Identification and characterization of a small molecule inhibitor of Fatty Acid binding proteins.
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.
Hertzel
Ann V
AV
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Hellberg
Kristina
K
Reynolds
Joseph M
JM
Kruse
Andrew C
AC
Juhlmann
Brittany E
BE
Smith
Anne J
AJ
Sanders
Mark A
MA
Ohlendorf
Douglas H
DH
Suttles
Jill
J
Bernlohr
David A
DA
D041721:3T3-L1 Cells; D000818:Animals; D020148:Butyric Acid; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors*; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D008024:Ligands; D008264:Macrophages; D051379:Mice; D015394:Molecular Structure; D011485:Protein Binding; D054852:Small Molecule Libraries
D050556:Fatty Acid-Binding Proteins; D006574:Heterocyclic Compounds, 2-Ring; D008024:Ligands; D054852:Small Molecule Libraries; D020148:Butyric Acid