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

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

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dc.contributor.author Cabrol, Christelle
dc.contributor.author Huzarska, Malwina A.
dc.contributor.author Dinolfo, Christopher
dc.contributor.author Rodriguez, Maria C.
dc.contributor.author Reinstatler, Lael
dc.contributor.author Ni, Jake
dc.contributor.author Yeh, Li-An
dc.contributor.author Stein, Ross L.
dc.contributor.author Leissring, Malcolm A.
dc.contributor.author Cuny, Gregory Douglas
dc.contributor.author Selkoe, Dennis J.
dc.date.accessioned 2011-04-22T14:45:05Z
dc.date.issued 2009
dc.identifier.citation Cabrol, Christelle, Malwina A. Huzarska, Christopher Dinolfo, Maria C. Rodriguez, Lael Reinstatler, Jake Ni, Li-An Yeh, et al. 2009. Small-Molecule Activators of Insulin-Degrading Enzyme Discovered through High-Throughput Compound Screening. PLoS ONE 4(4): e5274. en_US
dc.identifier.issn 1932-6203 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:4872636
dc.description.abstract Background: Hypocatabolism of the amyloid β-protein (Aβ) 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 Aβ by ∼700% and ∼400%, respectively, albeit only when Aβ 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. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi:10.1371/journal.pone.0005274 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668070/pdf/ en_US
dash.license LAA
dc.subject biochemistry en_US
dc.subject biomactomolecule-ligand interactions en_US
dc.subject drug discovery en_US
dc.subject neurological disorders en_US
dc.subject Alzheimer disease en_US
dc.subject pharmacology en_US
dc.subject drug development en_US
dc.title Small-Molecule Activators of Insulin-Degrading Enzyme Discovered through High-Throughput Compound Screening en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS ONE en_US
dash.depositing.author Cuny, Gregory Douglas
dc.date.available 2011-04-22T14:45:05Z
dash.affiliation.other HMS^Neurology-Brigham and Women's Hospital en_US
dash.affiliation.other HMS^Neurology-Brigham and Women's Hospital en_US

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