Carboxymethylated-kappa-casein: a convenient tool for the identification of polyphenolic inhibitors of amyloid fibril formation.
Reduced and carboxymethylated-kappa-casein (RCM-kappa-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 (Abeta), which is associated with Alzheimer's disease. In this study, a series of flavonoids, many known to be inhibitors of Abeta fibril formation, were screened for their ability to inhibit RCM-kappa-CN fibrilisation, and the results were compared with literature data on Abeta inhibition. Flavonoids that had a high degree of hydroxylation and molecular planarity gave good inhibition of RCM-kappa-CN fibril formation. IC(50) values were between 10- and 200-fold higher with RCM-kappa-CN than literature results for Abeta fibril inhibition, however, with few exceptions, they showed a similar trend in potency. The convenience and reproducibility of the RCM-kappa-CN assay make it an economic alternative first screen for Abeta inhibitory activity, especially for use with large compound libraries.
Carver
John A
JA
School of Chemistry and Physics, The University of Adelaide, Adelaide, South Australia 5005, Australia.
Duggan
Peter J
PJ
Ecroyd
Heath
H
Liu
Yanqin
Y
Meyer
Adam G
AG
Tranberg
C Elisabet
CE
D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002364:Caseins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008745:Methylation; D008892:Milk / Q000737:chemistry; D013329:Structure-Activity Relationship
D000682:Amyloid; D016229:Amyloid beta-Peptides; D002364:Caseins; D005419:Flavonoids