title: A multimeric quinacrine conjugate as a potential inhibitor of Alzheimer's beta-amyloid fibril formation.
abstract: Amyloid formation and accumulation of the amyloid beta-peptide (Abeta) in the brain is associated with Alzheimer's disease (AD) pathogenesis. Therefore, among the therapeutic approaches in development to fight the disease, the direct inhibition of the Abeta 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 derivatives, as compared to the monomer quinacrine, as a design principal for a novel class of inhibitors against Abeta fibril formation. The presented multimeric conjugate exhibits a cluster of four quinacrine derivatives on a rigid cyclopeptidic scaffold. Herein is reported the synthesis of the conjugate, together with the in vitro inhibitory evaluation of Abeta(1-40) fibrils using the thioflavin T fluorescence assay, and imaging with atomic force microscopy. Our data show that the multimeric compound inhibits Abeta(1-40) fibril formation with an IC(50) value of 20+/-10 microM, which contrasts with the nonactive monomeric analogue. 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 Abeta fibril formation.
authors.affiliation: Département de Chimie Moléculaire, UMR 5250, ICMG FR-2607, CNRS, Université Joseph Fourier, B.P. 53, 38041 Grenoble Cedex 9, France.
authors.forename: Gunnar T
authors.initials: GT
authors.lastname: Dolphin
authors.forename: Sabine
authors.initials: S
authors.lastname: Chierici
authors.forename: Myriam
authors.initials: M
authors.lastname: Ouberai
authors.forename: Pascal
authors.initials: P
authors.lastname: Dumy
authors.forename: Julian
authors.initials: J
authors.lastname: Garcia
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D052160:Benzothiazoles; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D018625:Microscopy, Atomic Force; D011485:Protein Binding / Q000187:drug effects; D011796:Quinacrine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence; D013844:Thiazoles / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D013844:Thiazoles; C009462:thioflavin T; D011796:Quinacrine