title: Synthesis and biological evaluation of clicked curcumin and clicked KLVFFA conjugates as inhibitors of beta-amyloid fibril formation.
abstract: Abnormal aggregation of beta-amyloid (Abeta) peptides into toxic aggregates has been identified as a key event in Alzheimer's disease (AD). Inhibition of this process has thus emerged as a major therapeutic track against AD. The present work describes the synthesis and in vitro study of a novel class of inhibitors. Two copies of Abeta-binding motifs (either curcumin or the KLVFFA peptide) are clicked via copper(I)-mediated azide-alkyne cycloaddition on a constrained cyclopeptide scaffold designed to interfere with Abeta aggregation. Our conjugates strongly inhibit amyloid fibril formation from Abeta(40) at low inhibitor to Abeta molar ratios (e.g., 0.02:1 in the case of the KLVFFA conjugate) at which Abeta-binding motifs alone are fully inactive (thioflavin T assays and atomic force microscopy observation). This work highlights the value of combining Abeta-recognition domains with a steric hindrance-inducing scaffold for preventing amyloid fibril formation.
authors.affiliation: Departement de Chimie Moleculaire (DCM), UMR 5250, ICMG-FR, Universite Joseph Fourier, BP 53, 38041 Grenoble Cedex 9, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Ouberai
authors.forename: Pascal
authors.initials: P
authors.lastname: Dumy
authors.forename: Sabine
authors.initials: S
authors.lastname: Chierici
authors.forename: Julian
authors.initials: J
authors.lastname: Garcia
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000517:prevention & control; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry; D003474:Curcumin / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C529399:amyloid beta-protein (16-20); D003474:Curcumin