期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 79, 期 -, 页码 184-193出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.04.009
关键词
Enzymes; Medicinal chemistry; Structure-activity relationships; Amyloid-beta peptides; Inhibitors; X-ray diffraction
资金
- INSERM
- University of Lille 2
- Pasteur Institute of Lille
- Region Nord Pas de Calais
- EDFR
- Etat [0823007, 0823008, 07-CPER 009-01, 2007-0172-02-CPER/3]
- ANR [11-JS07-015-01]
- FRM [DCM20111223046]
- NIH [GM81539]
- PRIM (Pole de Recherche Interdisciplinaire pour le Medicament)
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. (c) 2014 Elsevier Masson SAS. All rights reserved.
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