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Title: P2-Substituted N-Acylprolylpyrrolidine inhibitors of Prolyl Oligopeptidase: Biochemical evaluation, binding mode determination, and assessment in a cellular model of synucleinopathy
Authors: Van der Veken, Pieter ×
Fülöp, Vilmos
Rea, Dean
GĂ©rard, Melanie
Van Elzen, Roos
Joossens, Jurgen
Cheng, Jonathan D
Baekelandt, Veerle
De Meester, Ingrid
Lambeir, Anne-Marie
Augustyns, Koen #
Issue Date: Nov-2012
Publisher: ACS Publications
Series Title: Journal of Medicinal Chemistry vol:55 issue:22 pages:9856-9867
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 α-synuclein.
URI: 
ISSN: 0022-2623
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Biochemistry, Kulak (-)
Research Group for Neurobiology and Gene Therapy
× corresponding author
# (joint) last author

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