RESUMO
Prion diseases are fatal neurodegenerative diseases caused by the conformational transition of the cellular prion protein (PrPC) to the abnormal pathological prion protein (PrPSc). In this work, the effects of ellagic acid (EA) and pentagalloylglucose (PGG) on prion protein (PrP) fibrillization were investigated. Fluorescence quenching experiments indicated that both EA and PGG could specifically interact with native human PrP with binding affinities of 1.92 × 105 and 2.36 × 105 L·mol-1, respectively. Thioflavin-T (ThT) fluorescence assays showed that the binding of EA or PPG could effectively inhibit the nucleation and elongation of PrP fibrilization and reduce the amount of PrP fibrils generated. EA and PGG could also lead to a significant disaggregation of PrP fibrils. Circular dichroism (CD) measurements suggested that EA- or PPG-bound PrP could preserve a higher content of α-helical structures than ß-sheet-rich PrP fibrils. The PrP aggregates formed in the presence of EA or PGG showed lower resistance to proteinase K (PK) digestion. Overall, the present work reported the inhibitory effect of EA and PGG on PrP fibrillization. These two natural polyphenols could be potential prodrug molecules for the prevention and treatment of prion diseases.
Assuntos
Ácido Elágico/farmacologia , Taninos Hidrolisáveis/farmacologia , Proteína PrP 27-30/antagonistas & inibidores , Proteínas PrPC/química , Agregados Proteicos/efeitos dos fármacos , Sítios de Ligação , Ácido Elágico/química , Humanos , Taninos Hidrolisáveis/química , Cinética , Simulação de Acoplamento Molecular , Proteína PrP 27-30/química , Proteínas PrPC/antagonistas & inibidores , Proteínas PrPC/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Dobramento de Proteína/efeitos dos fármacos , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , TermodinâmicaRESUMO
On the basis of the structural homologies between ST1859 (1[(2-hydroxy-1-naphtyl)methyl]-2-naphthol) and the anti-prion agents and its anti-amyloidogenic activity, we tested whether this molecule altered the biochemical properties of aggregates formed in vitro by synthetic prion peptides and affected prion infectivity in experimental scrapie. Co-incubation of ST1859 with the peptides PrP 106-126 and PrP 82-146 reduced their fibrillogenic capacity and their resistance to digestion with protease K. Hamsters inoculated with the ST1859-treated homogenate showed a significant delay in the onset of clinical signs of disease and longer survival. Survival was also significantly longer in infected hamsters treated peripherally with ST1859 for the whole post-inoculation period until the onset of clinical symptoms. Similar results were found with the analogue ST1745. Our data indicate that ST1859 reduces prion infectivity and can exert a therapeutic effect in experimental scrapie.
