Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-β hydrolysis
| Autor: | Marion Gauriot, Virginie Pottiez, Valérie Landry, Malika Hamdane, Nathalie Hennuyer, Wei-Jen Tang, Julie Charton, Qing Guo, Olivier Sperandio, Bart Staels, Julie Dumont, Florence Leroux, Rebecca Deprez-Poulain, Xavier Marechal, Luc Buée, Marion Flipo, Benoit Deprez |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Stereochemistry
medicine.medical_treatment Acetates Insulysin Article Small Molecule Libraries Structure-Activity Relationship Drug Discovery Hydrolase medicine Insulin-degrading enzyme Tumor Cells Cultured Structure–activity relationship Humans Pharmacology chemistry.chemical_classification Amyloid beta-Peptides Dose-Response Relationship Drug Molecular Structure Chemistry Insulin Hydrolysis Organic Chemistry Imidazoles Substrate (chemistry) General Medicine Small molecule Enzyme Biochemistry |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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