One of the major pathological features of Alzheimer's disease is the deposition of β-amyloid peptide (Aβ). Cellular toxicity has been shown to be associated with fibrillar forms of Aβ; 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 Aβ 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 Aβ 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 Aβ and preventing it from forming fibrils. Understanding such drug-peptide interactions might aid the development of disease-modifying agents.

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Author notes

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Present address: Cerebrus, Oakdene Court, 613 Reading Road, Winnersh, Wokingham, RG41 5UA, U.K.