title: Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin.
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.
  
  
  RESULTS
  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 approximately 10(6) 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
  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.
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, United States of America. Leissring@mayo.edu
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Leissring
authors.forename: Enrico
authors.initials: E
authors.lastname: Malito
authors.forename: Sabrine
authors.initials: S
authors.lastname: Hedouin
authors.forename: Lael
authors.initials: L
authors.lastname: Reinstatler
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sahara
authors.forename: Samer O
authors.initials: SO
authors.lastname: Abdul-Hay
authors.forename: Shakeel
authors.initials: S
authors.lastname: Choudhry
authors.forename: Ghulam M
authors.initials: GM
authors.lastname: Maharvi
authors.forename: Abdul H
authors.initials: AH
authors.lastname: Fauq
authors.forename: Malwina
authors.initials: M
authors.lastname: Huzarska
authors.forename: Philip S
authors.initials: PS
authors.lastname: May
authors.forename: Sungwoon
authors.initials: S
authors.lastname: Choi
authors.forename: Todd P
authors.initials: TP
authors.lastname: Logan
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Turk
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Marika
authors.initials: M
authors.lastname: Manolopoulou
authors.forename: Wei-Jen
authors.initials: WJ
authors.lastname: Tang
authors.forename: Ross L
authors.initials: RL
authors.lastname: Stein
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Selkoe
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007339:Insulysin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D019151:Peptide Library; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D019151:Peptide Library; D007339:Insulysin