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
  • 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.