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

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.
Authors:
 [1] ;  [2] ;  [1] ;  [3] ;  [4] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [5] ;  [1] ;  [6] ;  [7] ;  [1] ;  [8] ;  [9] more »;  [9] ;  [1] ;  [1] ;  [1] ;  [8] ;  [1] ;  [3] ;  [4] ;  [6] ;  [1] « less
  1. Institut Pasteur de Lille and Universite de Lille and Institut National de la Sante et de la Recherche Medicale and Institut Federatif de Recherche (France)
  2. Institut Pasteur de Lille and Universite de Lille and Institut National de la Sante et de la Recherche Medicale (France)
  3. Univ. of Chicago, IL (United States)
  4. Universite Paris Descartes (France)
  5. Institut Pasteur de Lille and Universite de Lille Institut National de la Sante et de la Recherche Medicale (France)
  6. Institut Pasteur de Lille and Universite de Lille Institut National de la Sante et de la Recherche Medicale (France)
  7. Institut Pasteur de Lille and Universite de Lille Institut National de la Sante et de la Recherche Medicale(France)
  8. Universite de Lille (France)
  9. Universite d'Artois, Lens (France)
Publication Date:
OSTI Identifier:
1218714
Grant/Contract Number:
AC02-06CH11357
Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 6; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES Biological sciences; medical research