Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice - Université d'Artois Access content directly
Journal Articles Nature Communications Year : 2015

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

Damien Bosc
Julie Charton
Gonzague Berte
  • Function : Author
  • PersonId : 936331
Paul Hermant
  • Function : Author
François- Xavier Cantrelle
  • Function : Author
Peter van Endert

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.
Fichier principal
Vignette du fichier
catalyting_site_inhibition_of_insulin_degrading.pdf (1.02 Mo) Télécharger le fichier
Origin : Publication funded by an institution
Loading...

Dates and versions

hal-02511111 , version 1 (19-03-2020)

Licence

Attribution

Identifiers

Cite

Rebecca Déprez-Poulain, Nathalie Hennuyer, Damien Bosc, Wenguang Liang, Emmanuelle Enée, et al.. Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice. Nature Communications, 2015, 6 (8250), ⟨10.1038/ncomms9250⟩. ⟨hal-02511111⟩
102 View
90 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More