title: Designed Glycopeptidomimetics Disrupt Protein-Protein Interactions Mediating Amyloid β-Peptide Aggregation and Restore Neuroblastoma Cell Viability.
abstract: How anti-Alzheimer's drug candidates that reduce amyloid 1-42 peptide fibrillization interact with the most neurotoxic species is far from being understood. We report herein the capacity of sugar-based peptidomimetics to inhibit both Aβ1-42 early oligomerization and fibrillization. A wide range of bio- and physicochemical techniques, such as a new capillary electrophoresis method, nuclear magnetic resonance, and surface plasmon resonance, were used to identify how these new molecules can delay the aggregation of Aβ1-42. We demonstrate that these molecules interact with soluble oligomers in order to maintain the presence of nontoxic monomers and to prevent fibrillization. These compounds totally suppress the toxicity of Aβ1-42 toward SH-SY5Y neuroblastoma cells, even at substoichiometric concentrations. Furthermore, demonstration that the best molecule combines hydrophobic moieties, hydrogen bond donors and acceptors, ammonium groups, and a hydrophilic β-sheet breaker element provides valuable insight for the future structure-based design of inhibitors of Aβ1-42 aggregation.
authors.affiliation: Molécules Fluorées et Chimie Médicinale, BioCIS, Univ. Paris-Sud, CNRS, Université Paris Saclay , 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, Univ. Paris-Sud, CNRS, Université Paris Saclay , 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.|Protéines et Nanotechnologies en Sciences Séparatives, Institut Galien Paris-Sud, Univ. Paris-Sud, CNRS, Université Paris Saclay , 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, Univ. Paris-Sud, CNRS, Université Paris Saclay , 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: Isabelle
authors.initials: I
authors.lastname: Correia
authors.affiliation: Molécules Fluorées et Chimie Médicinale, BioCIS, Univ. Paris-Sud, CNRS, Université Paris Saclay , 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Nicolo
authors.initials: N
authors.lastname: Tonali
authors.affiliation: Molécules Fluorées et Chimie Médicinale, BioCIS, Univ. Paris-Sud, CNRS, Université Paris Saclay , 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Katia Fabiana
authors.initials: KF
authors.lastname: Fera
authors.affiliation: Molécules Fluorées et Chimie Médicinale, BioCIS, Univ. Paris-Sud, CNRS, Université Paris Saclay , 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.|Protéines et Nanotechnologies en Sciences Séparatives, Institut Galien Paris-Sud, Univ. Paris-Sud, CNRS, Université Paris Saclay , 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Iacone
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: Anaïs R F
authors.initials: AR
authors.lastname: Hoffmann
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: Molécules Fluorées et Chimie Médicinale, BioCIS, Univ. Paris-Sud, CNRS, Université Paris Saclay , 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Crousse
authors.affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University , Lancaster LA1 4YQ, U.K.
authors.forename: Mark
authors.initials: M
authors.lastname: Taylor
authors.affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University , Lancaster LA1 4YQ, U.K.
authors.forename: David
authors.initials: D
authors.lastname: Allsop
authors.affiliation: Protéines et Nanotechnologies en Sciences Séparatives, Institut Galien Paris-Sud, Univ. Paris-Sud, CNRS, Université Paris Saclay , 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Taverna
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: Molécules Fluorées et Chimie Médicinale, BioCIS, Univ. Paris-Sud, CNRS, Université Paris Saclay , 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ongeri
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006020:Glycopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000378:metabolism*; D057786:Peptidomimetics; D066329:Protein Aggregates / Q000187:drug effects*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy*; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D016229:Amyloid beta-Peptides; D006020:Glycopeptides; D010446:Peptide Fragments; D057786:Peptidomimetics; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42)