Nonpeptidic Oxazole-Based Prolyl Oligopeptidase Ligands with Disease-Modifying Effects on α-Synuclein Mouse Models of Parkinson's Disease.
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
08 06 2023
08 06 2023
Historique:
medline:
9
6
2023
pubmed:
30
5
2023
entrez:
29
5
2023
Statut:
ppublish
Résumé
Prolyl oligopeptidase (PREP) is a widely distributed serine protease in the human body cleaving proline-containing peptides; however, recent studies suggest that its effects on pathogenic processes underlying neurodegeneration are derived from direct protein-protein interactions (PPIs) and not from its regulation of certain neuropeptide levels. We discovered novel nonpeptidic oxazole-based PREP inhibitors, which deviate from the known structure-activity relationship for PREP inhibitors. These new compounds are effective modulators of the PPIs of PREP, reducing α-synuclein (αSyn) dimerization and enhancing protein phosphatase 2A activity in a concentration-response manner, as well as reducing reactive oxygen species production. From the best performing oxazoles,
Identifiants
pubmed: 37248563
doi: 10.1021/acs.jmedchem.3c00235
pmc: PMC10258805
doi:
Substances chimiques
alpha-Synuclein
0
Ligands
0
Prolyl Oligopeptidases
EC 3.4.21.26
Serine Endopeptidases
EC 3.4.21.-
Oxazoles
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7475-7496Références
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