Plakilactones from the marine sponge Plakinastrella mamillaris. Discovery of a new class of marine ligands of peroxisome proliferator-activated receptor gamma.
Article Details
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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
Drug Target Property Measurement pH Temperature (°C) Rosiglitazone Peroxisome proliferator-activated receptor gamma EC 50 (nM) 100 N/A N/A Details