reposiTUm: Identifying tissue-specific off-targets of lipase inhibitors in clinical development and used as research tools via competitive activity-based protein profiling

DC Field

Value

Language

dc.contributor.author

Reindl, Sarah

dc.contributor.author

Honeder, Sophie Elisabeth

dc.contributor.author

Pirchheim, Anita

dc.contributor.author

Bigl, Gabriela

dc.contributor.author

Gosset, Emilie

dc.contributor.author

Bradic, Ivan

dc.contributor.author

Kientzel, Katharina

dc.contributor.author

Grabner, Gernot

dc.contributor.author

Schittmayer-Schantl, Matthias

dc.contributor.author

Kratky, Dagmar

dc.contributor.author

Birner-Grünberger, Ruth

dc.date.accessioned

2025-09-15T10:27:10Z

dc.date.available

2025-09-15T10:27:10Z

dc.date.issued

2025-07-27

dc.identifier.citation

<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.</div> </div>

dc.identifier.uri

http://hdl.handle.net/20.500.12708/219090

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.

dc.description.sponsorship

FWF - Österr. Wissenschaftsfonds

dc.description.sponsorship

FWF - Österr. Wissenschaftsfonds

dc.language.iso

dc.subject

competitive activity-based proteomics

dc.title

Identifying tissue-specific off-targets of lipase inhibitors in clinical development and used as research tools via competitive activity-based protein profiling

dc.type

Presentation

dc.type

Vortrag

dc.contributor.affiliation

Medical University of Graz, Austria

dc.contributor.affiliation

TU Wien, Austria

dc.contributor.affiliation

TU Wien, Austria

dc.contributor.affiliation

Medical University of Graz, Austria

dc.contributor.affiliation

Medical University of Graz, Austria

dc.relation.grantno

F 7309-B21

dc.relation.grantno

COE 7

dc.type.category

Poster Presentation

tuw.project.title

Lipidhydrolyse im Krebs und in Lipid-assoziierten Krankheiten

tuw.project.title

COE Microbiomes drive Planetary Health

tuw.researchinfrastructure

Cell Culture Core Facility (CCCF)

tuw.researchTopic.id

tuw.researchTopic.name

Beyond TUW-research focus

tuw.researchTopic.value

100

tuw.publication.orgunit

E164-01-3 - Forschungsgruppe Bioanalytik

tuw.publication.orgunit

E056-12 - Fachbereich ENROL DP

tuw.author.orcid

0009-0000-6859-6902

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

tuw.event.startdate

27-07-2025

tuw.event.enddate

02-08-2025

tuw.event.online

On Site

tuw.event.type

Event for scientific audience

tuw.event.place

Brixen

tuw.event.country

tuw.event.presenter

Reindl, Sarah

tuw.event.track

Single Track

wb.sciencebranch

Chemie

wb.sciencebranch

Biologie

wb.sciencebranch

Pharmazie, Pharmakologie, Toxikologie

wb.sciencebranch.oefos

1040

wb.sciencebranch.oefos

1060

wb.sciencebranch.oefos

3012

wb.sciencebranch.value

item.languageiso639-1

item.openairetype

conference poster not in proceedings

item.openairecristype

http://purl.org/coar/resource_type/c_18co

item.grantfulltext

none

item.cerifentitytype

Publications

item.fulltext

no Fulltext

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

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

crisitem.project.funder

FWF - Österr. Wissenschaftsfonds

crisitem.project.funder

FWF - Österr. Wissenschaftsfonds

crisitem.project.grantno

F 7309-B21

crisitem.project.grantno

COE 7

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