Spiro-containing derivatives show antiparasitic activity against Trypanosoma brucei through inhibition of the trypanothione reductase enzyme
| Autor: | Alberto Bresciani, Esther Torrente De Haro, Giacomo Paonessa, Gianni Colotti, Antonino Missineo, Annarita Fiorillo, Cristina Alli, Theo Battista, Andrea Ilari, Steven J. Harper, Lorenzo Turcano |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Protein Conformation highthroughput screening RC955-962 Glutathione reductase Trypanothione Drug Evaluation Preclinical Plasma protein binding Crystallography X-Ray Biochemistry chemistry.chemical_compound 0302 clinical medicine Arctic medicine. Tropical medicine Zoonoses Medicine and Health Sciences NADH NADPH Oxidoreductases Enzyme Inhibitors chemistry.chemical_classification Protozoans Crystallography biology Physics trypanothione reductase Eukaryota HTS neglected tropical diseases Condensed Matter Physics Glutathione Chemistry Infectious Diseases Physical Sciences Crystal Structure Public aspects of medicine RA1-1270 Protein Binding Research Article Neglected Tropical Diseases Chemical Elements Trypanosoma Antiparasitic medicine.drug_class 030231 tropical medicine Trypanosoma brucei brucei Antiprotozoal Agents Trypanosoma brucei African Trypanosomiasis 03 medical and health sciences Trypanosomiasis medicine Trypanosoma Brucei Parasitic Diseases Solid State Physics Histidine Binding Sites Protozoan Infections Public Health Environmental and Occupational Health Organisms Biology and Life Sciences biology.organism_classification Tropical Diseases Parasitic Protozoans Carbon High-Throughput Screening Assays 030104 developmental biology Enzyme chemistry Enzymology Peptides Toluene Trypanosoma Brucei Gambiense |
| Zdroj: | 'PLoS Neglected Tropical Diseases ', vol: 14, pages: e0008339-1-e0008339-17 (2020) PLoS Neglected Tropical Diseases PLoS Neglected Tropical Diseases, Vol 14, Iss 5, p e0008339 (2020) |
| ISSN: | 1935-2735 |
| Popis: | 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. Author summary Trypanosoma brucei is a parasite responsible for neglected pathologies such as human African trypanosomiasis, also known as sleeping sickness. This disease is endemic in sub-Saharan Africa, with 70 million people at risk of infection. Current treatments for this type of disease are limited by their toxicity, administration in endemic countries and treatment resistance. Therapies against infectious diseases typically rely on targeting one or more components of the parasite that are not present in humans to ensure the best possible therapeutic window. In this case we aimed at targeting the Trypanosoma brucei trypanothione reductase (TR), one enzyme that synthesize the reduced trypanothione a key molecule for preserving the parasite redox balance. This enzyme does not exist in humans that have glutathione instead of trypanothione. Past attempts to identify novel inhibitors of this target has failed to generate drug-like molecules. To overcome this limitation we employed a recent, higher quality, TR activity assay to test a collection of compounds previously reported to be active against these parasites. This approach led to the identification and validation of a new chemotype with a unique mode of inhibition of TR. This chemical series is a drug-like starting point, in fact its core (spiro) is present in drugs approved for human use. |
| Databáze: | OpenAIRE |
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