Identification and Characterization of a Small Molecule Inhibitor of Fatty Acid Binding Proteins

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：October 8, 2009
• 年：2009
• 卷：52
• 期：19
• 页码：6024-6031
• 全文大小：858K
• 年卷期：v.52,no.19(October 8, 2009)
• ISSN：1520-4804

文摘

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 PPARγ 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.