1. Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice.
- Author
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Deprez-Poulain R, Hennuyer N, Bosc D, Liang WG, Enée E, Marechal X, Charton J, Totobenazara J, Berte G, Jahklal J, Verdelet T, Dumont J, Dassonneville S, Woitrain E, Gauriot M, Paquet C, Duplan I, Hermant P, Cantrelle FX, Sevin E, Culot M, Landry V, Herledan A, Piveteau C, Lippens G, Leroux F, Tang WJ, van Endert P, Staels B, and Deprez B
- Subjects
- Animals, Caco-2 Cells, Catalytic Domain, Diabetes Mellitus drug therapy, Drug Evaluation, Preclinical, Glucose Tolerance Test, Humans, Hydroxamic Acids pharmacology, Hydroxamic Acids therapeutic use, Male, Mice, Mice, Inbred C57BL, Microsomes, Liver, Molecular Targeted Therapy, Random Allocation, Structure-Activity Relationship, Triazoles pharmacology, Triazoles therapeutic use, Hydroxamic Acids chemical synthesis, Insulysin antagonists & inhibitors, Triazoles chemical synthesis
- 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.
- Published
- 2015
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