Common structural features determine the effectiveness of carvedilol, daunomycin and rolitetracycline as inhibitors of Alzheimer beta-amyloid fibril formation.
One of the major pathological features of Alzheimer's disease is the deposition of beta-amyloid peptide (Abeta). Cellular toxicity has been shown to be associated with fibrillar forms of Abeta; preventing this fibril formation is therefore viewed as a possible method of slowing disease progression in Alzheimer's disease. With the use of a series of tetracyclic and carbazole-type compounds as inhibitors of Abeta fibril formation, we here describe a number of common structural features that seem to be associated with the inhibitory properties of these agents. Compounds such as carvedilol, rolitetracycline and daunomycin, which are shown to inhibit Abeta fibril formation, also prevent the formation of species of peptide that demonstrate biological activity in a human neuroblastoma cell line. Molecular modelling data suggest that these compounds have in common the ability to adopt a specific three-dimensional pharmacophore conformation that might be essential for binding to Abeta and preventing it from forming fibrils. Understanding such drug-peptide interactions might aid the development of disease-modifying agents.
Howlett
D R
DR
Department of Neuroscience Research, SmithKline Beecham, New Frontiers Science Park-N, Third Avenue, Harlow, Essex CM19 5AW, U.K. david_howlett-1@sbphrd.com
George
A R
AR
Owen
D E
DE
Ward
R V
RV
Markwell
R E
RE
D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000648:ultrastructure; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000077261:Carvedilol; D002470:Cell Survival / Q000187:drug effects; D003630:Daunorubicin / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D008854:Microscopy, Electron; D008956:Models, Chemical; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D011108:Polymers; D011412:Propanolamines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D012382:Rolitetracycline / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013816:Thermodynamics; D013844:Thiazoles; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D002227:Carbazoles; D011108:Polymers; D011412:Propanolamines; D013778:Tetrazolium Salts; D013844:Thiazoles; D000077261:Carvedilol; C022616:thiazolyl blue; D012382:Rolitetracycline; D003630:Daunorubicin