These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
Gioiello_ChemRxiv.pdf (2.1 MB)
Garcinoic Acid Is a Natural and Selective Agonist of Pregnane X Receptor
Preprints are manuscripts made publicly available before they have been submitted for formal peer review and publication. They might contain new research findings or data. Preprints can be a draft or final version of an author's research but must not have been accepted for publication at the time of submission.
submitted on 19.12.2019 and posted on 23.12.2019by Desirée Bartolini, Francesca De Franco, Pierangelo Torquato, Rita Marinelli, Bruno Cerra, Riccardo Ronchetti, Arne Schön, Francesca Fallarino, Antonella De Luca, Guido Bellezza, Ivana Ferri, Angelo Sidoni, William G. Walton, Samuel J. Pellock, Matthew R. Redinbo, Sridhar Mani, Roberto Pellicciari, Antimo Gioiello, Francesco Galli
Pregnane X receptor (PXR) is a master
xenobiotic-sensing transcription factor with a key role in drug metabolism and
disposition. Its activity regulates a number of physiological processes in the
liver and intestine, and it is now a validated target for human diseases
associated with inﬂammation and dysregulation of the immune system. The
identification of chemical probes to investigate the therapeutic relevance of
the receptor is still highly desired. In fact, currently available PXR ligands
are not highly selective and can exhibit toxicity and/or potential oﬀ-target
eﬀects. In this study, we have identified the naturally-occurring garcinoic
acid as a selective and efficient PXR agonist. The properties of garcinoic acid
as a specific PXR agonist was demonstrated using different approaches -
screening on a panel of nuclear receptors, physical and thermodynamic
evaluation of binding affinity, and co-crystallization study. Cytotoxicity
assays, transcriptional and functional experiments were carried out in human liver
cells, in mouse liver and gut tissue to prove compound activity and target
engagement. Taken together, these data support the conclusion that garcinoic
acid efficiently activates PXR and may prove to be an amenable lead toward the
development of differentially acting PXR regulating compounds.