BindingMechanism of the Farnesoid X Receptor Marine Antagonist Suvanine Revealsa Strategy To Forestall Drug Modulation on Nuclear Receptors. Design,Synthesis, and Biological Evaluation of Novel Ligands.

Here, we report suvanine, a marinesponge sesterterpene, as an antagonist of the mammalian bile acidsensor farnesoid-X-receptor (FXR). Using suvanine as a template, weshed light on the molecular bases of FXR antagonism, identifying theessential conformational changes responsible for the transition fromthe agonist to the antagonist form. Molecular characterization ofthe nuclear corepressor NCoR and coactivator Src-1 revealed that receptorconformational changes are associated with a specific dynamic of recruitmentof these cofactors to the promoter of OSTα, a FXR regulatedgene. Using suvanine as a novel hit, a library of semisynthetic derivativeshas been designed and prepared, leading to pharmacological profilesranging from agonism to antagonism toward FXR. Deep pharmacologicalevaluation demonstrated that derivative 19representsa new chemotype of FXR modulator, whereas alcohol 6,with a simplified molecular scaffold, exhibits excellent antagonisticactivity. [ABSTRACT FROM AUTHOR]