Plakilactones from the Marine Sponge Plakinastrella mamillaris. Discovery of a New Class of Marine Ligands of Peroxisome Proliferator-Activated Receptor γ

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