Identification of indole-based activators of insulin degrading enzyme.
Basic Information
ID: ALA5154655
Journal: Eur J Med Chem
Title: Identification of indole-based activators of insulin degrading enzyme.
Authors: Kraupner N, Dinh CP, Wen X, Landry V, Herledan A, Leroux F, Bosc D, Charton J, Maillard C, Warenghem S, Duplan I, Piveteau C, Hennuyer N, Staels B, Deprez B, Deprez-Poulain R.
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.
CiteXplore: 34815130
DOI: 10.1016/j.ejmech.2021.113982
Patent ID: ┄