Amyloid is a fibrillar protein structure characterised by the presence of a stable, cross-β-sheet conformation. It is known for its pathogenic role in diseases such as Alzheimer’s disease, Type II diabetes and isolated atrial amyloidosis where the presence of amyloid is unwanted. However, amyloid has also been shown to have a functional role in many organisms, including mammals, bacteria and fungi. In fungi, amyloid is utilized to increase the infectivity of the fungus. Fungi such as Aspergillus fumigatus and Magnaporthe oryzae, responsible for invasive aspergillosis and rice blast disease respectively, both produce small proteins called hydrophobins. Hydrophobins form amyloid rodlet structures that aid in the fungal life cycle and facilitate infection of hosts.
Given the involvement of amyloid in human and plant diseases, prevention of amyloid fibril formation may provide an avenue for combating these diseases. We have tested a series of new small-molecule compounds that target the cross-β-sheet structure of amyloid. The effectiveness of the inhibitors has been assessed by thioflavin T fluorescence assays and verified by electron microscopy. The interaction of the small molecules with hydrophobins has been investigated by ion mobility–mass spectrometry. A Caenorhabditis elegans model of Alzheimer’s disease has been implemented to assess the efficacy of these small-molecules in vivo. We find that some of these small molecules are able to prevent assembly of a range of amyloids, both functional and pathogenic. This is likely because the small molecules bind to polypeptide sequences that adopt the cross-β conformation, which is a generic element of amyloid fibrils.