title: Identification and characterization of a small molecule inhibitor of Fatty Acid binding proteins.
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.
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Ann V
authors.initials: AV
authors.lastname: Hertzel
authors.forename: Kristina
authors.initials: K
authors.lastname: Hellberg
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Reynolds
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Kruse
authors.forename: Brittany E
authors.initials: BE
authors.lastname: Juhlmann
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Smith
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sanders
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Ohlendorf
authors.forename: Jill
authors.initials: J
authors.lastname: Suttles
authors.forename: David A
authors.initials: DA
authors.lastname: Bernlohr
mesh_terms: 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
chemical_list: D050556:Fatty Acid-Binding Proteins; D006574:Heterocyclic Compounds, 2-Ring; D008024:Ligands; D054852:Small Molecule Libraries; D020148:Butyric Acid