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-55was selected forin vivostudies. 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
andsubstantia nigra.