Carboxymethylated-κ-casein: A convenient tool for the identification of polyphenolic inhibitors of amyloid fibril formation

• Published in: Bioorganic & medicinal chemistry 2010, Vol.18 (1), p.222-228
• Main Authors: Carver, John A., Duggan, Peter J., Ecroyd, Heath, Liu, Yanqin, Meyer, Adam G., Tranberg, C. Elisabet
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Amyloid - antagonists & inhibitors; Amyloid - metabolism; Amyloid beta-Peptides - metabolism; Amyloid fibril; Animals; Caseins - antagonists & inhibitors; Caseins - chemistry; Caseins - metabolism; Catechin; Flavonoid; Flavonoids - chemistry; Flavonoids - pharmacology; Flavonol; Humans; Isoflavone; Methylation; Milk - chemistry; Polyphenol; Structure-Activity Relationship; κ-Casein
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.10.063

Reduced and carboxymethylated-κ-casein (RCM-κ-CN) is a milk-derived amyloidogenic protein that readily undergoes nucleation-dependent aggregation and amyloid fibril formation via a similar pathway to disease-specific amyloidogenic peptides like amyloid beta (Aβ), which is associated with Alzheimer’s disease. In this study, a series of flavonoids, many known to be inhibitors of Aβ fibril formation, were screened for their ability to inhibit RCM-κ-CN fibrilisation, and the results were compared with literature data on Aβ inhibition. Flavonoids that had a high degree of hydroxylation and molecular planarity gave good inhibition of RCM-κ-CN fibril formation. IC 50 values were between 10- and 200-fold higher with RCM-κ-CN than literature results for Aβ fibril inhibition, however, with few exceptions, they showed a similar trend in potency. The convenience and reproducibility of the RCM-κ-CN assay make it an economic alternative first screen for Aβ inhibitory activity, especially for use with large compound libraries.