Inhibition of fibril formation in beta-amyloid peptide by a novel series of benzofurans.
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.
Howlett
D R
DR
Department of Neuroscience, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park (North), Third Avenue, Harlow, Essex CM19 5AW, UK. David_Howlett-1@sbphrd.com
Perry
A E
AE
Godfrey
F
F
Swatton
J E
JE
Jennings
K H
KH
Spitzfaden
C
C
Wadsworth
H
H
Wood
S J
SJ
Markwell
R E
RE
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
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