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 .

Titel: New tricks of prolyl oligopeptidase inhibitors - A common drug therapy for several neurodegenerative diseases
Författare: Svarcbahs, Reinis; Julku, Ulrika; Kilpelainen, Tommi; Kyyrö, Mirva; Jäntti, Maria; Myohänen, Timo T.
Upphovmannens organisation: Regenerative pharmacology group
PREP in neurodegenerative disorders
Division of Pharmacology and Pharmacotherapy
Drug Research Program
Faculty of Pharmacy
Datum: 2019-03
Språk: eng
Sidantal: 8
Tillhör serie: Biochemical Pharmacology
ISSN: 0006-2952
Permanenta länken (URI):
Abstrakt: 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
Tau protein
Serine protease
317 Pharmacy
Referentgranskad: Ja
Licens: cc_by_nc_nd
Användningsbegränsning: openAccess
Parallelpublicerad version: acceptedVersion

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