A new class of aggregation inhibitor of amyloid-β peptide based on an O-acyl isopeptide

Inhibition of amyloid beta peptide (Ab) aggregation is a potential therapeutic approach to treat Alzheimer's disease. We report that an O-acyl isopeptide of A beta 1-42 (1) containing an ester bond at the Gly(25)-Ser(26) moiety inhibits A beta 1-42 fibril formation at equimolar ratio. Inhibitory activity was retained by an N-Me-beta-Ala(26) derivative (2), in which the ester of 1 was replaced with N-methyl amide to improve chemical stability at physiological pH. Inhibition was verified by fluorescence anisotropy, Western blot, and atomic force microscopy. This report suggests a new class of A beta aggregation inhibitor based on modification of A beta 1-42 at Gly(25)-Se-r26. (C) 2013 Elsevier Ltd. All rights reserved.