Amyloid fibrils, which are caused by abnormal conformation and misassembly of proteins, are responsible for several conformational diseases, including prion diseases. Various mutants of the protein fragment barnase module-1 (BM1-24) have been investigated to discover the structural principle of amyloid-like fibrils. The fibril formation seems to be determined mainly by the linear arrangement of hydrophobic residues [1,2]. In the present study, which is based on this essential linear arrangement of hydrophobic residues, we constructed a structural model of the mechanism of amyloid blocking. To examine possible mechanisms underlying the inhibition of amyloid formation by certain amyloid-forming fragments—BM1-24, prion180-193, Amyloid β, serum amyloid A protein1-27—peptides with hydrophilic substitutions for BM1-24 were prepared. The peptides of 8- and 16-residue lengths were designed to have hydrophilic residues  (Gln, Glu, Asn, Asp, and Arg) on only one side of the β-sheet. As shown by the increase in the intensity of fluorescence in thioflavin T-binding assays, amyloid fragments when left alone formed amyloids. However, when these fragments were mixed with the synthetic inhibitor peptide, the result was a decline in the intensity of fluorescence, suggesting that amyloid formation had been inhibited. Amyloidogenesis thus appears to be specifically inhibited by disrupting the hydrophobic interactions between core amyloid regions.

[1] Saiki, M., Honda, S., Kawasaki, K., Zhou, D., Konakahara, T., Morii, H. (2005) J. Mol. Biol., 348, 983-998.

[2] Saiki, M., Konakahara, T., Morii, H. (2006) Biochem Biophys Res Commun., 343, 1262-1271.