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

TY - JOUR

T1 - Multiple-peptide conjugates for binding β-amyloid plaques of Alzheimer's disease

AU - Zhang, Guobao

AU - Leibowitz, Michael J.

AU - Sinko, Patrick J.

AU - Stein, Stanley

PY - 2003

Y1 - 2003

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/12244305529

UR - https://www.scopus.com/pages/publications/12244305529#tab=citedBy

U2 - 10.1021/bc025526i

DO - 10.1021/bc025526i

M3 - Article

C2 - 12526697

SN - 1043-1802

VL - 14

SP - 86

EP - 92

JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

IS - 1

ER -