title: Plakilactones from the marine sponge Plakinastrella mamillaris. Discovery of a new class of marine ligands of peroxisome proliferator-activated receptor γ.
abstract: 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.
authors.affiliation: Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli Federico II, via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Festa
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Lauro
authors.forename: Simona
authors.initials: S
authors.lastname: De Marino
authors.forename: Maria Valeria
authors.initials: MV
authors.lastname: D'Auria
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Monti
authors.forename: Agostino
authors.initials: A
authors.lastname: Casapullo
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Amore
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.forename: Andrea
authors.initials: A
authors.lastname: Mencarelli
authors.forename: Sylvain
authors.initials: S
authors.lastname: Petek
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000818:Animals; D059001:Aquatic Organisms; D001665:Binding Sites; D005663:Furans / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D061065:Polyketides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D011161:Porifera / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D012717:Sesquiterpenes / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation
chemical_list: D005663:Furans; D047495:PPAR gamma; D061065:Polyketides; D012717:Sesquiterpenes; C542748:gracilioether B; C577113:plakilactone C; D015107:4-Butyrolactone