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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.authorStein, Ross L.
dc.contributor.authorLeissring, Malcolm A.
dc.contributor.authorCuny, Gregory Douglas
dc.contributor.authorSelkoe, Dennis J.
dc.date.accessioned2011-04-22T14:45:05Z
dc.date.issued2009
dc.identifier.citationCabrol, 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.issn1932-6203en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:4872636
dc.description.abstractBackground: 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.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pone.0005274en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668070/pdf/en_US
dash.licenseLAA
dc.subjectbiochemistryen_US
dc.subjectbiomactomolecule-ligand interactionsen_US
dc.subjectdrug discoveryen_US
dc.subjectneurological disordersen_US
dc.subjectAlzheimer diseaseen_US
dc.subjectpharmacologyen_US
dc.subjectdrug developmenten_US
dc.titleSmall-Molecule Activators of Insulin-Degrading Enzyme Discovered through High-Throughput Compound Screeningen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS ONEen_US
dash.depositing.authorCuny, Gregory Douglas
dc.date.available2011-04-22T14:45:05Z
dash.affiliation.otherHMS^Neurology-Brigham and Women's Hospitalen_US
dash.affiliation.otherHMS^Neurology-Brigham and Women's Hospitalen_US
dc.identifier.doi10.1371/journal.pone.0005274*
dash.authorsorderedfalse
dash.contributor.affiliatedCuny, Gregory Douglas
dash.contributor.affiliatedSelkoe, Dennis


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