Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes.

Autor:	Grabner GF; Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31/2, 8010 Graz, Austria., Guttenberger N; Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria., Mayer N; Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria., Migglautsch-Sulzer AK; Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria., Lembacher-Fadum C; Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria., Fawzy N; Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31/2, 8010 Graz, Austria., Bulfon D; Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31/2, 8010 Graz, Austria., Hofer P; Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31/2, 8010 Graz, Austria., Züllig T; Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31/2, 8010 Graz, Austria., Hartig L; Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31/2, 8010 Graz, Austria., Kulminskaya N; Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31/2, 8010 Graz, Austria., Chalhoub G; Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31/2, 8010 Graz, Austria., Schratter M; Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31/2, 8010 Graz, Austria., Radner FPW; Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31/2, 8010 Graz, Austria., Preiss-Landl K; Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31/2, 8010 Graz, Austria., Masser S; Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31/2, 8010 Graz, Austria., Lass A; Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31/2, 8010 Graz, Austria.; BioTechMed-Graz, Mozartgasse 12/2, 8010 Graz, Austria., Zechner R; Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31/2, 8010 Graz, Austria.; BioTechMed-Graz, Mozartgasse 12/2, 8010 Graz, Austria.; BioHealth Field of Excellence, University of Graz, Universitätsplatz 3, 8010 Graz, Austria., Gruber K; Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31/2, 8010 Graz, Austria.; BioTechMed-Graz, Mozartgasse 12/2, 8010 Graz, Austria.; BioHealth Field of Excellence, University of Graz, Universitätsplatz 3, 8010 Graz, Austria., Oberer M; Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31/2, 8010 Graz, Austria.; BioTechMed-Graz, Mozartgasse 12/2, 8010 Graz, Austria.; BioHealth Field of Excellence, University of Graz, Universitätsplatz 3, 8010 Graz, Austria., Breinbauer R; Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria.; BioTechMed-Graz, Mozartgasse 12/2, 8010 Graz, Austria., Zimmermann R; Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31/2, 8010 Graz, Austria.; BioTechMed-Graz, Mozartgasse 12/2, 8010 Graz, Austria.; BioHealth Field of Excellence, University of Graz, Universitätsplatz 3, 8010 Graz, Austria.
Jazyk:	angličtina
Zdroj:	Journal of the American Chemical Society [J Am Chem Soc] 2022 Apr 13; Vol. 144 (14), pp. 6237-6250. Date of Electronic Publication: 2022 Apr 01.
DOI:	10.1021/jacs.1c10836
Abstrakt:	Chronically elevated circulating fatty acid levels promote lipid accumulation in nonadipose tissues and cause lipotoxicity. Adipose triglyceride lipase (ATGL) critically determines the release of fatty acids from white adipose tissue, and accumulating evidence suggests that inactivation of ATGL has beneficial effects on lipotoxicity-driven disorders including insulin resistance, steatohepatitis, and heart disease, classifying ATGL as a promising drug target. Here, we report on the development and biological characterization of the first small-molecule inhibitor of human ATGL. This inhibitor, designated NG-497, selectively inactivates human and nonhuman primate ATGL but not structurally and functionally related lipid hydrolases. We demonstrate that NG-497 abolishes lipolysis in human adipocytes in a dose-dependent and reversible manner. The combined analysis of mouse- and human-selective inhibitors, chimeric ATGL proteins, and homology models revealed detailed insights into enzyme-inhibitor interactions. NG-497 binds ATGL within a hydrophobic cavity near the active site. Therein, three amino acid residues determine inhibitor efficacy and species selectivity and thus provide the molecular scaffold for selective inhibition.
Databáze:	MEDLINE
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