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Eur J Med Chem. 2019 Jun 24;179:557-566. doi: 10.1016/j.ejmech.2019.06.057. [Epub ahead of print]

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

Author information

1
Univ. Lille, Inserm, Institut Pasteur de Lille, U1177, Drugs and Molecules for Living Systems, F-59000, Lille, France.
2
APTEEUS, F-59000, Lille, France.
3
Univ. Lille, Inserm, Institut Pasteur de Lille, U1177, Drugs and Molecules for Living Systems, F-59000, Lille, France; European Genomic Institute for Diabetes, EGID, University of Lille, F-59000, France.
4
Department of Medicine, University of California at San Diego, CA 92093, La Jolla, United States.
5
Ben-May Institute for Cancer Research, The University of Chicago, IL 60637, Chicago, United States.
6
Univ. Lille, Inserm, Institut Pasteur de Lille, U1177, Drugs and Molecules for Living Systems, F-59000, Lille, France; APTEEUS, F-59000, Lille, France; European Genomic Institute for Diabetes, EGID, University of Lille, F-59000, France.
7
Univ. Lille, Inserm, Institut Pasteur de Lille, U1177, Drugs and Molecules for Living Systems, F-59000, Lille, France; European Genomic Institute for Diabetes, EGID, University of Lille, F-59000, France; Institut Universitaire de France, F- 75231, Paris, France. Electronic address: rebecca.deprez@univ-lille.fr.

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

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