2. Academic Validation
  3. Identification of indole-based activators of insulin degrading enzyme

Identification of indole-based activators of insulin degrading enzyme

  • Eur J Med Chem. 2022 Jan 15;228:113982. doi: 10.1016/j.ejmech.2021.113982.
Nicolas Kraupner 1,  Chau Phi Dinh 1,  Xiaoan Wen 1,  Valérie Landry 1,  Adrien Herledan 1,  Florence Leroux 2,  Damien Bosc 1,  Julie Charton 2,  Clara Maillard 1,  Sandrine Warenghem 1,  Isabelle Duplan 3,  Catherine Piveteau 1,  Nathalie Hennuyer 3,  Bart Staels 3,  Benoit Deprez 2,  Rebecca Deprez-Poulain 4
Affiliations

Affiliations

  • 1 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000, Lille, France.
  • 2 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000, Lille, France; European Genomic Institute for Diabetes, EGID, University of Lille, F-59000, France.
  • 3 Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000, Lille, France; European Genomic Institute for Diabetes, EGID, University of Lille, F-59000, France.
  • 4 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000, Lille, France; European Genomic Institute for Diabetes, EGID, University of Lille, F-59000, France. Electronic address: [email protected].
PMID: 34815130 DOI: 10.1016/j.ejmech.2021.113982
Abstract

Insulin degrading Enzyme (IDE) is a zinc metalloprotease that cleaves numerous substrates among which Amyloid-β and Insulin. It has been linked through genetic studies to the risk of type-2 diabetes (T2D) or Alzheimer's disease (AD). Pharmacological activation of IDE is an attractive therapeutic strategy in AD. While IDE inhibition gave paradoxal activity in glucose homeostasis, recent studies, in particular in the liver suggest that IDE activators could be also of interest in diabetes. Here we describe the discovery of an original series of IDE activators by screening and structure-activity relationships. Early cellular studies show that hit 1 decreases glucose-stimulating Insulin secretion. Docking studies revealed it has an unprecedented extended binding to the polyanion-binding site of IDE. These indole-based pharmacological tools are activators of both Aβ and Insulin hydrolysis by IDE and could be helpful to explore the multiple roles of IDE.

Keywords

Activators; Insulin-degrading enzyme; Metalloenzymes; Screening.

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