ArticlePLoS neglected tropical diseases2020
Spiro-containing derivatives show antiparasitic activity against Trypanosoma brucei through inhibition of the trypanothione reductase enzyme.
Article in PLoS neglected tropical diseases, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 20 citations in OpenAlex.
- Antitrypanosomal Activity and Molecular Docking Studies of Lobetyolin FromBioMed research international · 2026Article
- Targeting Trypanothione Synthetase and Trypanothione Reductase: Development of Common Inhibitors to Tackle Trypanosomatid Disease.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Targeting Trypanothione Metabolism in Trypanosomatids.Molecules (Basel, Switzerland) · 2024Review
- AnHeliyon · 2024Article
- Polyamine Metabolism for Drug Intervention in Trypanosomatids.Pathogens (Basel, Switzerland) · 2024Review
- In Silico Exploration of the Trypanothione Reductase (TryR) ofInternational journal of molecular sciences · 2023Article
- Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies.International journal of molecular sciences · 2023Review
- Innovative Approach for a Classic Target: Fragment Screening on Trypanothione Reductase Reveals New Opportunities for Drug Design.Frontiers in molecular biosciences · 2022Article
- Targeting Trypanothione Reductase, a Key Enzyme in the Redox Trypanosomatid Metabolism, to Develop New Drugs against Leishmaniasis and Trypanosomiases.Molecules (Basel, Switzerland) · 2020Review
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Authors and funding
11 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Trypanothione reductase (TR) is a key enzyme that catalyzes the reduction of trypanothione, an antioxidant dithiol that protects Trypanosomatid parasites from oxidative stress induced by mammalian host defense systems. TR is considered an attractive target for the development of novel anti-parasitic agents as it is essential for parasite survival but has no close homologue in humans. We report here the identification of spiro-containing derivatives as inhibitors of TR from Trypanosoma brucei (TbTR), the parasite responsible for Human African Trypanosomiasis. The hit series, identified by high throughput screening, was shown to bind TbTR reversibly and to compete with the trypanothione (TS2) substrate. The prototype compound 1 from this series was also found to impede the growth of Trypanosoma brucei parasites in vitro. The X-ray crystal structure of TbTR in complex with compound 1 solved at 1.98 Å allowed the identification of the hydrophobic pocket where the inhibitor binds, placed close to the catalytic histidine (His 461') and lined by Trp21, Val53, Ile106, Tyr110 and Met113. This new inhibitor is specific for TbTR and no activity was detected against the structurally similar human glutathione reductase (hGR). The central spiro scaffold is known to be suitable for brain active compounds in humans thus representing an attractive starting point for the future treatment of the central nervous system stage of T. brucei infections.
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