Publication
Title
P2-substituted N-acylprolylpyrrolidine inhibitors of prolyl oligopeptidase : biochemical evaluation, binding mode determination, and assessment in a cellular model of synucleinopathy
Author
Abstract
We have investigated the effect of regiospecifically , introducing substituents in the P2 part of the typical dipeptide derived basic structure of PREP inhibitors. This hitherto unexplored modification type can be used to improve target affinity, selectivity, and physicochemical parameters in drug discovery programs focusing on PREP inhibitors. Biochemical evaluation of the Produced inhibitors identified, several substituent types that significantly increase target affinity, thereby reducing the need for an electrophilic "warhead" functionality. Pronounced PREP specificity within the group Of Clan SC proteases was generally observed. Omission of the P1 electrophilic function did not affect the overall binding mode of three representative compounds, as studied by X-ray crystallography, while the P2 substituents were demonstrated to be accommodated in a cavity of PREP that, to date, has not been probed by inhibitors. Finally, we report on results of selected inhibitors in a SH-SY5Y cellular model of synucleinopathy and demonstrate a significant antiaggregation effect on alpha-synuclein.
Language
English
Source (journal)
Journal of medicinal chemistry. - Washington, D.C., 1963, currens
Publication
Washington, D.C. : 2012
ISSN
0022-2623
Volume/pages
55:22(2012), p. 9856-9867
ISI
000311461500038
Full text (Publisher's DOI)
UAntwerpen
Faculty/Department
Research group
[E?say:metaLocaldata.cgzprojectinf]
Oligopeptidase inhibitors in brain function and dysfunction: towards new therapeutic strategies for neuroprotection (NEUROPRO).
Investigation of prolyl oligopeptidase as a therapeutic target for neuropathological diseases: inhibitors, substrates and ligands.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 04.02.2013
Last edited 04.10.2017
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