Multiple-Peptide Conjugates for Binding β-Amyloid Plaques of Alzheimer's Disease
- 7 December 2002
- journal article
- Published by American Chemical Society (ACS) in Bioconjugate Chemistry
- Vol. 14 (1), 86-92
- https://doi.org/10.1021/bc025526i
Abstract
Formation of beta-amyloid plaques in Alzheimer's disease is initiated by intermolecular contact of the 5-amino acid sequence, KLVFF, in beta-amyloid peptides ranging in size from 40 to 43 residues. Through optimization of binding avidity using structure/function studies, we have found that the retro-inverso peptide, ffvlk, binds artificial fibrils made from Abeta(1)(-)(40) with moderate affinity (K(d) = 5 x 10(-)(7) M). Conjugates having two copies of this peptide, whether connected by a long poly(ethylene glycol) (PEG) spacer or just two amino acids, display about 100-fold greater affinity for fibrils. Placing six copies of ffvlk on a branched PEG resulted in a 10 000-fold greater affinity (K(d) = 1 x 10(-)(10) M) than the monomer peptide. This increased affinity was accompanied by more effective inhibition of the thioflavin T fluorescence signal, which correlates with neurotoxicity of plaques and fibrils. We propose that conjugates bearing several copies of ffvlk may be useful as diagnostic and therapeutic agents for Alzheimer's disease.Keywords
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