Plakilactones from the marine sponge Plakinastrella mamillaris. Discovery of a new class of marine ligands of peroxisome proliferator-activated receptor gamma.

Article Details

Citation

Festa C, Lauro G, De Marino S, D'Auria MV, Monti MC, Casapullo A, D'Amore C, Renga B, Mencarelli A, Petek S, Bifulco G, Fiorucci S, Zampella A

Plakilactones from the marine sponge Plakinastrella mamillaris. Discovery of a new class of marine ligands of peroxisome proliferator-activated receptor gamma.

J Med Chem. 2012 Oct 11;55(19):8303-17. doi: 10.1021/jm300911g. Epub 2012 Sep 19.

PubMed ID
22934537 [ View in PubMed
]
Abstract

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 alpha,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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
RosiglitazonePeroxisome proliferator-activated receptor gammaEC 50 (nM)100N/AN/ADetails