Projects per year
Abstract
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.
Original language | English |
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Pages (from-to) | 6237–6250 |
Number of pages | 14 |
Journal | Journal of the American Chemical Society |
Volume | 144 |
Issue number | 14 |
Early online date | 1 Apr 2022 |
DOIs | |
Publication status | Published - 13 Apr 2022 |
ASJC Scopus subject areas
- General Chemistry
- Biochemistry
- Catalysis
- Colloid and Surface Chemistry
Fields of Expertise
- Human- & Biotechnology
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Dive into the research topics of 'Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes'. Together they form a unique fingerprint.Projects
- 2 Finished
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Atglistatin - Preclinical development of small molecule inhibitors targeting human adipose triglyceride lipase
1/05/17 → 30/04/21
Project: Research project
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FWF-Inhibitoren für hATGL - Development of Small Molecule Inhibitors Targeting Human Adipose Triglyceride Lipase
1/08/15 → 31/07/19
Project: Research project