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Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-ß hydrolysis.
Charton, Julie; Gauriot, Marion; Guo, Qing; Hennuyer, Nathalie; Marechal, Xavier; Dumont, Julie; Hamdane, Malika; Pottiez, Virginie; Landry, Valerie; Sperandio, Olivier; Flipo, Marion; Buee, Luc; Staels, Bart; Leroux, Florence; Tang, Wei-Jen; Deprez, Benoit; Deprez-Poulain, Rebecca.
Afiliación
  • Charton J; INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France.
  • Gauriot M; INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France.
  • Guo Q; Ben-May Institute for Cancer Research, The University of Chicago, W421 Chicago, IL, USA.
  • Hennuyer N; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; INSERM U1011 Nuclear Receptors, Cardiovascular Diseases and Diabetes, Lille F-59000, France; European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Marechal X; INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France.
  • Dumont J; INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France.
  • Hamdane M; Univ Lille Nord de France, Lille F-59000, France; INSERM U837 Neurodegenerative Diseases and Neuronal Death, Lille F-59000, France; CHRU, Lille F-59000, France.
  • Pottiez V; INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France.
  • Landry V; INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France.
  • Sperandio O; CDithem Platform/IGM, Paris, France; Inserm UMR-S 973/MTi, University Paris Diderot, Paris, France.
  • Flipo M; INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France.
  • Buee L; Univ Lille Nord de France, Lille F-59000, France; INSERM U837 Neurodegenerative Diseases and Neuronal Death, Lille F-59000, France; CHRU, Lille F-59000, France.
  • Staels B; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; INSERM U1011 Nuclear Receptors, Cardiovascular Diseases and Diabetes, Lille F-59000, France; European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Leroux F; INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France.
  • Tang WJ; Ben-May Institute for Cancer Research, The University of Chicago, W421 Chicago, IL, USA.
  • Deprez B; INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France. Electronic address: benoit.deprez@univ-lille2.fr.
  • Deprez-Poulain R; INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France. Electronic address: rebecca.deprez@univ-lille2.fr.
Eur J Med Chem ; 79: 184-93, 2014 May 22.
Article en En | MEDLINE | ID: mdl-24735644
ABSTRACT
Insulin degrading enzyme (IDE) is a highly conserved zinc metalloprotease that is involved in the clearance of various physiologically peptides like amyloid-beta and insulin. This enzyme has been involved in the physiopathology of diabetes and Alzheimer's disease. We describe here a series of small molecules discovered by screening. Co-crystallization of the compounds with IDE revealed a binding both at the permanent exosite and at the discontinuous, conformational catalytic site. Preliminary structure-activity relationships are described. Selective inhibition of amyloid-beta degradation over insulin hydrolysis was possible. Neuroblastoma cells treated with the optimized compound display a dose-dependent increase in amyloid-beta levels.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos beta-Amiloides / Bibliotecas de Moléculas Pequeñas / Imidazoles / Insulisina / Acetatos Límite: Humans Idioma: En Revista: Eur J Med Chem Año: 2014 Tipo del documento: Article País de afiliación: Francia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos beta-Amiloides / Bibliotecas de Moléculas Pequeñas / Imidazoles / Insulisina / Acetatos Límite: Humans Idioma: En Revista: Eur J Med Chem Año: 2014 Tipo del documento: Article País de afiliación: Francia