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 deposi tion of beta-amyloid peptide (A beta). Cellular toxicity has been shown to be associated with fibrillar forms of A beta preventing this fibril formati on is therefore viewed as a possible method of slowing disease progression in Alzheimer's disease. With the use of a series of tetracyclic and carbazo le-type compounds as inhibitors of A beta fibril formation, we here describ e a number of common structural features that seem to be associated with th e inhibitory properties of these agents. Compounds such as carvedilol, roli tetracycline and daunomycin, which are shown to inhibit A beta fibril:forma tion, also prevent the formation of species of peptide that demonstrate bio logical activity in a human neuroblastoma cell line. Molecular modelling da ta suggest that these compounds have in common the ability to adopt a speci fic three-dimensional pharmacophore conformation that might be essential fo r binding to A beta and preventing it from forming fibrils. Understanding s uch drug-peptide interactions might aid the development of disease-modifyin g agents.