Inhibition of the aggregation process of amyloid β peptide (Aβ) would be a promising target for the development of an anti-Alzheimer's disease agent. In this context, a number of fragment peptides of Aβ, [1] in many cases with modifications (e.g., N-methylation, replacement with D-amino acid), have been reported as aggregation inhibitors of full-length Aβ. The amino acid sequences in any of the inhibitors correspond to β-strand-forming regions of Aβ, which are crucial for self-recognition of Aβ to progress packings into fibrillar aggregates.
We previously reported that an O-acyl isopeptide of Aβ1–42 (1), in which a Gly25–Ser26 amide bond of Aβ1–42 was isomerized to an ester bond at the β-hydroxy group of Ser26, exhibited considerably lower aggregation potency than Aβ1–42. [2] Here, we demonstrate that 1 also has a capability of inhibiting fibril formation of Aβ1–42 at equimolar ratio. In addition, the inhibitory activity was retained in the N-Me-β-Ala26 derivative 2, in which the ester of 1 was replaced with N-methyl amide to avoid O-to-N acyl rearrangement under the neutral pH conditions, verified by the measurements of fluorescence anisotropy, western blot analysis and atomic force microscopy. The results would provide a valuable insight into the design of new class of aggregation inhibitor of Aβ, with a key modification at Gly25–Ser26, towards an anti-Alzheimer’s disease agent.