Synthesis and Biological Evaluation of Clicked Curcumin and Clicked KLVFFA Conjugates as Inhibitors of β-Amyloid Fibril Formation

Abnormal aggregation of β-amyloid (Aβ) 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 Aβ-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 Aβ aggregation. Our conjugates strongly inhibit amyloid fibril formation from Aβ40 at low inhibitor to Aβ molar ratios (e.g., 0.02:1 in the case of the KLVFFA conjugate) at which Aβ-binding motifs alone are fully inactive (thioflavin T assays and atomic force microscopy observation). This work highlights the value of combining Aβ-recognition domains with a steric hindrance-inducing scaffold for preventing amyloid fibril formation.