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

Rebecca Déprez-Poulain 1, 2 Nathalie Hennuyer 3, 2 Damien Bosc 2 Wenguang Liang 4 Emmanuelle Enée 5 Xavier Marechal 2 Julie Charton 2 Jane Totobenazara 2 Gonzague Berte 1 Jouda Jahklal 2 Tristan Verdelet 2 Julie Dumont 3 Sandrine Dassonneville 2 Eloise Woitrain 3 Marion Gauriot 2 Charlotte Paquet 6 Isabelle Duplan 3 Paul Hermant François- Xavier Cantrelle Emmanuel Sevin 7 Maxime Culot 7 Valérie Landry 8 Adrien Herledan 9 Catherine Piveteau 9 Guy Lippens 10 Florence Leroux 9 Wei-Jen Tang 11 Peter van Endert 12 Bart Staels 3 Benoit Déprez 9
1 Biostructures et Decouverte de Medicament
2 Institut Pasteur de Lille
3 RNMCD - Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011
4 The University of Chicago Medicine [Chicago]
5 INSERM - Institut National de la Santé et de la Recherche Médicale
6 M3T - Mécanismes de la Tumorigénèse et Thérapies Ciblées (M3T) - UMR 8161
7 LBHE - Laboratoire de la Barrière Hémato-Encéphalique
8 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204
9 M2SV - Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177
10 UGSF - Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576
11 Ben May Institute Cancer Research
12 UPD5 - Université Paris Descartes - Paris 5
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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Rebecca Déprez-Poulain, Nathalie Hennuyer, Damien Bosc, Wenguang Liang, Emmanuelle Enée, et al.. Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice. Nature Communications, Nature Publishing Group, 2015, 6 (8250), ⟨10.1038/ncomms9250⟩. ⟨hal-02511111⟩

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