New tricks of prolyl oligopeptidase inhibitors - A common drug therapy for several neurodegenerative diseases

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Svarcbahs , R , Julku , U , Kilpelainen , T , Kyyrö , M , Jäntti , M & Myohänen , T T 2019 , ' New tricks of prolyl oligopeptidase inhibitors - A common drug therapy for several neurodegenerative diseases ' , Biochemical Pharmacology , vol. 161 , pp. 113-120 . https://doi.org/10.1016/j.bcp.2019.01.013

Title: New tricks of prolyl oligopeptidase inhibitors - A common drug therapy for several neurodegenerative diseases
Author: Svarcbahs, Reinis; Julku, Ulrika; Kilpelainen, Tommi; Kyyrö, Mirva; Jäntti, Maria; Myohänen, Timo T.
Other contributor: University of Helsinki, Regenerative pharmacology group
University of Helsinki, Regenerative pharmacology group
University of Helsinki, PREP in neurodegenerative disorders
University of Helsinki, PREP in neurodegenerative disorders
University of Helsinki, PREP in neurodegenerative disorders
University of Helsinki, Faculty of Pharmacy




Date: 2019-03
Language: eng
Number of pages: 8
Belongs to series: Biochemical Pharmacology
ISSN: 0006-2952
DOI: https://doi.org/10.1016/j.bcp.2019.01.013
URI: http://hdl.handle.net/10138/312566
Abstract: Changes in prolyl oligopeptidase (PREP) expression levels, protein distribution, and activity correlate with aging and are reported in many neurodegenerative conditions. Together with decreased neuropeptide levels observed in aging and neurodegeneration, and PREP's ability to cleave only small peptides, PREP was identified as a druggable target. Known PREP non-enzymatic functions were disregarded or attributed to PREP enzymatic activity, and several potent small molecule PREP inhibitors were developed during early stages of PREP research. These showed a lot of potential but with variable results in experimental memory models, however, the initial excitement was short-lived and all of the clinical trials were discontinued in either Phase I or II clinical trials for unknown reasons. Recently, PREP's ability to form protein-protein interactions, alter cell proliferation and autophagy has gained more attention than earlier recognized catalytical activity. Of new findings, particularly the aggregation of alpha-synuclein (aSyn) that is seen in the presence of PREP is especially interesting because PREP inhibitors are capable of altering aSyn-PREP interaction in a manner that reduces the aSyn dimerization process. Therefore, it is possible that PREP inhibitors that are altering interactions could have different characteristics than those aimed for strong inhibition of catalytic activity. Moreover, PREP co-localization with aSyn, tau, and amyloid-beta hints to PREP's possible role not only in the synucleinopathies but in other neurodegenerative diseases as well. This commentary will focus on less well-acknowledged non-enzymatic functions of PREP that may provide a better approach for the development of PREP inhibitors for the treatment of neurodegenerative disorders.
Subject: Neurodegeneration
Aipha-synuclein
Tau protein
Amyloid-beta
Autophagy
Serine protease
POSTPROLINE CLEAVING ENZYME
SUBSTRATE-GATING MECHANISM
ALPHA-SYNUCLEIN
ENDOPEPTIDASE INHIBITOR
PARKINSONS-DISEASE
ACTIVE-SITE
TAU-PROTEIN
ARGININE-VASOPRESSIN
MOLECULAR-DYNAMICS
MOTOR BEHAVIOR
317 Pharmacy
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