Pharmacological Profiles of Peptide Drug Candidates for the Treatment of Alzheimer's Disease

Amyloid plaques in brain, composed of aggregates of amyloid-β peptide, play a central role in the pathogenesis of Alzheimer's disease and represent a good target for treatment. We have shown previously that a 5-amino acid β-sheet breaker peptide (iAβ5p), end-protected, has the ability to induce...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2003-04, Vol.278 (16), p.13905-13911
Main Authors: Adessi, Céline, Frossard, Marie-José, Boissard, Christophe, Fraga, Santiago, Bieler, Sylvain, Ruckle, Thomas, Vilbois, Francis, Robinson, Sandra M., Mutter, Manfred, Banks, William A., Soto, Claudio
Format: Article
Language:English
Subjects:
Alzheimer Disease - drug therapy
Amyloid beta-Peptides - chemistry
Amyloid beta-Peptides - pharmacology
Animals
Binding Sites
Blood-Brain Barrier
Brain - drug effects
Brain - metabolism
Carbon - chemistry
Chromatography, High Pressure Liquid
Drug Design
Kinetics
Lead - pharmacology
Ligands
Mice
Models, Chemical
Peptide Biosynthesis
Peptide Fragments - chemistry
Peptide Fragments - pharmacology
Peptides - chemistry
Protein Binding
Protein Structure, Secondary
Protein Structure, Tertiary
Structure-Activity Relationship
Time Factors
Tritium - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Amyloid plaques in brain, composed of aggregates of amyloid-β peptide, play a central role in the pathogenesis of Alzheimer's disease and represent a good target for treatment. We have shown previously that a 5-amino acid β-sheet breaker peptide (iAβ5p), end-protected, has the ability to induce a dramatic reduction in amyloid deposition in two different transgenic Alzheimer's models (Permanne, B., Adessi, C., Saborio, G. P., Fraga, S., Frossard, M.-J., Dewachter, I., Van Dorpe, J., Banks, W. A., Van Leuven, F., and Soto, C. (2002) FASEB J. 16, 860–862). The aim of this study was to evaluate the effect of chemical modifications of the peptide bonds at the metabolite cleavage sites on the pharmacological properties of iAβ5p derivatives. Using a rational approach, peptide analogs were designed and tested for in vitro activity and enzymatic stability. One peptide analog containing a methyl group introduced at the nitrogen atom of one amide bond showed increased stability in vitro, a 10-fold higherin vivo half-life, and good brain uptake compared with iAβ5p while maintaining a similar activity in vitro. Our results suggest that the pharmacological profile of β-sheet breaker peptides can be improved to produce compounds with drug-like properties that might offer a new promise in the treatment of Alzheimer's disease.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M211976200