Stereoselective Interactions of Peptide Inhibitors with the β-Amyloid Peptide

• Published in: The Journal of biological chemistry 2003-09, Vol.278 (37), p.34874
• Main Authors: Robert J. Chalifour, Richard W. McLaughlin, Louis Lavoie, Céline Morissette, Nadine Tremblay, Marie BoulÃ, Philippe Sarazin, Dino Stéa, Diane Lacombe, Patrick Tremblay, Francine Gervais
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M212694200

Residues 16–20 of the β-amyloid peptide (Aβ) function as a self-recognition element during Aβ assembly into fibers. Peptides containing this motif retain the ability to interact with Aβ 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 Aβ adopting the β-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 -Aβ, on the principle that enantiomeric proteins exhibit reciprocal chiral biochemical interactions. With d -Aβ, l -KLVFFA was the more potent inhibitor, rather than d -KLVFFA. Most significantly, d -peptides were more potent at reducing the toxicity of both Aβ 1–40 and Aβ 1–42 toward neuronal cells in culture. This unforeseen heterochiral stereoselectivity of Aβ for d -peptide inhibitors should be considered during future design of peptide-based inhibitors of Aβ neurotoxicity and fibrillogenesis.