title: Binding mechanism of the farnesoid X receptor marine antagonist suvanine reveals a strategy to forestall drug modulation on nuclear receptors. Design, synthesis, and biological evaluation of novel ligands.
abstract: Here, we report suvanine, a marine sponge sesterterpene, as an antagonist of the mammalian bile acid sensor farnesoid-X-receptor (FXR). Using suvanine as a template, we shed light on the molecular bases of FXR antagonism, identifying the essential conformational changes responsible for the transition from the agonist to the antagonist form. Molecular characterization of the nuclear corepressor NCoR and coactivator Src-1 revealed that receptor conformational changes are associated with a specific dynamic of recruitment of these cofactors to the promoter of OSTα, a FXR regulated gene. Using suvanine as a novel hit, a library of semisynthetic derivatives has been designed and prepared, leading to pharmacological profiles ranging from agonism to antagonism toward FXR. Deep pharmacological evaluation demonstrated that derivative 19 represents a new chemotype of FXR modulator, whereas alcohol 6, with a simplified molecular scaffold, exhibits excellent antagonistic activity.
authors: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
authors: Francesco Saverio
authors: FS
authors: Di Leva
authors: Carmen
authors: C
authors: Festa
authors: Claudio
authors: C
authors: D'Amore
authors: Simona
authors: S
authors: De Marino
authors: Barbara
authors: B
authors: Renga
authors: Maria Valeria
authors: MV
authors: D'Auria
authors: Ettore
authors: E
authors: Novellino
authors: Vittorio
authors: V
authors: Limongelli
authors: Angela
authors: A
authors: Zampella
authors: Stefano
authors: S
authors: Fiorucci
mesh_terms: D000818:Animals; D001665:Binding Sites; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D056970:Co-Repressor Proteins / Q000235:genetics; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics; D011161:Porifera; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D054830:Sesterterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D056970:Co-Repressor Proteins; D008024:Ligands; D008156:Luciferases; D026901:Membrane Transport Proteins; D056920:Nuclear Receptor Coactivator 1; D018160:Receptors, Cytoplasmic and Nuclear; D054830:Sesterterpenes; D000099150:Receptor, Farnesoid X-Activated; C476575:organic solute transporter alpha, human; C582927:suvanine; C464660:obeticholic acid