<div class="csl-bib-body">
<div class="csl-entry">Reindl, S., Honeder, S. E., Pirchheim, A., Bigl, G., Gosset, E., Bradic, I., Kientzel, K., Grabner, G., Schittmayer-Schantl, M., Kratky, D., & Birner-Grünberger, R. (2025, July 27). <i>Identifying tissue-specific off-targets of lipase inhibitors in clinical development and used as research tools via competitive activity-based protein profiling</i> [Poster Presentation]. Brixen Proteomics Summerschool 2025, Brixen, Italy. http://hdl.handle.net/20.500.12708/219090</div>
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dc.identifier.uri
http://hdl.handle.net/20.500.12708/219090
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dc.description.abstract
Lipid hydrolases are essential regulators of lipid metabolism and their dysregulation can contribute to a range of diseases, including obesity, cardiovascular and central nervous system disorders as well as metabolic syndromes. Lipase inhibitors are used in clinical development to treat several of these conditions and serve as valuable research tools to study the role of lipases in diverse diseases, enabling researchers to dissect lipid metabolic pathways and study the downstream effects on physiological processes. However, off-target effects in both applications can compromise full target selectivity and confound both experimental results and therapeutic outcomes.
To address this, we employed competitive activity-based protein profiling (ABPP) to identify novel lipase inhibitor off-targets across different tissues. In competitive ABPP, small molecule probes compete with endogenous substrates by covalently binding to the enzyme's active site and terminally blocking it. Our approach combines a serine hydrolase-targeting probe with inhibitor treatment against the lipolytic enzymes Adipose Triglyceride Lipase (ATGL), Hormone Sensitive Lipase (HSL), Monoacylglycerol Lipase (MGL) or Lysosomal Acid Lipase (LAL) in LX-2 human hepatic stellate cells, murine liver tissue, murine primary hepatocytes as well as in murine bone marrow-derived macrophages (BMDM). With this method, we identify several known as well as some unknown off-targets for MGL inhibitors JZL-184 and Lu AG06466, LAL inhibitors Lalistat-1 and Lalistat-2, as well as HSL inhibitor Hi 76-0079. We further observed differences in the lipase activity profiles between hepatocytes and BMDM. The identified off-targets were validated via over-expression in Expi293F cells and subsequent activity-based gel electrophoresis.
In conclusion, our comprehensive approach utilizing competitive ABPP uncovers tissue-specific off-targets of prominent lipase inhibitors used in lipolytic enzyme research as well as in clinical development, shedding light on their potential implications for therapeutic effect as well as cellular function and underscoring the significance of considering tissue variability when studying lipase inhibition effects.
en
dc.description.sponsorship
FWF - Österr. Wissenschaftsfonds
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dc.description.sponsorship
FWF - Österr. Wissenschaftsfonds
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dc.language.iso
en
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dc.subject
competitive activity-based proteomics
en
dc.title
Identifying tissue-specific off-targets of lipase inhibitors in clinical development and used as research tools via competitive activity-based protein profiling
en
dc.type
Presentation
en
dc.type
Vortrag
de
dc.contributor.affiliation
Medical University of Graz, Austria
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dc.contributor.affiliation
TU Wien, Austria
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dc.contributor.affiliation
TU Wien, Austria
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dc.contributor.affiliation
Medical University of Graz, Austria
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dc.contributor.affiliation
Medical University of Graz, Austria
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dc.relation.grantno
F 7309-B21
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dc.relation.grantno
COE 7
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dc.type.category
Poster Presentation
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tuw.project.title
Lipidhydrolyse im Krebs und in Lipid-assoziierten Krankheiten
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tuw.project.title
COE Microbiomes drive Planetary Health
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tuw.researchinfrastructure
Cell Culture Core Facility (CCCF)
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tuw.researchTopic.id
X1
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tuw.researchTopic.name
Beyond TUW-research focus
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tuw.researchTopic.value
100
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tuw.publication.orgunit
E164-01-3 - Forschungsgruppe Bioanalytik
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tuw.publication.orgunit
E056-12 - Fachbereich ENROL DP
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tuw.author.orcid
0009-0000-6859-6902
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tuw.author.orcid
0000-0002-7110-9957
-
tuw.author.orcid
0000-0003-3249-655X
-
tuw.author.orcid
0000-0003-1357-7573
-
tuw.author.orcid
0000-0003-3950-0312
-
tuw.event.name
Brixen Proteomics Summerschool 2025
en
tuw.event.startdate
27-07-2025
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tuw.event.enddate
02-08-2025
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tuw.event.online
On Site
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tuw.event.type
Event for scientific audience
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tuw.event.place
Brixen
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tuw.event.country
IT
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tuw.event.presenter
Reindl, Sarah
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tuw.event.track
Single Track
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wb.sciencebranch
Chemie
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wb.sciencebranch
Biologie
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wb.sciencebranch
Pharmazie, Pharmakologie, Toxikologie
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wb.sciencebranch.oefos
1040
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wb.sciencebranch.oefos
1060
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wb.sciencebranch.oefos
3012
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wb.sciencebranch.value
50
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wb.sciencebranch.value
25
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wb.sciencebranch.value
25
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item.grantfulltext
none
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item.cerifentitytype
Publications
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item.fulltext
no Fulltext
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item.openairecristype
http://purl.org/coar/resource_type/c_18co
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item.openairetype
conference poster not in proceedings
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item.languageiso639-1
en
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crisitem.author.dept
E164-01-3 - Forschungsgruppe Bioanalytik
-
crisitem.author.dept
E164-01-3 - Forschungsgruppe Bioanalytik
-
crisitem.author.dept
Medical University of Graz, Austria
-
crisitem.author.dept
TU Wien, Austria
-
crisitem.author.dept
TU Wien, Austria
-
crisitem.author.dept
Medical University of Graz, Austria
-
crisitem.author.dept
E164-01-3 - Forschungsgruppe Bioanalytik
-
crisitem.author.dept
Medical University of Graz, Austria
-
crisitem.author.dept
E164-01 - Forschungsbereich Imaging und Instrumentelle Analytische Chemie
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crisitem.author.orcid
0009-0000-6859-6902
-
crisitem.author.orcid
0000-0002-7110-9957
-
crisitem.author.orcid
0000-0003-3249-655X
-
crisitem.author.orcid
0000-0003-1357-7573
-
crisitem.author.orcid
0000-0003-3950-0312
-
crisitem.author.parentorg
E164-01 - Forschungsbereich Imaging und Instrumentelle Analytische Chemie
-
crisitem.author.parentorg
E164-01 - Forschungsbereich Imaging und Instrumentelle Analytische Chemie
-
crisitem.author.parentorg
E164-01 - Forschungsbereich Imaging und Instrumentelle Analytische Chemie
-
crisitem.author.parentorg
E164 - Institut für Chemische Technologien und Analytik
