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

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Déprez-Poulain, Rebecca | Hennuyer, Nathalie | Bosc, Damien | Liang, Wenguang | Enée, Emmanuelle | Marechal, Xavier | Charton, Julie | Totobenazara, Jane | Berte, Gonzague | Jahklal, Jouda | Verdelet, Tristan | Dumont, Julie | Dassonneville, Sandrine | Woitrain, Eloise | Gauriot, Marion | Paquet, Charlotte | Duplan, Isabelle | Hermant, Paul | Cantrelle, François- Xavier | Sevin, Emmanuel | Culot, Maxime | Landry, Valérie | Herledan, Adrien | Piveteau, Catherine | Lippens, Guy | Leroux, Florence | Tang, Wei-Jen | van Endert, Peter | Staels, Bart | Déprez, Benoit

Edité par CCSD ; Nature Publishing Group -

International audience. 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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