Département de chimie moléculaire

Abnormal aggregation of $\beta$-amyloid (A$\beta$) 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 A$\beta$-binding motifs (either curcumin or the KLVFFA peptide) are clicked via copper(I)-mediated azide-alkyne cycloaddn. on a constrained cyclopeptide scaffold designed to interfere with A$\beta$ aggregation. The authors conjugates strongly inhibit amyloid fibril formation from A$\beta$40 at low inhibitor to A$\beta$ molar ratios (e.g., 0.02:1 in the case of the KLVFFA conjugate) at which A$\beta$-binding motifs alone are fully inactive (thioflavin T assays and at. force microscopy observation). This work highlights the value of combining A$\beta$-recognition domains with a steric hindrance-inducing scaffold for preventing amyloid fibril formation. [on SciFinder(R)]