Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice

@article{DeprezPoulain2015CatalyticSI,
  title={Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice},
  author={Rebecca Deprez-Poulain and Nathalie Hennuyer and Damien Bosc and Wenguang G. Liang and Emmanuelle Énée and Xavier Mar{\'e}chal and Julie Charton and Jane Totobenazara and Gonzague Berte and Jouda Jahklal and Tristan Verdelet and Julie Dumont and Sandrine Dassonneville and Eloise Woitrain and Marion Gauriot and Charlotte Paquet and Isabelle Duplan and Paul Hermant and François-Xavier Cantrelle and Emmanuel Sevin and Maxime Culot and Val{\'e}rie Landry and Adrien Herledan and Catherine Piveteau and Guy Lippens and Florence Leroux and Wei-Jen Tang and Peter van Endert and Bart Staels and Beno{\^i}t D{\'e}prez},
  journal={Nature Communications},
  year={2015},
  volume={6}
}
Insulin-degrading enzyme (IDE) is a protease that cleaves insulin and other bioactive peptides such as amyloid-β. Knockout and genetic studies have linked IDE to Alzheimer's disease and type-2 diabetes. As the major insulin-degrading protease, IDE is a candidate drug target in diabetes. Here we have used kinetic target-guided synthesis to design the first catalytic site inhibitor of IDE suitable for in vivo studies (BDM44768). Crystallographic and small angle X-ray scattering analyses show that… 
Identification of indole-based activators of insulin degrading enzyme.
Antibody-Mediated Inhibition of Insulin-Degrading Enzyme Improves Insulin Activity in a Diabetic Mouse Model
TLDR
It is discovered that one intraperitoneal administration of the IDE-specific antibody in STZ-induced diabetic mice improved insulin activity in an insulin tolerance test (ITT) assay and reduced blood glucose levels.
Substrate-selective inhibitors that reprogram the activity of insulin-degrading enzyme
TLDR
Using a high-throughput screen for non-active-site ligands, potent and highly specific small-molecule inhibitors are discovered that alter IDE’s substrate selectivity and offer a blueprint for modulating other enzymes in a substrate-selective manner to unlock their therapeutic potential.
Targeting Insulin-Degrading Enzyme to Treat Type 2 Diabetes Mellitus
  • Wei-Jen Tang
  • Biology, Chemistry
    Trends in Endocrinology & Metabolism
  • 2016
Inhibition of Insulin Degrading Enzyme to Control Diabetes Mellitus and its Applications on some Other Chronic Disease: a Critical Review.
TLDR
The factors that modulate insulin reformation by IDE and interaction of IDE are summarised and some recent reports on IDE inhibitors against AD and T2D are summarized.
Peptide hydroxamate derivatives as regulators for insulin receptor signaling and its degradation by zinc metalloprotease in diabetic rats
TLDR
A novel synthesized peptide hydroxamic acid II containing tryptophan and a sulfonamide bond has been prepared and administration to diabetic rats significantly reduced IDE protein, glucagon levels, improved insulin receptor signaling, insulin sensitivity and lipid profile, and induced certain up-regulation of IDE mRNA expression.
Multiple functions of insulin-degrading enzyme: a metabolic crosslight?
TLDR
A comprehensive vision of the very complex scenario in which IDE takes part is addressed, outlining its crucial role in interconnecting several relevant cellular processes, suggesting a major implication in proteins turnover and cell homeostasis.
Modulation of Insulin Sensitivity by Insulin-Degrading Enzyme
TLDR
Current knowledge about IDE’s function as a regulator of insulin secretion and hepatic insulin sensitivity is discussed, both evaluating the classical view of IDE as an insulin protease and also exploring evidence for several non-proteolytic functions.
Degradation of Alzheimer’s amyloid-β by a catalytically inactive insulin-degrading enzyme
TLDR
It is revealed that zinc binding to Aβ(1-40) inactivates cf-E111Q-IDE’s catalytic function, whereas zinc removal restores its function as evidenced from high-speed AFM, electron microscopy, chromatography, and NMR results.
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References

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Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones
TLDR
The discovery of a physiologically active IDE inhibitor identified from a DNA-templated macrocycle library and an X-ray structure of the macrocycle bound to IDE reveals that it engages a binding pocket away from the catalytic site, which explains its remarkable selectivity.
Designed Inhibitors of Insulin-Degrading Enzyme Regulate the Catabolism and Activity of Insulin
TLDR
The inhibitors described are the first to potently and selectively inhibit IDE or indeed any member of this atypical zinc-metalloprotease superfamily and 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.
Insulin-degrading enzyme: structure-function relationship and its possible roles in health and disease.
TLDR
The recently solved crystal structures of an inactive IDE mutant bound to four different substrates indicate, in accordance with previous compelling biochemical data, that peptide backbone conformation and size are major determinants of IDE recognition and substrate selectivity.
Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism
TLDR
The molecular basis for substrate recognition and allosteric regulation of IDE could aid in designing IDE-based therapies to control cerebral amyloid-β and blood sugar concentrations.
Optimization of peptide hydroxamate inhibitors of insulin-degrading enzyme reveals marked substrate-selectivity.
TLDR
This work presents a facile synthetic route that yields enantiomerically pure derivatives comparable in potency to the parent compounds and demonstrates that potent, small-molecule IDE inhibitors can be developed that can be highly substrate selective.
Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo
TLDR
In vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and DM2 and provide a mechanism for the recently recognized association among hyperinsulinemia, diabetes, and AD.
Proteolytically Inactive Insulin-Degrading Enzyme Inhibits Amyloid Formation Yielding Non-Neurotoxic Aβ Peptide Aggregates
TLDR
The results suggest that IDE has a chaperone-like activity upon amyloid-forming peptides and whether other highly conserved metallopeptidases have a dual protease-chaperone function to prevent the formation of toxic peptide oligomers from bacteria to mammals.
Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo.
TLDR
In vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and DM2 and provide a mechanism for the recently recognized association among hyperinsulinemia, diabetes, and AD.
Deletion of Insulin-Degrading Enzyme Elicits Antipodal, Age-Dependent Effects on Glucose and Insulin Tolerance
TLDR
The results indicate that the diabetic phenotype in IDE-KO mice is instead an emergent compensatory response to chronic hyperinsulinemia resulting from complete deletion of IDE in all tissues throughout life.
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