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 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 incubated with SC[6/8]A decreased, which correlated with the reduction of amyloid cytotoxicity. Overall, the SC[n]A effectively inhibits Aβ 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 .

Biomedical Applications of Calixarenes: State of the Art and Perspectives

“…Reprinted with permission from ref. [170]. Copyright 2016 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim.…”

Biomedizinische Anwendungen von Calixarenen: Stand der Wissenschaft und Perspektiven

“…Nachdruck mit freundlicher Genehmigung aus Lit. [170]. Copyright 2016 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim.…”

NMR Spectroscopy of supramolecular chemistry on protein surfaces

“…In this review, we focus mostly on ligands that recognize either positively or negatively charged patches on a protein surface, discussing the molecules shown in Figure 1 in greater detail. Ligands designed to recognize positively charged regions, containing lysine (Lys) and arginine (Arg) residues, on a protein include supramolecular tweezers [5][6][7][8][9][10][11][12][13][14][15][16][17][18] as well as sulfonatoand phosphonato-calixarenes [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]. These ligands contain negatively charged functionalities interacting with the positively charged head groups of Lys and Arg, often combined with a moiety that cradles the hydrophobic portion of the aliphatic side chain.…”

“…In calixarenes with negatively charged sulfonate [20][21][22]24,25,[27][28][29][30][31][32]34,36,37] or phosphonate [23,33,35] substitu-ents, the aliphatic side chain of the amino acid lines the aromatic bowl-like structure of the calixarene, while the positively charged end group being situated between the sulfonate or phosphonate groups. While sulfonato-calix [4]arenes can bind unmodified Lys and Arg residues, their strength lies in the recognition and even tighter binding of methylated lysines [29].…”

“…The calixarenes can successfully bind to methylated histone tails and thus inhibit the binding of epigenetic reader proteins [30][31][32]. Negatively charged calixarene ligands have further been used to inhibit enzymatic activity [33][34][35] and amyloid fibril formation [36][37][38].…”