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

Inhibition of amyloid β peptide (Aβ) aggregation is a potential therapeutic approach to treat Alzheimer's disease. We report that an O-acyl isopeptide of Aβ1-42 (1) containing an ester bond at the Gly25-Ser26 moiety inhibits Aβ1-42 fibril formation at equimolar ratio. Inhibitory activity was retained by an N-Me-β-Ala26 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 Aβ aggregation inhibitor based on modification of Aβ1-42 at Gly25-Ser26.