Design and synthesis of ß-strand-fixed peptides inhibiting aggregation of amyloid ß-protein.

Aggregation of 42-residue amyloid ß-protein (Aß42) can be prevented by ß-sheet breaker peptides (BSBps) homologous to LVFFA residues, which are included in a ß-sheet region of Aß42 aggregates. To enhance the affinity of BSBps to the Aß42 aggregates, we designed and synthesized ß-strand-fixed peptides (BSFps) whose side chains were cross-linked by ring closing metathesis. Conformation analysis verified that the designed peptides could be fixed in ß-strand conformation. Among the synthesized pentapeptides, 1 and 12, whose side chains of 2nd and 4th residues were cross-linked, significantly inhibited the aggregation of Aß42. This suggested that ß-strand-fixation of BSBps could enhance their inhibitory activity against the Aß42 aggregation. However, pentapeptides 1 and 12 had little effect on morphology of Aß42 aggregates (fibrils) and neurotoxicity of Aß42 against SH-SY5Y cells.