title: Multiple-peptide conjugates for binding beta-amyloid plaques of Alzheimer's disease.
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.
authors.affiliation: Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey 08854, USA.
authors.forename: Guobao
authors.initials: G
authors.lastname: Zhang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Leibowitz
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Sinko
authors.forename: Stanley
authors.initials: S
authors.lastname: Stein
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D003432:Cross-Linking Reagents; D019281:Dimerization; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry*; D011092:Polyethylene Glycols; D011485:Protein Binding; D017433:Protein Structure, Secondary / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D003432:Cross-Linking Reagents; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D011092:Polyethylene Glycols