Journal Article

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

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

2015

Overview

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. Inhibiting insulin-degrading enzyme (IDE) has been proposed as a potential therapeutic strategy for the treatment of patients with diabetes. Here, the authors develop a novel IDE inhibitor but find that, surprisingly, IDE inhibition has negative effects on glucose tolerance in mice.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Pub. Group
• Subject: 140/131 / 631/443/319/1642/137 / 631/45/607/468 / 692/700/565 / Alzheimer's disease / Animals / BASIC BIOLOGICAL SCIENCES / Binding sites / Biological sciences / Caco-2 Cells / Catalytic activity / Catalytic Domain / Chemical synthesis / Crystallography / Degradation / Design / Diabetes / Diabetes Mellitus - drug therapy / Drug Evaluation, Preclinical / Enzymes / Experiments / Glucose / Glucose Tolerance Test / Homeostasis / Humanities and Social Sciences / Humans / Hydroxamic Acids - chemical synthesis / Hydroxamic Acids - pharmacology / Hydroxamic Acids - therapeutic use / In vivo methods and tests / Insulin / Insulysin - antagonists & inhibitors / Life Sciences / Male / medical research / Mice / Mice, Inbred C57BL / Microsomes, Liver / Molecular Targeted Therapy / multidisciplinary / Peptides / Protease / Random Allocation / Reagents / Science / Science (multidisciplinary) / Small angle X ray scattering / Structure-Activity Relationship / Triazoles - chemical synthesis / Triazoles - pharmacology / Triazoles - therapeutic use