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Journal Articles European Journal of Medicinal Chemistry Year : 2019

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

Terence Beghyn
  • Function : Author

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.
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Dates and versions

hal-03243182 , version 1 (25-10-2021)

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Attribution - NonCommercial

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Florence Leroux, Damien Bosc, Terence Beghyn, Paul Hermant, Sandrine Warenghem, et al.. Identification of ebselen as a potent inhibitor of insulin degrading enzyme by a drug repurposing screening. European Journal of Medicinal Chemistry, 2019, 179, pp.557-566. ⟨10.1016/j.ejmech.2019.06.057⟩. ⟨hal-03243182⟩
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