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.
Molécules Fluorées et Chimie Médicinale, BioCIS UMR-CNRS 8076, IPSIT, LabEx LERMIT, Université Paris-Sud 11, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
Bertrand
B
Dorgeret
Lucie
L
Khemtémourian
Isabelle
I
Correia
Jean-Louis
JL
Soulier
Olivier
O
Lequin
Sandrine
S
Ongeri
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000648:ultrastructure; D005960:Glucosides / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D005960:Glucosides; D058228:Islet Amyloid Polypeptide; D057786:Peptidomimetics