Inhibition of prolyl oligopeptidase: A promising pathway to prevent the progression of age-related macular degeneration
Autor: | Laura Hellinen, Ali Koskela, Elina Vattulainen, Mikko Liukkonen, Christine Wegler, Andrea Treyer, Niklas Handin, Richard Svensson, Timo Myöhänen, Antti Poso, Kai Kaarniranta, Per Artursson, Arto Urtti |
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Přispěvatelé: | Faculty of Pharmacy, Regenerative pharmacology group, Drug Research Program, Divisions of Faculty of Pharmacy, PREP in neurodegenerative disorders, Division of Pharmacology and Pharmacotherapy, Division of Pharmaceutical Biosciences, Drug Delivery Unit, Drug Delivery |
Jazyk: | angličtina |
Rok vydání: | 2022 |
Předmět: |
Proteomics
Target engagement RM1-950 Cell Line Inhibitory Concentration 50 Macular Degeneration 03 medical and health sciences 0302 clinical medicine DIGESTION Autophagy Humans ASSAYS KYP-2047 Retinal pigment epithelium 030304 developmental biology Pharmacology 0303 health sciences Prolyl oligopeptidase inhibitor Dose-Response Relationship Drug Age-related macular degeneration Biochemistry and Molecular Biology TOTAL PROTEIN General Medicine RETINAL-PIGMENT EPITHELIUM eye diseases 3. Good health Phenotype 317 Pharmacy CELLS sense organs Therapeutics. Pharmacology Prolyl Oligopeptidases Microtubule-Associated Proteins 030217 neurology & neurosurgery Biokemi och molekylärbiologi |
Zdroj: | Biomedicine & Pharmacotherapy, Vol 146, Iss, Pp 112501-(2022) |
ISSN: | 0753-3322 |
Popis: | Dry age-related macular degeneration (AMD) is a currently untreatable vision threatening disease. Impaired proteasomal clearance and autophagy in the retinal pigment epithelium (RPE) and subsequent photoreceptor damage are connected with dry AMD, but detailed pathophysiology is still unclear. In this paper, we discover inhibition of cytosolic protease, prolyl oligopeptidase (PREP), as a potential pathway to treat dry AMD. We showed that PREP inhibitor exposure induced autophagy in the RPE cells, shown by increased LC3-II levels and decreased p62 levels. PREP inhibitor treatment increased total levels of autophagic vacuoles in the RPE cells. Global proteomics was used to examine the phenotype of a commonly used cell model displaying AMD characteristics, oxidative stress and altered protein metabolism, in vitro. These RPE cells displayed induced protein aggregation and clear alterations in macromolecule metabolism, confirming the relevance of the cell model. Differences in intracellular target engagement of PREP inhibitors were observed with cellular thermal shift assay (CETSA). These differences were explained by intracellular drug exposure (the unbound cellular partition coefficient, Kpuu). Importantly, our data is in line with previous observations regarding the discrepancy between PREP's cleaving activity and outcomes in autophagy. This highlights the need to further explore PREP's role in autophagy so that more effective compounds can be designed to battle diseases in which autophagy induction is needed. The present work is the first report investigating the PREP pathway in the RPE and we predict that the PREP inhibitors can be further optimized for treatment of dry AMD. |
Databáze: | OpenAIRE |
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