Accumulation of aberrant protein aggregates, such as amyloid 尾 peptide (A尾), due to decreased proteasome activities, might contribute to the neurodegeneration in Alzheimer's disease. In this study, lithocholic acid derivatives 3伪-
O-pimeloyl-lithocholic acid methyl ester (
2) and its isosteric isomer (
6) were found to activate the chymotrypsin-like activity of the proteasome at an EC
50 of 7.8 and 4.3 渭M, respectively. Replacing the C24 methyl ester in
2 with methylamide resulted in a complete devoid of proteasome activating activity. Epimerizing the C3 substituent from an 伪 to 尾 orientation transformed the activator into a proteasome inhibitor. Unlike the cellular proteasome activator PA28, proteasome activated by
2 was not inhibited by A尾. Furthermore,
2 potently antagonized the inhibitory effect of A尾 on the proteasome. In summary, compound
2 represents a novel class of small molecules that not only activates the proteasome but also antagonizes the inhibitory effect of A尾 on the proteasome.
Keywords:
proteasome activator; lithocholic acid; Alzheimer's disease; amyloid 尾