Abstract |
Molecular disruption of the lipid carrier AFABP/aP2 in mice results in improved insulin sensitivity and protection from atherosclerosis. Because small molecule inhibitors may be efficacious in defining the mechanism(s) of AFABP/aP2 action, a chemical library was screened and identified 1 (HTS01037) as a pharmacologic ligand capable of displacing the fluorophore 1-anilinonaphthalene 8-sulfonic acid from the lipid binding cavity. The X-ray crystal structure of 1 bound to AFABP/aP2 revealed that the ligand binds at a structurally similar position to a long-chain fatty acid. Similar to AFABP/aP2 knockout mice, 1 inhibits lipolysis in 3T3-L1 adipocytes and reduces LPS-stimulated inflammation in cultured macrophages. 1 acts as an antagonist of the protein- protein interaction between AFABP/aP2 and hormone sensitive lipase but does not activate PPARgamma in macrophage or CV-1 cells. These results identify 1 as an inhibitor of fatty acid binding and a competitive antagonist of protein- protein interactions mediated by AFABP/aP2.
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Authors | Ann V Hertzel, Kristina Hellberg, Joseph M Reynolds, Andrew C Kruse, Brittany E Juhlmann, Anne J Smith, Mark A Sanders, Douglas H Ohlendorf, Jill Suttles, David A Bernlohr |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 52
Issue 19
Pg. 6024-31
(Oct 08 2009)
ISSN: 1520-4804 [Electronic] United States |
PMID | 19754198
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Fatty Acid-Binding Proteins
- Heterocyclic Compounds, 2-Ring
- Ligands
- Small Molecule Libraries
- Butyric Acid
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Topics |
- 3T3-L1 Cells
- Animals
- Butyric Acid
- Crystallography, X-Ray
- Drug Evaluation, Preclinical
- Fatty Acid-Binding Proteins
(antagonists & inhibitors)
- Heterocyclic Compounds, 2-Ring
(chemistry, pharmacology)
- Inflammation
(chemically induced, drug therapy)
- Ligands
- Macrophages
- Mice
- Molecular Structure
- Protein Binding
- Small Molecule Libraries
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