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A Multimeric Quinacrine Conjugate as a Potential Inhibitor of Alzheimer's β‐Amyloid Fibril Formation
Author(s) -
Dolphin Gunnar T.,
Chierici Sabine,
Ouberai Myriam,
Dumy Pascal,
Garcia Julian
Publication year - 2008
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200700602
Subject(s) - fibril , thioflavin , conjugate , chemistry , biophysics , peptide , in vitro , monomer , amyloid (mycology) , acridine , biochemistry , alzheimer's disease , biology , medicine , inorganic chemistry , mathematical analysis , mathematics , disease , organic chemistry , pathology , polymer
Amyloid formation and accumulation of the amyloid β‐peptide (A β ) 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 A β 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 A β 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 A β 1–40 fibrils using the thioflavin T fluorescence assay, and imaging with atomic force microscopy. Our data show that the multimeric compound inhibits A β 1–40 fibril formation with an IC 50 value of 20±10 μ M , 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 A β fibril formation.