title: Inhibition of fibril formation in beta-amyloid peptide by a novel series of benzofurans.
abstract: A series of benzofuran derivatives have been identified as inhibitors of fibril formation in the beta-amyloid peptide. The activity of these compounds has been assessed by a novel fibril-formation-specific immunoassay and for their effects on the production of a biologically active fibril product. The inhibition afforded by the compounds seems to be associated with their binding to beta-amyloid, as identified by scintillation proximity binding assay. Binding assays and NMR studies also indicate that the inhibition is associated with self-aggregation of the compounds. There is a close correlation between the activity of the benzofurans as inhibitors of fibril formation and their ability to bind to beta-amyloid. Non-benzofuran inhibitors of the fibril formation process do not seem to bind to the same site on the beta-amyloid molecule as the benzofurans. Thus a specific recognition site might exist for benzofurans on beta-amyloid, binding to which seems to interfere with the ability of the peptide to form fibrils.
authors.affiliation: Department of Neuroscience, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park (North), Third Avenue, Harlow, Essex CM19 5AW, UK. David_Howlett-1@sbphrd.com
authors.forename: D R
authors.initials: DR
authors.lastname: Howlett
authors.forename: A E
authors.initials: AE
authors.lastname: Perry
authors.forename: F
authors.initials: F
authors.lastname: Godfrey
authors.forename: J E
authors.initials: JE
authors.lastname: Swatton
authors.forename: K H
authors.initials: KH
authors.lastname: Jennings
authors.forename: C
authors.initials: C
authors.lastname: Spitzfaden
authors.forename: H
authors.initials: H
authors.lastname: Wadsworth
authors.forename: S J
authors.initials: SJ
authors.lastname: Wood
authors.forename: R E
authors.initials: RE
authors.lastname: Markwell
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000648:ultrastructure; D000906:Antibodies; D001572:Benzofurans / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001667:Binding, Competitive; D003224:Congo Red / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005562:Formazans; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007118:Immunoassay / Q000379:methods; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008854:Microscopy, Electron; D009454:Neurofibrils / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010446:Peptide Fragments / Q000378:metabolism* / Q000648:ultrastructure; D011485:Protein Binding / Q000187:drug effects; D012995:Solubility; D013778:Tetrazolium Salts; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; D001572:Benzofurans; D005562:Formazans; D010446:Peptide Fragments; D013778:Tetrazolium Salts; C078592:amyloid beta-protein (1-40); C079782:MTT formazan; D003224:Congo Red