Abstract
Prolyl oligopeptidase (PREP) and dipeptidyl-peptidase 9 (DPP9) are two related serine proteases. PREP is mainly expressed in the central nervous system. This proposal will focus on the possibility to inhibit aggregation of alpha-synuclein (alphaSYN) using active-site directed inhibitors of PREP. alphaSYN plays a key role in the pathophysiologies of Parkinson's and related diseases, where aggregates of alphaSYN precipitate as neurotoxic Lewy-bodies. There are currently no PREPinhibitors that are optimized to block alphaSYN aggregation and that have a biological profile that allows drug development. The proposal will therefore deliver optimized PREP inhibitors. In addition, a PREP-targeting imaging probe will be delivered to image (alphaSYN) in the brain. DPP9 has a wider expression in the human body than PREP, and is also present in the human brain. DPP9 is strongly linked to inflammatory processes, also in the context of neuro-inflammation. The latter is present in nearly all neurodegenerative diseases, including in synucleinopathies and Alzheimer's disease. It is also an early marker of disease that is present before symptoms appear. Of note, there are currently no selective DPP9 inhibitors available. Availability of the latter is essential to obtain preclinical validation of DPP9 inhibitors as novel agents that target neurodegeneration. In addition, the project aims to deliver a DPP9-selective probe for use in neurodegenerative disease imaging.
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