RESUMEN
Into the fold: Prion diseases are neurodegenerative disorders characterized by the accumulation in the brain of a self-replicating, misfolded isoform (PrPSc ) of the cellular prion protein (PrPC ). No therapies are available for these pathologies. We capitalized on previously described cell-based assays to screen a library of small molecules, and identified 55, a compound capable of counteracting both prion replication and toxicity. Compound 55 may represent the starting point for the development of a completely new class of therapeutics for prion diseases.
Asunto(s)
Proteínas Priónicas/metabolismo , Bibliotecas de Moléculas Pequeñas/metabolismo , Animales , Encéfalo/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células HEK293 , Humanos , Concentración 50 Inhibidora , Mutagénesis , Proteínas PrPSc/antagonistas & inhibidores , Proteínas PrPSc/genética , Proteínas PrPSc/metabolismo , Enfermedades por Prión/metabolismo , Enfermedades por Prión/patología , Proteínas Priónicas/antagonistas & inhibidores , Proteínas Priónicas/genética , Unión Proteica , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/toxicidadRESUMEN
We report the discovery of the bicyclic octahydrocyclohepta[b]pyrrol-4(1H)-one scaffold as a new chemotype with anti-HCV activity on genotype 1b and 2a subgenomic replicons. The most potent compound 34 displayed EC50 values of 1.8 µM and 4.5 µM in genotype 1b and 2a, respectively, coupled with the absence of any antimetabolic effect (gt 1b SI = 112.4; gt 2a SI = 44.2) in a cell-based assay. Compound 34 did not target HCV NS5B, IRES, NS3 helicase, or selected host factors, and thus future work will involve the unique mechanism of action of these new antiviral compounds.