Designed Inhibitors of Insulin-Degrading Enzyme Regulate the Catabolism and Activity of Insulin

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Designed Inhibitors of Insulin-Degrading Enzyme Regulate the Catabolism and Activity of Insulin

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dc.contributor.author Leissring, Malcolm A.
dc.contributor.author Malito, Enrico
dc.contributor.author Hedouin, Sabrine
dc.contributor.author Reinstatler, Lael
dc.contributor.author Sahara, Tomoko
dc.contributor.author Abdul-Hay, Samer O.
dc.contributor.author Choudhry, Shakeel
dc.contributor.author Maharvi, Ghulam M.
dc.contributor.author Fauq, Abdul H.
dc.contributor.author Huzarska, Malwina
dc.contributor.author May, Philip S.
dc.contributor.author Logan, Todd P.
dc.contributor.author Turk, Benjamin E.
dc.contributor.author Manolopoulou, Marika
dc.contributor.author Tang, Wei-Jen
dc.contributor.author Stein, Ross L.
dc.contributor.author Choi, Sungwoon
dc.contributor.author Cantley, Lewis C.
dc.contributor.author Cuny, Gregory Douglas
dc.contributor.author Selkoe, Dennis J.
dc.date.accessioned 2011-02-14T23:55:01Z
dc.date.issued 2010
dc.identifier.citation Leissring, Malcolm A., Enrico Malito, Sabrine Hedouin, Lael Reinstatler, Tomoko Sahara, Samer O. Abdul-Hay, Shakeel Choudhry, et al. 2010. Designed Inhibitors of Insulin-Degrading Enzyme Regulate the Catabolism and Activity of Insulin. PLoS ONE 5(5): e10504. en_US
dc.identifier.issn 1932-6203 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:4725505
dc.description.abstract Background: Insulin is a vital peptide hormone that is a central regulator of glucose homeostasis, and impairments in insulin signaling cause diabetes mellitus. In principle, it should be possible to enhance the activity of insulin by inhibiting its catabolism, which is mediated primarily by insulin-degrading enzyme (IDE), a structurally and evolutionarily distinctive zinc-metalloprotease. Despite interest in pharmacological inhibition of IDE as an attractive anti-diabetic approach dating to the 1950s, potent and selective inhibitors of IDE have not yet emerged. Methodology/Principal Findings: We used a rational design approach based on analysis of combinatorial peptide mixtures and focused compound libraries to develop novel peptide hydroxamic acid inhibitors of IDE. The resulting compounds are ∼106 times more potent than existing inhibitors, non-toxic, and surprisingly selective for IDE vis-à-vis conventional zinc-metalloproteases. Crystallographic analysis of an IDE-inhibitor complex reveals a novel mode of inhibition based on stabilization of IDE's “closed,” inactive conformation. We show further that pharmacological inhibition of IDE potentiates insulin signaling by a mechanism involving reduced catabolism of internalized insulin. Conclusions/Significance: The inhibitors we describe are the first to potently and selectively inhibit IDE or indeed any member of this atypical zinc-metalloprotease superfamily. The distinctive structure of IDE's active site, and the mode of action of our inhibitors, suggests that it may be possible to develop inhibitors that cross-react minimally with conventional zinc-metalloproteases. Significantly, our results reveal that insulin signaling is normally regulated by IDE activity not only extracellularly but also within cells, supporting the longstanding view that IDE inhibitors could hold therapeutic value for the treatment of diabetes. 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.0010504 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866327/pdf/ en_US
dash.license LAA
dc.subject biochemistry en_US
dc.subject drug discovery en_US
dc.subject chemical biology en_US
dc.subject chemical biology of the cell en_US
dc.subject physiology en_US
dc.subject endocrinology en_US
dc.subject deabetes and endocrinology en_US
dc.subject type 2 diabetes en_US
dc.subject pharmacology en_US
dc.subject drug development en_US
dc.title Designed Inhibitors of Insulin-Degrading Enzyme Regulate the Catabolism and Activity of Insulin 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 Cantley, Lewis C.
dc.date.available 2011-02-14T23:55:01Z
dash.affiliation.other HMS^Systems Biology en_US
dash.affiliation.other HMS^Medicine- Beth Israel-Deaconess en_US
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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