Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli Federico II, via D. Montesano 49, 80131 Napoli, Italy.
J Med Chem. 2012 Oct 11;55(19):8303-17. doi: 10.1021/jm300911g. Epub 2012 Sep 19.
In this paper we report the isolation and the molecular characterization of a new class of PPARγ ligands from the marine environment. Biochemical characterization of a library of 13 oxygenated polyketides isolated from the marine sponge Plakinastrella mamillaris allowed the discovery of gracilioether B and plakilactone C as selective PPARγ ligands in transactivation assays. Both agents covalently bind to the PPARγ ligand binding domain through a Michael addition reaction involving a protein cysteine residue and the α,β-unsaturated ketone in their side chains. Additionally, gracilioether C is a noncovalent agonist for PPARγ, and methyl esters 1 and 2 are noncovalent antagonists. Structural requirements for the interaction of these agents within the PPARγ ligand binding domain were obtained by docking analysis. Gracilioether B and plakilactone C regulate the expression of PPARγ-dependent genes in the liver and inhibit the generation of inflammatory mediators by macrophages.
本文从海洋环境中分离并对一类新型的过氧化物酶体增殖物激活受体γ（PPARγ）配体进行了分子特征分析。从海洋海绵 Plakinastrella mamillaris 中分离出的 13 种含氧聚酮文库的生化特征分析，发现 gracilioether B 和 plakilactone C 是过氧化物酶体增殖物激活受体γ（PPARγ）转录激活试验中的选择性配体。这两种药物通过涉及蛋白质半胱氨酸残基和其侧链中α，β-不饱和酮的迈克尔加成反应，共价结合到 PPARγ 配体结合域。此外，gracilioether C 是 PPARγ 的非共价激动剂，而甲酯 1 和 2 是非共价拮抗剂。通过对接分析获得了这些药物在 PPARγ 配体结合域相互作用的结构要求。gracilioether B 和 plakilactone C 调节肝脏中 PPARγ 依赖性基因的表达，并抑制巨噬细胞中炎症介质的产生。
