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.
Highlights
Trypanosoma spp. and Leishmania spp. are parasites belonging to Tryanosomatidae family that includes important pathogens of both human and animal
In the present work we identify a new inhibitor of T. brucei Trypanothione reductase (TR) (TbTR) by small molecule screening using an optimized luminescence assay able to measure in vitro TbTR activity [23]
The compounds that are made available through the CNCCS collection (c. 150000 compounds - www.cnccs.it) were crossed with the PubChem database to select those that were reported to be active in confirmatory Trypanosomatid survival assays. 3097 compounds were identified that were cherry-picked from 10 mM DMSO solutions and arrayed for testing in the present work
Summary
Trypanosoma spp. and Leishmania spp. are parasites belonging to Tryanosomatidae family that includes important pathogens of both human and animal. Oral compounds like fexinidazole or oxaboroles have come to fruition.[5] Fexinidazole, in particular is the first all-oral drug targeting both early and late stages of T. brucei gambiense sleeping sickness. [6] the inherent toxicity of some of these treatments, together with the dissemination of drug resistance [2,7,8], and the limited central nervous system (CNS) penetration to treat late stage HAT has limited the employment of these molecules, highlighting the need for new therapies to treat Trypanosoma parasite infections [2,8]. As a consequence the discovery and of new scaffolds able to inhibit TR activity is compulsory
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