para‐Sulfonatocalix[n]arenes Inhibit Amyloid β‐Peptide Fibrillation and Reduce Amyloid Cytotoxicity

Abstract Amyloid β‐peptide (Aβ) fibrillation is a major hallmark of Alzheimer's disease (AD). Inhibition of Aβ fibrillation is thus considered to be an effective strategy for AD prevention and treatment. Here we show that para ‐sulfonatocalix[ n ]arenes (SC[ n ]A, n =4, 6, 8), a class of amphiphilic calixarene derivatives, can bind to Aβ 42 through nonspecific and multipoint hydrophobic interactions. Their binding leads to a pronounced delay in β‐sheet adoption and formation of multiple secondary structures of the peptide, accompanied by changes at the level of the fibrillary architecture. Furthermore, the ζ‐potential value of Aβ 42 incubated with SC[6/8]A decreased, which correlated with the reduction of amyloid cytotoxicity. Overall, the SC[ n ]A effectively inhibits Aβ 42 fibrillation and reduces amyloid cytotoxicity, and SC[8]A showed the best performance among the three macrocycles, possibly owing to its having the strongest interactions with Aβ 42 .