Although amyloid-forming proteins have diverse structures and sequences, all undergo a conformational change to form amyloid aggregates that have a characteristic cross-β-structure. In spite of the fact that the mechanistic details of this process are poorly understood, numerous strategies for the development of inhibitors of amyloid formation have been proposed. In most cases, chemically diverse compounds inhibit by binding to an elongated form of the protein in a β-strand conformation. However, this approach could favor the formation of prefibrillar oligomeric species, which are thought to be toxic.
We have utilized an alternative approach, in which a helical coiled-coil-based inhibitor peptide engages a coiled-coil-based amyloid-forming model peptide in a stable coiled-coil arrangement, thereby precluding rearrangement into a β-sheet conformation and the subsequent formation of amyloid-like fibrils. Moreover, we have shown that the helix-forming peptide is able to disassemble mature amyloid-like fibrils (Brandenburg, Chem. Eur. J., 2011).