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Inhibition of proly...
Inhibition of prolyl oligopeptidase : A promising pathway to prevent the progression of age-related macular degeneration
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- Hellinen, Laura (författare)
- Uppsala universitet,Institutionen för farmaci,Univ Eastern Finland, Fac Hlth Sci, Sch Pharm, Kuopio 70210, Finland.
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- Koskela, Ali (författare)
- Univ Eastern Finland, Inst Clin Med, Dept Ophthalmol, POB 1627, FIN-70211 Kuopio, Finland.
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- Vattulainen, Elina (författare)
- Univ Eastern Finland, Inst Clin Med, Dept Ophthalmol, POB 1627, FIN-70211 Kuopio, Finland.
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- Liukkonen, Mikko (författare)
- Univ Eastern Finland, Inst Clin Med, Dept Ophthalmol, POB 1627, FIN-70211 Kuopio, Finland.
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- Wegler, Christine (författare)
- Uppsala universitet,Institutionen för farmaci
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- Treyer, Andrea (författare)
- Uppsala universitet,Institutionen för farmaci
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- Handin, Niklas (författare)
- Uppsala universitet,Institutionen för farmaci
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- Svensson, Richard (författare)
- Uppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab
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- Myohanen, Timo (författare)
- Univ Eastern Finland, Fac Hlth Sci, Sch Pharm, Kuopio 70210, Finland.;Univ Helsinki, Fac Pharm, Div Pharmacol & Pharmacotherapy, Helsinki, Finland.
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- Poso, Antti (författare)
- Univ Eastern Finland, Fac Hlth Sci, Sch Pharm, Kuopio 70210, Finland.
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- Kaarniranta, Kai (författare)
- Univ Helsinki, Fac Pharm, Div Pharmacol & Pharmacotherapy, Helsinki, Finland.;Kuopio Univ Hosp, Dept Ophthalmol, POB 1777, FIN-70211 Kuopio, Finland.
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- Artursson, Per (författare)
- Uppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab,Uppsala Univ, Dept Pharm, S-75123 Uppsala, Sweden.;Uppsala Univ, Drug Optimizat & Pharmaceut Profiling Platform, S-75123 Uppsala, Sweden.;Uppsala Univ, Sci Life Lab, Drug Discovery & Dev Platform, S-75123 Uppsala, Sweden.
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- Urtti, Arto (författare)
- Univ Eastern Finland, Fac Hlth Sci, Sch Pharm, Kuopio 70210, Finland.;Univ Helsinki, Fac Pharm, Div Pharmaceut Biosci, Drug Res Programme, POB 56, FI-00014 Helsinki, Finland.;St Petersburg State Univ, Lab Biohybrid Technol, Inst Chem, St Petersburg 198504, Russia.
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(creator_code:org_t)
- Elsevier, 2022
- 2022
- Engelska.
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Ingår i: Biomedicine and Pharmacotherapy. - : Elsevier. - 0753-3322 .- 1950-6007. ; 146
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Nyckelord
- Prolyl oligopeptidase inhibitor
- Age-related macular degeneration
- Autophagy
- Retinal pigment epithelium
- Proteomics
- Target engagement
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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- Av författaren/redakt...
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Hellinen, Laura
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Koskela, Ali
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Vattulainen, Eli ...
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Liukkonen, Mikko
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Wegler, Christin ...
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Treyer, Andrea
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visa fler...
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Handin, Niklas
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Svensson, Richar ...
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Myohanen, Timo
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Poso, Antti
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Kaarniranta, Kai
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Artursson, Per
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Urtti, Arto
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Uppsala universitet