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. The derivative 2 was synthesized by using conventional Fmoc solid phase peptide synthesis. Fmoc-N-Me-β-Ala-OH was introduced in the same manner as other amino acids. After TFA treatment, crude peptide was reduced by dimethylsulfide and NH₄I followed by reverse-phase HPLC purification. Inhibitory activity of 2 was 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.