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

Aggregation of 42-residue amyloid beta-protein (A beta 42) can be prevented by beta-sheet breaker peptides (BSBps) homologous to LVFFA residues, which are included in a beta-sheet region of A beta 42 aggregates. To enhance the affinity of BSBps to the A beta 42 aggregates, we designed and synthesized beta-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 beta-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 A beta 42. This suggested that beta-strand-fixation of BSBps could enhance their inhibitory activity against the A beta 42 aggregation. However, pentapeptides 1 and 12 had little effect on morphology of A beta 42 aggregates (fibrils) and neurotoxicity of A beta 42 against SH-SY5Y cells.