Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin

Malcolm A. Leissring, Enrico Malito, Sabrine Hedouin, Lael Reinstatler, Tomoko Sahara, Samer O. Abdul-Hay, Shakeel Choudhry, Ghulam M. Maharvi, Abdul H. Fauq, Malwina Huzarska, Philip S. May, Sungwoon Choi, Todd P. Logan, Benjamin E. Turk, Lewis C. Cantley, Marika Manolopoulou, Wei Jen Tang, Ross L. Stein, Gregory D. Cuny, Dennis J. Selkoe

Research output: Contribution to journalArticle

71 Citations (Scopus)

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 zincmetalloprotease. 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 zincmetalloproteases. 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. Copyright:

Original languageEnglish (US)
Article numbere10504
JournalPLoS One
Volume5
Issue number5
DOIs
StatePublished - 2010

Fingerprint

Insulysin
insulin
Insulin
metabolism
enzymes
Metalloproteases
Enzyme Inhibitors
Medical problems
Zinc
enzyme inhibitors
Pharmacology
Hydroxamic Acids
metalloproteinases
Peptides
Peptide Hormones
Enzyme activity
zinc
Libraries
peptides
Conformations

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Leissring, M. A., Malito, E., Hedouin, S., Reinstatler, L., Sahara, T., Abdul-Hay, S. O., ... Selkoe, D. J. (2010). Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin. PLoS One, 5(5), [e10504]. https://doi.org/10.1371/journal.pone.0010504

Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin. / Leissring, Malcolm A.; Malito, Enrico; Hedouin, Sabrine; Reinstatler, Lael; Sahara, Tomoko; Abdul-Hay, Samer O.; Choudhry, Shakeel; Maharvi, Ghulam M.; Fauq, Abdul H.; Huzarska, Malwina; May, Philip S.; Choi, Sungwoon; Logan, Todd P.; Turk, Benjamin E.; Cantley, Lewis C.; Manolopoulou, Marika; Tang, Wei Jen; Stein, Ross L.; Cuny, Gregory D.; Selkoe, Dennis J.

In: PLoS One, Vol. 5, No. 5, e10504, 2010.

Research output: Contribution to journalArticle

Leissring, MA, Malito, E, Hedouin, S, Reinstatler, L, Sahara, T, Abdul-Hay, SO, Choudhry, S, Maharvi, GM, Fauq, AH, Huzarska, M, May, PS, Choi, S, Logan, TP, Turk, BE, Cantley, LC, Manolopoulou, M, Tang, WJ, Stein, RL, Cuny, GD & Selkoe, DJ 2010, 'Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin', PLoS One, vol. 5, no. 5, e10504. https://doi.org/10.1371/journal.pone.0010504
Leissring MA, Malito E, Hedouin S, Reinstatler L, Sahara T, Abdul-Hay SO et al. Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin. PLoS One. 2010;5(5). e10504. https://doi.org/10.1371/journal.pone.0010504
Leissring, Malcolm A. ; Malito, Enrico ; Hedouin, Sabrine ; Reinstatler, Lael ; Sahara, Tomoko ; Abdul-Hay, Samer O. ; Choudhry, Shakeel ; Maharvi, Ghulam M. ; Fauq, Abdul H. ; Huzarska, Malwina ; May, Philip S. ; Choi, Sungwoon ; Logan, Todd P. ; Turk, Benjamin E. ; Cantley, Lewis C. ; Manolopoulou, Marika ; Tang, Wei Jen ; Stein, Ross L. ; Cuny, Gregory D. ; Selkoe, Dennis J. / Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin. In: PLoS One. 2010 ; Vol. 5, No. 5.
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AU - Leissring, Malcolm A.

AU - Malito, Enrico

AU - Hedouin, Sabrine

AU - Reinstatler, Lael

AU - Sahara, Tomoko

AU - Abdul-Hay, Samer O.

AU - Choudhry, Shakeel

AU - Maharvi, Ghulam M.

AU - Fauq, Abdul H.

AU - Huzarska, Malwina

AU - May, Philip S.

AU - Choi, Sungwoon

AU - Logan, Todd P.

AU - Turk, Benjamin E.

AU - Cantley, Lewis C.

AU - Manolopoulou, Marika

AU - Tang, Wei Jen

AU - Stein, Ross L.

AU - Cuny, Gregory D.

AU - Selkoe, Dennis J.

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N2 - 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 zincmetalloprotease. 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 zincmetalloproteases. 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. Copyright:

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