Amyloid plaques in brain, composed of aggregates of
amyloid-beta 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 beta-sheet breaker
peptide (iA beta 5p), 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 iA beta 5p 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 higher in vivo half-life, and good brain uptake compared with iA beta 5p while maintaining a similar activity in vitro. Our results suggest that the pharmacological profile of beta-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.