title: Discovery of novel inhibitors of amyloid β-peptide 1-42 aggregation.
abstract: Alzheimer's disease, characterized by deposits of amyloid β-peptide (Aβ), is the most common neurodegenerative disease, but it still lacks a specific treatment. We have discovered five chemically unrelated inhibitors of the in vitro aggregation of the Aβ17-40 peptide by screening two commercial chemical libraries. Four of them (1-4) exhibit relatively low MCCs toward HeLa cells (17-184 μM). The usefulness of compounds 1-4 to inhibit the in vivo aggregation of Aβ1-42 has been demonstrated using two fungi models, Saccharomyces cerevisiae and Podospora anserina, previously transformed to express Aβ1-42. Estimated IC(50)s are around 1-2 μM. Interestingly, addition of any of the four compounds to sonicated preformed P. anserina aggregates completely inhibited the appearance of SDS-resistant oligomers. This combination of HTP in vitro screening with validation in fungi models provides an efficient way to identify novel inhibitory compounds of Aβ1-42 aggregation for subsequent testing in animal models.
authors.affiliation: Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Pedro Cerbuna 12, 50009 Zaragoza, Spain.
authors.forename: Laura C
authors.initials: LC
authors.lastname: López
authors.forename: Suzana
authors.initials: S
authors.lastname: Dos-Reis
authors.forename: Alba
authors.initials: A
authors.lastname: Espargaró
authors.forename: José A
authors.initials: JA
authors.lastname: Carrodeguas
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Maddelein
authors.forename: Salvador
authors.initials: S
authors.lastname: Ventura
authors.forename: Javier
authors.initials: J
authors.lastname: Sancho
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D006367:HeLa Cells; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048468:Podospora / Q000187:drug effects*; D055503:Protein Multimerization / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D006571:Heterocyclic Compounds; D010446:Peptide Fragments; D012333:RNA, Messenger; C075222:amyloid beta-protein (1-42)