| Autor: |
Kilpeläinen TP, Pätsi HT, Svarcbahs R, Julku UH, Eteläinen TS, Cui H; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland., Auno S, Sipari N; Viikki Metabolomics Unit, Department of Biosciences, University of Helsinki, Viikinkaari 5 E, 00014 Helsinki, Finland., Norrbacka S, Leino TO, Jäntti M, Myöhänen TT; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland., Wallén EAA |
| Abstrakt: |
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, HUP-55 was selected for in vivo studies. Its brain penetration was evaluated, and it was tested in αSyn virus vector-based and αSyn transgenic mouse models of Parkinson's disease, where it restored motor impairment and reduced levels of oligomerized αSyn in the striatum and substantia nigra . |
