Multiple-peptide conjugates for binding β-amyloid plaques of Alzheimer's disease

Guobao Zhang, Michael J Leibowitz, Patrick J. Sinko, Stanley Stein

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Formation of β-amyloid plaques in Alzheimer's disease is initiated by intermolecular contact of the 5-amino acid sequence, KLVFF, in β-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 Aβ1-40 with moderate affinity (Kd = 5 × 10-10 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 (Kd = 1 × 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.

Original languageEnglish (US)
Pages (from-to)86-92
Number of pages7
JournalBioconjugate Chemistry
Volume14
Issue number1
DOIs
StatePublished - Jan 2003
Externally publishedYes

Fingerprint

Amyloid Plaques
Amyloid
Peptides
Alzheimer Disease
Polyethylene glycols
Amino acids
Bearings (structural)
Ethylene Glycol
Amino Acids
Amino Acid Sequence
Fluorescence
Monomers
Therapeutics

ASJC Scopus subject areas

  • Chemistry(all)
  • Organic Chemistry
  • Clinical Biochemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry

Cite this

Multiple-peptide conjugates for binding β-amyloid plaques of Alzheimer's disease. / Zhang, Guobao; Leibowitz, Michael J; Sinko, Patrick J.; Stein, Stanley.

In: Bioconjugate Chemistry, Vol. 14, No. 1, 01.2003, p. 86-92.

Research output: Contribution to journalArticle

Zhang, Guobao ; Leibowitz, Michael J ; Sinko, Patrick J. ; Stein, Stanley. / Multiple-peptide conjugates for binding β-amyloid plaques of Alzheimer's disease. In: Bioconjugate Chemistry. 2003 ; Vol. 14, No. 1. pp. 86-92.
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