Small-molecule activators of insulin-degrading enzyme discovered through high-throughput compound screening.

ABSTRACT:

Background

Hypocatabolism of the amyloid beta-protein (Abeta) by insulin-degrading enzyme (IDE) is implicated in the pathogenesis of Alzheimer disease (AD), making pharmacological activation of IDE an attractive therapeutic strategy. However, it has not been established whether the proteolytic activity of IDE can be enhanced by drug-like compounds.

Methodology/principal findings

Based on the finding that ATP and other nucleotide polyphosphates modulate IDE activity at physiological concentrations, we conducted parallel high-throughput screening campaigns in the absence or presence of ATP and identified two compounds--designated Ia1 and Ia2--that significantly stimulate IDE proteolytic activity. Both compounds were found to interfere with the crosslinking of a photoaffinity A

SUBMITTER: Cabrol C 

PROVIDER: S-EPMC2668070 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature