Constrained peptidomimetics reveal detailed geometric requirements of covalent prolyl oligopeptidase inhibitors.

Détails

ID Serval
serval:BIB_F1F9BE70E98B
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Constrained peptidomimetics reveal detailed geometric requirements of covalent prolyl oligopeptidase inhibitors.
Périodique
Journal of Medicinal Chemistry
Auteur(s)
Lawandi J., Toumieux S., Seyer V., Campbell P., Thielges S., Juillerat-Jeanneret L., Moitessier N.
ISSN
1520-4804[electronic]
Statut éditorial
Publié
Date de publication
2009
Volume
52
Numéro
21
Pages
6672-6684
Langue
anglais
Résumé
Prolyl oligopeptidases cleave peptides on the carboxy side of internal proline residues and their inhibition has potential in the treatment of human brain disorders. Using our docking program fitted, we have designed a series of constrained covalent inhibitors, built from a series of bicyclic scaffolds, to study the optimal shape required for these small molecules. These structures bear nitrile functional groups that we predicted to covalently bind to the catalytic serine of the enzyme. Synthesis and biological assays using human brain-derived astrocytic cells and endothelial cells and human fibroblasts revealed that these compounds act as selective inhibitors of prolyl oligopeptidase activity compared to prolyl-dipeptidyl-aminopeptidase activity, are able to penetrate the cells and inhibit intracellular activities in intact living cells. This integrated computational and experimental study shed light on the binding mode of inhibitors in the enzyme active site and will guide the design of future drug-like molecules.
Mots-clé
Thiazolidine Lactam Peptidomimetics, Endopeptidase Inhibitor, Alzheimers-Disease, Proline Endopeptidase, Docking Ligands, S 17092, Jtp-4819, Pro-Leu-Gly-Nh2, Mimetics, Protein
Pubmed
Web of science
Création de la notice
24/11/2009 17:03
Dernière modification de la notice
03/03/2018 22:39
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