Small-Molecule Activators of Insulin-Degrading Enzyme Discovered through High-Throughput Compound Screening

Simple item page
dc.contributor.authorCabrol, Christelle
dc.contributor.authorHuzarska, Malwina A.
dc.contributor.authorDinolfo, Christopher
dc.contributor.authorRodriguez, Maria C.
dc.contributor.authorReinstatler, Lael
dc.contributor.authorNi, Jake
dc.contributor.authorYeh, Li-An
dc.contributor.authorCuny, Gregory D.
dc.contributor.authorStein, Ross L.
dc.contributor.authorSelkoe, Dennis J.
dc.contributor.authorLeissring, Malcolm A.
dc.date.accessioned2020-03-10T17:32:06Z
dc.date.available2020-03-10T17:32:06Z
dc.date.issued4/22/2009
dc.description.abstractBackground-Hypocatabolism of the amyloid ?-protein (A?) 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 ATP analogue to IDE, suggesting that they interact with a bona fide ATP-binding domain within IDE. Unexpectedly, we observed highly synergistic activation effects when the activity of Ia1 or Ia2 was tested in the presence of ATP, a finding that has implications for the mechanisms underlying ATP-mediated activation of IDE. Notably, Ia1 and Ia2 activated the degradation of A? by ?700% and ?400%, respectively, albeit only when A? was presented in a mixture also containing shorter substrates. Conclusions/Significance-This study describes the first examples of synthetic small-molecule activators of IDE, showing that pharmacological activation of this important protease with drug-like compounds is achievable. These novel activators help to establish the putative ATP-binding domain as a key modulator of IDE proteolytic activity and offer new insights into the modulatory action of ATP. Several larger lessons abstracted from this screen will help inform the design of future screening campaigns and facilitate the eventual development of IDE activators with therapeutic utility.
dc.identifier.citationCopyright 2009 PLoS ONE. Recommended citation: Cabrol, Christelle, Malwina A. Huzarska, Christopher Dinolfo, Maria C. Rodriguez, Lael Reinstatler, Jake Ni, Li-An Yeh et al. "Small-molecule activators of insulin-degrading enzyme discovered through high-throughput compound screening." PloS one 4, no. 4 (2009): e5274. doi:10.1371/journal.pone.0005274. URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005274. Reproduced in accordance with the original pulbisher's licensing terms and with permission from the authors.
dc.identifier.urihttps://hdl.handle.net/10657/5973
dc.language.isoen_US
dc.publisherPLoS ONE
dc.subjectProteases
dc.subjectHydrolysis
dc.subjectAlzheimer's disease
dc.subjectLibrary screening
dc.subjectHigh throughput screening
dc.subjectRecombination reactions
dc.subjectStatistical data
dc.subjectCross-linking
dc.titleSmall-Molecule Activators of Insulin-Degrading Enzyme Discovered through High-Throughput Compound Screening
dc.typeArticle

Files

Original bundle

Now showing 1 - 1 of 1
Thumbnail Image
Name:
Cuny_2009_Smallmoleculeactivatorcompoundscreening.pdf
Size:
311.79 KB
Format:
Adobe Portable Document Format
Download

License bundle

Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
4.69 KB
Format:
Plain Text
Description:
Download

Collections

UH Faculty, Staff, and Student Works