Download MendeleyIdentification and characterization of a small molecule inhibitor of Fatty Acid binding proteins.
Hertzel, A.V., Hellberg, K., Reynolds, J.M., Kruse, A.C., Juhlmann, B.E., Smith, A.J., Sanders, M.A., Ohlendorf, D.H., Suttles, J., Bernlohr, D.A.(2009) J Med Chem 52: 6024-6031
- PubMed: 19754198
- DOI: https://doi.org/10.1021/jm900720m
- Primary Citation of Related Structures:
3HK1 - PubMed 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.
Organizational Affiliation:
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
