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

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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Leroux F,Bosc D,Beghyn T,Hermant P,Warenghem S,Landry V,Pottiez V,Guillaume V,Charton J,Herledan A,Urata S,Liang W,Sheng L,Tang WJ,Deprez B,Deprez-Poulain R

doi

10.1016/j.ejmech.2019.06.057

subject

Has Abstract

pub_date

2019-10-01 00:00:00

pages

557-566

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(19)30584-7

journal_volume

179

pub_type

杂志文章

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