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

Rebecca Deprez-Poulain (), Nathalie Hennuyer, Damien Bosc, Wenguang G. Liang, Emmanuelle Enée, Xavier Marechal, Julie Charton, Jane Totobenazara, Gonzague Berte, Jouda Jahklal, Tristan Verdelet, Julie Dumont, Sandrine Dassonneville, Eloise Woitrain, Marion Gauriot, Charlotte Paquet, Isabelle Duplan, Paul Hermant, François- Xavier Cantrelle, Emmanuel Sevin, Maxime Culot, Valerie Landry, Adrien Herledan, Catherine Piveteau, Guy Lippens, Florence Leroux, Wei-Jen Tang (), Peter van Endert, Bart Staels and Benoit Deprez ()
Additional contact information
Rebecca Deprez-Poulain: Institut Pasteur de Lille
Nathalie Hennuyer: Institut Pasteur de Lille
Damien Bosc: Institut Pasteur de Lille
Wenguang G. Liang: Ben-May Institute for Cancer Research, The University of Chicago
Emmanuelle Enée: Institut National de la Sante et de la Recherche Medicale, Unité 1151; Université Paris Descartes, Sorbonne Paris Cité; Centre National de la Recherche Scientifique, , Unité 8253
Xavier Marechal: Institut Pasteur de Lille
Julie Charton: Institut Pasteur de Lille
Jane Totobenazara: Institut Pasteur de Lille
Gonzague Berte: Institut Pasteur de Lille
Jouda Jahklal: Institut Pasteur de Lille
Tristan Verdelet: Institut Pasteur de Lille
Julie Dumont: Institut Pasteur de Lille
Sandrine Dassonneville: Institut Pasteur de Lille
Eloise Woitrain: Institut Pasteur de Lille
Marion Gauriot: Institut Pasteur de Lille
Charlotte Paquet: Institut Pasteur de Lille
Isabelle Duplan: Institut Pasteur de Lille
Paul Hermant: Institut Pasteur de Lille
François- Xavier Cantrelle: Centre National de la Recherche Scientifique, UMR 8576, Structural and Functional Glycobiology, Université de Lille
Emmanuel Sevin: Université d'Artois, LBHE, EA2465
Maxime Culot: Université d'Artois, LBHE, EA2465
Valerie Landry: Institut Pasteur de Lille
Adrien Herledan: Institut Pasteur de Lille
Catherine Piveteau: Institut Pasteur de Lille
Guy Lippens: Centre National de la Recherche Scientifique, UMR 8576, Structural and Functional Glycobiology, Université de Lille
Florence Leroux: Institut Pasteur de Lille
Wei-Jen Tang: Ben-May Institute for Cancer Research, The University of Chicago
Peter van Endert: Institut National de la Sante et de la Recherche Medicale, Unité 1151; Université Paris Descartes, Sorbonne Paris Cité; Centre National de la Recherche Scientifique, , Unité 8253
Bart Staels: Institut Pasteur de Lille
Benoit Deprez: Institut Pasteur de Lille

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9250

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