Stereoselective interactions of peptide inhibitors with the beta-amyloid peptide.
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.
Chalifour
Robert J
RJ
Neurochem Inc., Saint-Laurent, Quebec H4S 2A1, Canada.
McLaughlin
Richard W
RW
Lavoie
Louis
L
Morissette
Céline
C
Tremblay
Nadine
N
Boulé
Marie
M
Sarazin
Philippe
P
Stéa
Dino
D
Lacombe
Diane
D
Tremblay
Patrick
P
Gervais
Francine
F
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
D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D010446:Peptide Fragments