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

• DOI: 10.1038/ncomms9250
• Publication Date: 2015-09-23T11:19:58Z
• Authors: Rebecca Deprez-Po...; Nathalie Hennuyer; Damien Bosc; Wenguang G. Liang; Emmanuelle Enée; Xavier Marechal; Julie Charton; Jane Totobenazara; Gonzague Berte; Jouda Jahklal; Tristan Verdelet; Julie Dumont; Sandrine Dassonne...; Eloise Woitrain; Marion Gauriot; Charlotte Paquet; Isabelle Duplan; Paul Hermant; François- Xavier ...; Emmanuel Sevin; Maxime Culot; Valerie Landry; Adrien Herledan; Catherine Piveteau; Guy Lippens; Florence Leroux; Wei-Jen Tang; Peter van Endert; Bart Staels; Benoit Deprez
• Keywords: Insulin-degrading enzyme; Homeostasis

Abstract Insulin-degrading enzyme (IDE) is a protease that cleaves insulin and other bioactive peptides such as amyloid-β. Knockout genetic studies have linked IDE to Alzheimer’s disease type-2 diabetes. As the major insulin-degrading protease, candidate drug target in Here we used kinetic target-guided synthesis design first catalytic site inhibitor of suitable for vivo (BDM44768). Crystallographic small angle X-ray scattering analyses show it locks closed conformation. Among panel metalloproteases, BDM44768 selectively inhibits IDE. Acute treatment mice with increases signalling surprisingly impairs glucose tolerance an IDE-dependent manner. These results confirm involved pathways modulate short-term homeostasis, but casts doubt on general usefulness inhibition activity treat