| Revista: | Memorias do Instituto Oswaldo Cruz |
| Base de datos: | PERIÓDICA |
| Número de sistema: | 000459448 |
| ISSN: | 0074-0276 |
| Autores: | Gomes, Bárbara Figueira1 Senger, Mario Roberto1 Moreira-Filho, José Teófilo2 Vasconcellos-Junior, Fabio Jorge de1 Dantas, Rafael Ferreira1 Owens, Raymond3 Andrade, Carolina Horta2 Neves, Bruno Junior2 Silva-Junior, Floriano Paes1 |
| Instituciones: | 1Fundacao Oswaldo Cruz, Instituto Oswaldo Cruz, Rio de Janeiro. Brasil 2Universidade Federal de Goias, Faculdade de Farmacia, Goiania, Goias. Brasil 3University of Oxford, Oxford, Oxfordshire. Reino Unido |
| Año: | 2023 |
| Volumen: | 118 |
| País: | Brasil |
| Idioma: | Inglés |
| Tipo de documento: | Artículo |
| Enfoque: | Experimental, aplicado |
| Resumen en inglés | Schistosomiasis is a neglected tropical disease caused by trematodes of the genus Schistosoma, with a limited treatment, mainly based on the use of praziquantel (PZQ). Currently, several aspartic proteases genes have already been identified within the genome of Schistosoma species. At least one enzyme encoded from this gene family (SmAP), named SmCD1, has been validated for the development of schistosomicidal drugs, since it has a key role in haemoglobin digestion by worms. OBJECTIVE In this work, we integrated a structure-based virtual screening campaign, enzymatic assays and adult worms ex vivo experiments aiming to discover the first classes of SmCD1 inhibitors. METHODS Initially, the 3D-structures of SmCD1, SmCD2 and SmCD3 were generated using homology modelling approach. Using these models, we prioritised 50 compounds from 20,000 compounds from ChemBridge database for further testing in adult worm aqueous extract (AWAE) and recombinant SmCD1 using enzymatic assays. FINDINGS Seven compounds were confirmed as hits and among them, two compounds representing new chemical scaffolds, named 5 and 19, had IC50 values against SmCD1 close to 100 μM while presenting binding efficiency indexes comparable to or even higher than pepstatin, a classical tight-binding peptide inhibitor of aspartyl proteases. Upon activity comparison against mammalian enzymes, compound 50 was selective and the most potent against the AWAE aspartic protease activity (IC50 = 77.7 μM). Combination of computational and experimental results indicate that compound 50 is a selective inhibitor of SmCD2. Compounds 5, 19 and 50 tested at low concentrations (10 uM) were neither cytotoxic against WSS-1 cells (48 h) nor could kill adult worms ex-vivo, although compounds 5 and 50 presented a slight decrease on female worms motility on late incubations times (48 or 72 h). MAIN CONCLUSION Overall, the inhibitors identified in this work represent promising hits for further hit-to |
| Disciplinas: | Biología |
| Palabras clave: | Protozoarios, Bioquímica, Inhibidores enzimáticos, Proteasa aspártica, Monitoreo virtual, Schistosoma mansoni |
| Keyword: | Protozoa, Biochemistry, Enzyme inhibitors, Schistosoma mansoni, Aspartic protease, Virtual screening |
| Texto completo: | Texto completo (Ver HTML) Texto completo (Ver PDF) |
