Département de chimie moléculaire

Amyloid formation and accumulation of the amyloid $\beta$-peptide (A$\beta$) in the brain is assocd. with Alzheimer's disease (AD) pathogenesis. Therefore, among the therapeutic approaches in development to fight the disease, the direct inhibition of the A$\beta$ self-assembly process is currently widely investigated and is one of the most promising approaches. In this study we investigated the potential of a multimeric display of quinacrine derivs., as compared to the monomer quinacrine, as a design principal for a novel class of inhibitors against A$\beta$ fibril formation. The presented multimeric conjugate exhibits a cluster of four quinacrine derivs. on a rigid cyclopeptidic scaffold. Herein is reported the synthesis of the conjugate, together with the in vitro inhibitory evaluation of A$\beta$1-40 fibrils using the thioflavin T fluorescence assay, and imaging with at. force microscopy. Our data show that the multimeric compd. inhibits A$\beta$1-40 fibril formation with an IC50 value of 20 ± 10 $μ$M, which contrasts with the nonactive monomeric analog. This work suggests that assembling multiple copies of acridine moieties to a central scaffold, for multiple interactions, is a promising strategy for the engineering of inhibitors against A$\beta$ fibril formation. [on SciFinder(R)]