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 language | English (US) |
|---|---|
| Pages (from-to) | 86-92 |
| Number of pages | 7 |
| Journal | Bioconjugate Chemistry |
| Volume | 14 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2003 |
| Externally published | Yes |
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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 journal › Article
}
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 - 2003/1
Y1 - 2003/1
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.
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UR - http://www.scopus.com/inward/citedby.url?scp=12244305529&partnerID=8YFLogxK
U2 - 10.1021/bc025526i
DO - 10.1021/bc025526i
M3 - Article
C2 - 12526697
AN - SCOPUS:12244305529
VL - 14
SP - 86
EP - 92
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
SN - 1043-1802
IS - 1
ER -