Identification of ebselen as a potent inhibitor of insulin degrading enzyme by a drug repurposing screening

Eur J Med Chem. 2019 Oct 1;179:557-566. doi: 10.1016/j.ejmech.2019.06.057. Epub 2019 Jun 24.

Abstract

Insulin-degrading enzyme, IDE, is a metalloprotease implicated in the metabolism of key peptides such as insulin, glucagon, β-amyloid peptide. Recent studies have pointed out its broader role in the cell physiology. In order to identify new drug-like inhibitors of IDE with optimal pharmacokinetic properties to probe its multiple roles, we ran a high-throughput drug repurposing screening. Ebselen, cefmetazole and rabeprazole were identified as reversible inhibitors of IDE. Ebselen is the most potent inhibitor (IC50(insulin) = 14 nM). The molecular mode of action of ebselen was investigated by biophysical methods. We show that ebselen induces the disorder of the IDE catalytic cleft, which significantly differs from the previously reported IDE inhibitors. IDE inhibition by ebselen can explain some of its reported activities in metabolism as well as in neuroprotection.

Keywords: Drug repurposing; Ebselen; Enzymes; Inhibitors; Screening.

MeSH terms

  • Azoles / chemistry
  • Azoles / pharmacology*
  • Biocatalysis
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Drug Repositioning*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • High-Throughput Screening Assays
  • Humans
  • Insulysin / antagonists & inhibitors*
  • Insulysin / metabolism
  • Molecular Structure
  • Organoselenium Compounds / chemistry
  • Organoselenium Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • Azoles
  • Enzyme Inhibitors
  • Organoselenium Compounds
  • ebselen
  • Insulysin