Stereoselective interactions of peptide inhibitors with the β-amyloid peptide

Residues 16 - 20 of the beta-amyloid peptide (Abeta) function as a self-recognition element during Abeta assembly into fibers. Peptides containing this motif retain the ability to interact with Abeta and, in some cases, potently inhibit its assembly. Replacing L- with D-amino acids could stabilize such peptides and permit their evaluation as therapeutic agents for Alzheimer's disease. Here we have assessed the effect that such a chiral reversal has on inhibitory potency. D-enantiomers of five peptides, KLVFFA, KKLVFFA, KFVFFA, KIVFFA, and KVVFFA, were unexpectedly more active as inhibitors in an in vitro fibrillogenesis assay. Circular dichroism showed that D-KLVFFA more effectively prevented Abeta adopting the beta-sheet secondary structure correlated with fibrillogenesis. Electron microscopy showed that fiber formation was also more strongly inhibited by D-KLVFFA. Heterochiral inhibition was confirmed using D-Abeta, on the principle that enantiomeric proteins exhibit reciprocal chiral biochemical interactions. With D-Abeta, L-KLVFFA was the more potent inhibitor, rather than D-KLVFFA. Most significantly, D-peptides were more potent at reducing the toxicity of both Abeta(1-40) and Abeta(1-42) toward neuronal cells in culture. This unforeseen heterochiral stereoselectivity of Abeta for D-peptide inhibitors should be considered during future design of peptide-based inhibitors of Abeta neurotoxicity and fibrillogenesis.