2. Academic Validation
  3. Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice

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

  • Nat Commun. 2015 Sep 23;6:8250. doi: 10.1038/ncomms9250.
Rebecca Deprez-Poulain 1 2 3 4 5,  Nathalie Hennuyer 1 2 6,  Damien Bosc 1 2 3 4 5,  Wenguang G Liang 7,  Emmanuelle Enée 8,  Xavier Marechal 1 2 3 4 5,  Julie Charton 1 2 3 4 5,  Jane Totobenazara 1 2 3 4 5,  Gonzague Berte 1 2 3 4 5,  Jouda Jahklal 1 2 3 4 5,  Tristan Verdelet 1 2 3 4 5,  Julie Dumont 1 2 3 4 5,  Sandrine Dassonneville 1 2 3 4 5,  Eloise Woitrain 1 2 6,  Marion Gauriot 1 2 3 4 5,  Charlotte Paquet 1 2 6,  Isabelle Duplan 1 2 6,  Paul Hermant 1 2 3 4 5,  François-Xavier Cantrelle 9,  Emmanuel Sevin 10,  Maxime Culot 10,  Valerie Landry 1 2 3 4 5,  Adrien Herledan 1 2 3 4 5,  Catherine Piveteau 1 2 3 4 5,  Guy Lippens 9,  Florence Leroux 1 2 3 4 5,  Wei-Jen Tang 7,  Peter van Endert 8,  Bart Staels 1 2 6,  Benoit Deprez 1 2 3 4 5
Affiliations

Affiliations

  • 1 Institut Pasteur de Lille, Lille F-59000, France.
  • 2 Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.
  • 3 Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems, Lille F-59000, France.
  • 4 Institut Federatif de Recherche 142, Molecular and Cellular Medicine, Lille F-59000, France.
  • 5 Pole de Recherche Interdisciplinaire pour le Medicament, Lille F-59000, France.
  • 6 Institut National de la Sante et de la Recherche Medicale, U1011 Nuclear Receptors, Cardiovascular Diseases and Diabetes, European Genomic Institute for Diabetes, Lille F-59000, France.
  • 7 Ben-May Institute for Cancer Research, The University of Chicago, Chicago, Illinois 60637, USA.
  • 8 Institut National de la Sante et de la Recherche Medicale, Unité 1151; Université Paris Descartes, Sorbonne Paris Cité; Centre National de la Recherche Scientifique, , Unité 8253, Paris, France.
  • 9 Centre National de la Recherche Scientifique, UMR 8576, Structural and Functional Glycobiology, Université de Lille, Lille F-59000, France.
  • 10 Université d'Artois, LBHE, EA2465, Lens F-62300, France.
PMID: 26394692 DOI: 10.1038/ncomms9250
Abstract

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 it locks IDE in a closed conformation. Among a panel of metalloproteases, BDM44768 selectively inhibits IDE. Acute treatment of mice with BDM44768 increases Insulin signalling and surprisingly impairs glucose tolerance in an IDE-dependent manner. These results confirm that IDE is involved in pathways that modulate short-term glucose homeostasis, but casts doubt on the general usefulness of the inhibition of IDE catalytic activity to treat diabetes.

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