Sugar-based peptidomimetics inhibit amyloid β-peptide aggregation

Alzheimer’s disease is characterized by the oligomerization and amyloid fibril formation of amyloid β-peptide (Aβ). We describe a novel class of small water-soluble Aβ binding peptidomimetics based on two hydrophobic Ala-Val and Val-Leu dipeptides linked to a d-glucopyranosyl scaffold through aminoalkyl and carboxyethyl links in C1 and C6 positions. These compounds combine the targeting of hydrophobic recognition interfaces with an original hydrophilic sugar β-breakage strategy. These molecules were shown, by fluorescence thioflavin-T assays, to dramatically slow down the kinetics of amyloid fibril formation even at a low peptidomimetics to Aβ ratio of 0.1:1. Electron microscopy images revealed that the peptidomimetics efficiently reduced the amount of typical amyloid fibrils. NMR saturation transfer difference experiments indicated that these molecules interact with Aβ aggregated species through their hydrophobic amino acid residues. This inhibition effect was found to be sequence-specific since these molecules did not alter the kinetics of aggregation of another amyloid peptide, IAPP, involved in type 2 diabetes mellitus.

Sugar-based peptidomimetics bind to Aβ peptide, as shown by NMR spectroscopy. Fluorescence thioflavin-T assays and electron microscopy indicate that these molecules efficiently slow down the kinetics of amyloid fibril formation.Figure optionsDownload as PowerPoint slideHighlights
► A novel class of small water-soluble Aβ binding peptidomimetics is described.
► Two hydrophobic dipeptides are linked to a d-glucopyranosyl scaffold.
► The molecules slow down the kinetics of b-amyloid fibril formation at a low ratio.
► The amount of typical amyloid fibrils is reduced.
► The inhibition is sequence-specific, no effect on IAPP aggregation is observed.