title: Structure-activity relationships of sugar-based peptidomimetics as modulators of amyloid β-peptide early oligomerization and fibrillization.
abstract: Alzheimer's disease is a neurodegenerative disorder linked to oligomerization and fibrillization of amyloid β peptides. Aβ1-42 being the most aggregative and neurotoxic amyloid peptide, we report herein the capacity of sugar-based pentapeptide analogs to modulate the Aβ1-42 aggregation process using thioflavin fluorescence and transmission electron microscopy assays. The importance of the free hydroxyl groups of the sugar moiety, used as a β-breaker element, is confirmed since hydroxylated compounds inhibit the aggregation process while benzylated ones enhance it. Furthermore, the most effective molecules were also evaluated by a recently developed capillary electrophoresis method, providing in vitro monitoring of the crucial, very early stages of the self-assembly process. This technique allowed us to investigate the effect of these compounds on the small non-fibrillar Aβ1-42 oligomers suspected by several groups worldwide as highly neurotoxic. We clearly demonstrated that molecules delaying the aggregation can stabilize the monomeric peptide or promote the formation of soluble oligomeric species. In contrast, molecules that accelerate the aggregation can prevent the presence of small toxic oligomers.
authors.affiliation: Molécules Fluorées et Chimie Médicinale, BioCIS UMR-CNRS 8076, LabEx LERMIT, Université Paris-Sud, Faculté de Pharmacie, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Julia
authors.initials: J
authors.lastname: Kaffy
authors.affiliation: Molécules Fluorées et Chimie Médicinale, BioCIS UMR-CNRS 8076, LabEx LERMIT, Université Paris-Sud, Faculté de Pharmacie, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France; Protéines et Nanotechnologies en Sciences Séparatives, Institut Galien de Paris Sud, UMR-CNRS 8612, Université Paris-Sud, Faculté de Pharmacie, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Brinet
authors.affiliation: Molécules Fluorées et Chimie Médicinale, BioCIS UMR-CNRS 8076, LabEx LERMIT, Université Paris-Sud, Faculté de Pharmacie, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Soulier
authors.affiliation: Sorbonne Universités - UPMC Univ Paris 06, Ecole Normale Supérieure - PSL Research University, CNRS UMR 7203 LBM, 4 Place Jussieu, 75252 Paris Cedex 05, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Khemtémourian
authors.affiliation: Sorbonne Universités - UPMC Univ Paris 06, Ecole Normale Supérieure - PSL Research University, CNRS UMR 7203 LBM, 4 Place Jussieu, 75252 Paris Cedex 05, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lequin
authors.affiliation: Protéines et Nanotechnologies en Sciences Séparatives, Institut Galien de Paris Sud, UMR-CNRS 8612, Université Paris-Sud, Faculté de Pharmacie, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Taverna
authors.affiliation: Molécules Fluorées et Chimie Médicinale, BioCIS UMR-CNRS 8076, LabEx LERMIT, Université Paris-Sud, Faculté de Pharmacie, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Crousse
authors.affiliation: Molécules Fluorées et Chimie Médicinale, BioCIS UMR-CNRS 8076, LabEx LERMIT, Université Paris-Sud, Faculté de Pharmacie, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France. Electronic address: sandrine.ongeri@u-psud.fr.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ongeri
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000187:drug effects; D002241:Carbohydrates / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry* / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry* / Q000187:drug effects; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D002241:Carbohydrates; D009842:Oligopeptides; D010446:Peptide Fragments; D057786:Peptidomimetics; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; Amyloid β-peptide; Capillary electrophoresis; Glycopeptides; Oligomers; Peptidomimetics