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  • Title: Synthesis and biological evaluation of clicked curcumin and clicked KLVFFA conjugates as inhibitors of beta-amyloid fibril formation.
    Author: Ouberai M, Dumy P, Chierici S, Garcia J.
    Journal: Bioconjug Chem; 2009 Nov; 20(11):2123-32. PubMed ID: 19821579.
    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.
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