title: Stereoselective interactions of peptide inhibitors with the beta-amyloid peptide.
abstract: Residues 16-20 of the beta-amyloid peptide (A beta) function as a self-recognition element during A beta assembly into fibers. Peptides containing this motif retain the ability to interact with A beta 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 A beta 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-A beta, 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 A beta1-40 and A beta 1-42 toward neuronal cells in culture. This unforeseen heterochiral stereoselectivity of A beta for D-peptide inhibitors should be considered during future design of peptide-based inhibitors of A beta neurotoxicity and fibrillogenesis.
authors.affiliation: Neurochem Inc., Saint-Laurent, Quebec H4S 2A1, Canada.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Chalifour
authors.forename: Richard W
authors.initials: RW
authors.lastname: McLaughlin
authors.forename: Louis
authors.initials: L
authors.lastname: Lavoie
authors.forename: Céline
authors.initials: C
authors.lastname: Morissette
authors.forename: Nadine
authors.initials: N
authors.lastname: Tremblay
authors.forename: Marie
authors.initials: M
authors.lastname: Boulé
authors.forename: Philippe
authors.initials: P
authors.lastname: Sarazin
authors.forename: Dino
authors.initials: D
authors.lastname: Stéa
authors.forename: Diane
authors.initials: D
authors.lastname: Lacombe
authors.forename: Patrick
authors.initials: P
authors.lastname: Tremblay
authors.forename: Francine
authors.initials: F
authors.lastname: Gervais
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000494:pharmacology*; D002942:Circular Dichroism; D007700:Kinetics; D009498:Neurotoxins / Q000737:chemistry / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
chemical_list: D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D010446:Peptide Fragments