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

Author

Listed:
  • Rebecca Deprez-Poulain

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems
    Institut Federatif de Recherche 142, Molecular and Cellular Medicine)

  • Nathalie Hennuyer

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1011 Nuclear Receptors, Cardiovascular Diseases and Diabetes, European Genomic Institute for Diabetes)

  • Damien Bosc

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems
    Institut Federatif de Recherche 142, Molecular and Cellular Medicine)

  • 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
    Université Paris Descartes, Sorbonne Paris Cité)

  • Xavier Marechal

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems
    Institut Federatif de Recherche 142, Molecular and Cellular Medicine)

  • Julie Charton

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems
    Institut Federatif de Recherche 142, Molecular and Cellular Medicine)

  • Jane Totobenazara

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems
    Institut Federatif de Recherche 142, Molecular and Cellular Medicine)

  • Gonzague Berte

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems
    Institut Federatif de Recherche 142, Molecular and Cellular Medicine)

  • Jouda Jahklal

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems
    Institut Federatif de Recherche 142, Molecular and Cellular Medicine)

  • Tristan Verdelet

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems
    Institut Federatif de Recherche 142, Molecular and Cellular Medicine)

  • Julie Dumont

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems
    Institut Federatif de Recherche 142, Molecular and Cellular Medicine)

  • Sandrine Dassonneville

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems
    Institut Federatif de Recherche 142, Molecular and Cellular Medicine)

  • Eloise Woitrain

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1011 Nuclear Receptors, Cardiovascular Diseases and Diabetes, European Genomic Institute for Diabetes)

  • Marion Gauriot

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems
    Institut Federatif de Recherche 142, Molecular and Cellular Medicine)

  • Charlotte Paquet

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1011 Nuclear Receptors, Cardiovascular Diseases and Diabetes, European Genomic Institute for Diabetes)

  • Isabelle Duplan

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1011 Nuclear Receptors, Cardiovascular Diseases and Diabetes, European Genomic Institute for Diabetes)

  • Paul Hermant

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems
    Institut Federatif de Recherche 142, Molecular and Cellular Medicine)

  • 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
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems
    Institut Federatif de Recherche 142, Molecular and Cellular Medicine)

  • Adrien Herledan

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems
    Institut Federatif de Recherche 142, Molecular and Cellular Medicine)

  • Catherine Piveteau

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems
    Institut Federatif de Recherche 142, Molecular and Cellular Medicine)

  • Guy Lippens

    (Centre National de la Recherche Scientifique, UMR 8576, Structural and Functional Glycobiology, Université de Lille)

  • Florence Leroux

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems
    Institut Federatif de Recherche 142, Molecular and Cellular Medicine)

  • 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
    Université Paris Descartes, Sorbonne Paris Cité)

  • Bart Staels

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1011 Nuclear Receptors, Cardiovascular Diseases and Diabetes, European Genomic Institute for Diabetes)

  • Benoit Deprez

    (Institut Pasteur de Lille
    Université de Lille, Institut Federatif de Recherche 114
    Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems
    Institut Federatif de Recherche 142, Molecular and Cellular Medicine)

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.

Suggested Citation

  • Rebecca Deprez-Poulain & Nathalie Hennuyer & Damien Bosc & Wenguang G. Liang & Emmanuelle Enée & Xavier Marechal & Julie Charton & Jane Totobenazara & Gonzague Berte & Jouda Jahklal & Tristan Verdelet, 2015. "Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9250
    DOI: 10.1038/ncomms9250
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    Cited by:

    1. Wenguang G. Liang & Juwina Wijaya & Hui Wei & Alex J. Noble & Jordan M. Mancl & Swansea Mo & David Lee & John V. Lin King & Man Pan & Chang Liu & Carla M. Koehler & Minglei Zhao & Clinton S. Potter & , 2022. "Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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