title: Pharmacological profiles of peptide drug candidates for the treatment of Alzheimer's disease.
abstract: 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.
authors.affiliation: Serono Pharmaceutical Research Institute, 1228 Geneva, Switzerland.
authors.forename: Céline
authors.initials: C
authors.lastname: Adessi
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Frossard
authors.forename: Christophe
authors.initials: C
authors.lastname: Boissard
authors.forename: Santiago
authors.initials: S
authors.lastname: Fraga
authors.forename: Sylvain
authors.initials: S
authors.lastname: Bieler
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruckle
authors.forename: Francis
authors.initials: F
authors.lastname: Vilbois
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Robinson
authors.forename: Manfred
authors.initials: M
authors.lastname: Mutter
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
authors.forename: Claudio
authors.initials: C
authors.lastname: Soto
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002244:Carbon / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D007700:Kinetics; D007854:Lead / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008956:Models, Chemical; D010452:Peptide Biosynthesis; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013997:Time Factors; D014316:Tritium / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D008024:Ligands; D010446:Peptide Fragments; D010455:Peptides; C075222:amyloid beta-protein (1-42); C474023:iAbeta5 peptide; D014316:Tritium; D007854:Lead; D002244:Carbon