Plakilactones from the marine sponge Plakinastrella mamillaris. Discovery of a new class of marine ligands of Peroxisome Proliferator-Activated Receptor gamma

In this paper we report the isolation and the molecular characterization of a new class of PPARgamma 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 PPARgamma ligands in transactivation assays. Both agents covalently bind to the PPARgamma ligand binding domain through a Michael addition reaction involving a protein cysteine residue and the alfa,beta-unsaturated ketone in their side chains. Additionally, gracilioether C is a noncovalent agonist for PPARgamma, and methyl esters 1 and 2 are noncovalent antagonists. Structural requirements for the interaction of these agents within the PPARgamma ligand binding domain were obtained by docking analysis. Gracilioether B and plakilactone C regulate the expression of PPARgamma-dependent genes in the liver and inhibit the generation of inflammatory mediators by macrophages.