Chemical and physical variability in structural isomers of an L/D α-sheet peptide designed to inhibit amyloidogenesis.

There has been much interest in synthetic peptides as inhibitors of aggregation associated with amyloid diseases. Of particular interest are compounds that target the cytotoxic soluble oligomers preceding the formation of mature, nontoxic fibrils. This study explores physical and chemical differences between two de novo-designed peptides that share an identical primary structure but differ in backbone chirality at six key positions. We show that the presence of alternating L/D-amino acid motifs dramatically increases aqueous solubility, enforces alpha-sheet secondary structure, and inhibits aggregation of the beta-amyloid peptide implicated in Alzheimer's disease, in addition to neutralizing its cytotoxicity. In contrast, the all-L-amino acid isomer does not form alpha-sheet structure and is insoluble and inactive.