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 - 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

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.

Domaines: Sciences du Vivant [q-bio]

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, 2015, 6 (8250), ⟨10.1038/ncomms9250⟩. ⟨hal-02511111⟩