title: Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice.
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.
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems, Lille F-59000, France.|Institut Federatif de Recherche 142, Molecular and Cellular Medicine, Lille F-59000, France.|Pole de Recherche Interdisciplinaire pour le Medicament, Lille F-59000, France.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Deprez-Poulain
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1011 Nuclear Receptors, Cardiovascular Diseases and Diabetes, European Genomic Institute for Diabetes, Lille F-59000, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Hennuyer
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems, Lille F-59000, France.|Institut Federatif de Recherche 142, Molecular and Cellular Medicine, Lille F-59000, France.|Pole de Recherche Interdisciplinaire pour le Medicament, Lille F-59000, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Bosc
authors.affiliation: Ben-May Institute for Cancer Research, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Wenguang G
authors.initials: WG
authors.lastname: Liang
authors.affiliation: 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, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Enée
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems, Lille F-59000, France.|Institut Federatif de Recherche 142, Molecular and Cellular Medicine, Lille F-59000, France.|Pole de Recherche Interdisciplinaire pour le Medicament, Lille F-59000, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Marechal
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems, Lille F-59000, France.|Institut Federatif de Recherche 142, Molecular and Cellular Medicine, Lille F-59000, France.|Pole de Recherche Interdisciplinaire pour le Medicament, Lille F-59000, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Charton
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems, Lille F-59000, France.|Institut Federatif de Recherche 142, Molecular and Cellular Medicine, Lille F-59000, France.|Pole de Recherche Interdisciplinaire pour le Medicament, Lille F-59000, France.
authors.forename: Jane
authors.initials: J
authors.lastname: Totobenazara
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems, Lille F-59000, France.|Institut Federatif de Recherche 142, Molecular and Cellular Medicine, Lille F-59000, France.|Pole de Recherche Interdisciplinaire pour le Medicament, Lille F-59000, France.
authors.forename: Gonzague
authors.initials: G
authors.lastname: Berte
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems, Lille F-59000, France.|Institut Federatif de Recherche 142, Molecular and Cellular Medicine, Lille F-59000, France.|Pole de Recherche Interdisciplinaire pour le Medicament, Lille F-59000, France.
authors.forename: Jouda
authors.initials: J
authors.lastname: Jahklal
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems, Lille F-59000, France.|Institut Federatif de Recherche 142, Molecular and Cellular Medicine, Lille F-59000, France.|Pole de Recherche Interdisciplinaire pour le Medicament, Lille F-59000, France.
authors.forename: Tristan
authors.initials: T
authors.lastname: Verdelet
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems, Lille F-59000, France.|Institut Federatif de Recherche 142, Molecular and Cellular Medicine, Lille F-59000, France.|Pole de Recherche Interdisciplinaire pour le Medicament, Lille F-59000, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Dumont
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems, Lille F-59000, France.|Institut Federatif de Recherche 142, Molecular and Cellular Medicine, Lille F-59000, France.|Pole de Recherche Interdisciplinaire pour le Medicament, Lille F-59000, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Dassonneville
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1011 Nuclear Receptors, Cardiovascular Diseases and Diabetes, European Genomic Institute for Diabetes, Lille F-59000, France.
authors.forename: Eloise
authors.initials: E
authors.lastname: Woitrain
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems, Lille F-59000, France.|Institut Federatif de Recherche 142, Molecular and Cellular Medicine, Lille F-59000, France.|Pole de Recherche Interdisciplinaire pour le Medicament, Lille F-59000, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Gauriot
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1011 Nuclear Receptors, Cardiovascular Diseases and Diabetes, European Genomic Institute for Diabetes, Lille F-59000, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Paquet
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1011 Nuclear Receptors, Cardiovascular Diseases and Diabetes, European Genomic Institute for Diabetes, Lille F-59000, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Duplan
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems, Lille F-59000, France.|Institut Federatif de Recherche 142, Molecular and Cellular Medicine, Lille F-59000, France.|Pole de Recherche Interdisciplinaire pour le Medicament, Lille F-59000, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Hermant
authors.affiliation: Centre National de la Recherche Scientifique, UMR 8576, Structural and Functional Glycobiology, Université de Lille, Lille F-59000, France.
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Cantrelle
authors.affiliation: Université d'Artois, LBHE, EA2465, Lens F-62300, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Sevin
authors.affiliation: Université d'Artois, LBHE, EA2465, Lens F-62300, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Culot
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems, Lille F-59000, France.|Institut Federatif de Recherche 142, Molecular and Cellular Medicine, Lille F-59000, France.|Pole de Recherche Interdisciplinaire pour le Medicament, Lille F-59000, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Landry
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems, Lille F-59000, France.|Institut Federatif de Recherche 142, Molecular and Cellular Medicine, Lille F-59000, France.|Pole de Recherche Interdisciplinaire pour le Medicament, Lille F-59000, France.
authors.forename: Adrien
authors.initials: A
authors.lastname: Herledan
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems, Lille F-59000, France.|Institut Federatif de Recherche 142, Molecular and Cellular Medicine, Lille F-59000, France.|Pole de Recherche Interdisciplinaire pour le Medicament, Lille F-59000, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Piveteau
authors.affiliation: Centre National de la Recherche Scientifique, UMR 8576, Structural and Functional Glycobiology, Université de Lille, Lille F-59000, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Lippens
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems, Lille F-59000, France.|Institut Federatif de Recherche 142, Molecular and Cellular Medicine, Lille F-59000, France.|Pole de Recherche Interdisciplinaire pour le Medicament, Lille F-59000, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Leroux
authors.affiliation: Ben-May Institute for Cancer Research, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Wei-Jen
authors.initials: WJ
authors.lastname: Tang
authors.affiliation: 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, Paris, France.
authors.forename: Peter
authors.initials: P
authors.lastname: van Endert
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1011 Nuclear Receptors, Cardiovascular Diseases and Diabetes, European Genomic Institute for Diabetes, Lille F-59000, France.
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.|Université de Lille, Institut Federatif de Recherche 114, Lille F-59000, France.|Institut National de la Sante et de la Recherche Medicale, U1177 Drugs and Molecules for Living Systems, Lille F-59000, France.|Institut Federatif de Recherche 142, Molecular and Cellular Medicine, Lille F-59000, France.|Pole de Recherche Interdisciplinaire pour le Medicament, Lille F-59000, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Deprez
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D020134:Catalytic Domain; D003920:Diabetes Mellitus / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D005951:Glucose Tolerance Test; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D007339:Insulysin / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver; D058990:Molecular Targeted Therapy; D011897:Random Allocation; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C000607809:BDM44768; D006877:Hydroxamic Acids; D014230:Triazoles; D007339:Insulysin