| |
[摘要]：Alzheimer's disease (AD) is the most common cause of dementia, and currently there is no clinical treatment to cure it or to halt its progression. Aggregation and fibril formation of beta-amyloid peptides (A beta) are central events in the pathogenesis of AD. Many efforts have been spent on the development of effective inhibitors to prevent A beta fibrillogenesis and cause disaggregation of preformed A beta fibrils. In this study, the conjugates of ferrocene and Gly-Pro-Arg (GPR) tripeptide, Boc-Gly-Pro-Arg(NO2)-Fca-OMe (4, GPR-Fca) and Fc-Gly-Pro-Arg-OMe (7, Fc-GPR) (Fc: ferrocene; Fca: ferrocene amino acid) were synthesized by HOBT/HBTU protocol in solution. These ferrocene GPR conjugates were employed to inhibit A beta(1-42) fibrillogenesis and to disaggregate preformed A beta fibrils. The inhibitory properties of ferrocene GPR conjugates on A beta(1-42) fibrillogenesis were evaluated by thioflavin T (ThT) fluorescence assay, and confirmed by atomic force microscopy (AFM) analysis. The interaction between the ferrocene GPR conjugates and A beta(1-42) was monitored by electrochemical means. Our results showed that both GPR and GPR-Fca can significantly inhibit the fibril formation of A beta(1-42), and cause disaggregation of the preformed fibrils. As expected, GPR-Fca shows stronger inhibitory effect on A beta(1-42) fibrillogenesis than that of its parent peptide GPR. In contrast, Fc-GPR shows no inhibitory effect on fibrillogenesis of A beta(1-42). Furthermore, GPR-Fca demonstrates significantly protection against A beta-induced cytotoxicity and exhibits high resistance to proteolysis and good lipophilicity. (C) 2012 Elsevier Ltd. All rights reserved. |
|
