Synthesis and Biological Evaluation of Clicked Curcumin and Clicked KLVFFA Conjugates as Inhibitors of β-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.

Curcumin promotes fibril formation in F isomer of human serum albumin via amorphous aggregation

“…Earlier we have also shown that the curcumin rescues the protein from aggregation by increasing the reconfiguration rate [15]. Moreover, many researchers using a diverse group of peptides and proteins have demonstrated that curcumin inhibits fibril formation through one or other mechanisms [11,[14][15][16][17][18][19][20]. These studies form a very strong basis for the inhibitor hypothesis of curcumin.…”

“…These results indicated that F isomers preincubated with curcumin acquired a state which is more susceptible to aggregation than the N isomer. Curcumin, the main polyphenolic compound found in the spice turmeric, has been shown to inhibit fibrillar aggregation of different types of protein and peptides [14][15][16][17][18][19][20]. Recently, two independent works on the effect of curcumin on the amyloid fibril formation showed that curcumin promoted amyloid fibril formation by binding to oligomeric species of intrinsically disordered proteins (IDPs) [21,22].…”

Using Graphene Oxide High Near‐Infrared Absorbance for Photothermal Treatment of Alzheimer's Disease

“…Their therapeutic use is limited by their poor targeting and low permeability to the bloodbrain barrier (BBB) and/or toxic effects. [ 8 ] To overcome these limitations, novel molecules and materials designed to inhibit A β aggregation and disaggregate A β fi brils are urgently needed. It is known that amyloid formation is highly dependent upon multiple factors such as pH, temperature, protein concentration, and ionic strength.…”

New Horizons for Diagnostics and Therapeutic Applications of Graphene and Graphene Oxide

“…[ 181 ] However, the therapeutic use of AD agents at present is limited by their poor targeting and low permeability to the bloodbrain barrier (BBB) and/or toxic effects. [ 182 ] So exploring local heat generation (hyperthermia) can act as an effective means to dissolve amyloid deposits of A β . Irradiation in the NIR window can penetrate tissues with suffi cient intensity and higher spatial precision for inducing localized hyperthermia, while avoiding nonspecifi c heating of surrounding tissues.…”