discovery paradigm, as it will be discussed further ahead in this review.…”