No abstract

No abstract

Only praziquantel is available for treating schistosomiasis, a disease affecting more than 200 million people. Praziquantel-resistant worms have been selected for in the lab and low cure rates from mass drug administration programs suggest that resistance is evolving in the field. Thioredoxin glutathione reductase (TGR) is essential for schistosome survival and a validated drug target. TGR inhibitors identified to date are irreversible and/or covalent inhibitors with unacceptable off-target effects. In this work, we identify noncovalent TGR inhibitors with efficacy against schistosome infections in mice, meeting the criteria for lead progression indicated by WHO. Comparisons with previous in vivo studies with praziquantel suggests that these inhibitors outperform the drug of choice for schistosomiasis against juvenile worms.

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.

The demonstration of the first enzyme-based electrode to detect glucose, published in 1967 by S. J. Updike and G. P. Hicks, kicked off huge efforts in building sensors where biomolecules are exploited as native or modified to achieve new or improved sensing performances. In this growing area, bionanotechnology has become prominent in demonstrating how nanomaterials can be tailored into responsive nanostructures using biomolecules and integrated into sensors to detect different analytes, e.g., biomarkers, antibiotics, toxins and organic compounds as well as whole cells and microorganisms with very high sensitivity. Accounting for the natural affinity between biomolecules and almost every type of nanomaterials and taking advantage of well-known crosslinking strategies to stabilize the resulting hybrid nanostructures, biosensors with broad applications and with unprecedented low detection limits have been realized. This review depicts a comprehensive collection of the most recent biochemical and biophysical strategies for building hybrid devices based on bioconjugated nanomaterials and their applications in label-free detection for diagnostics, food and environmental analysis.