期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 7, 页码 3701-3712出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00012
关键词
-
资金
- Italian Ministry of University
- National Technology Agrifood Cluster, Health and Nutrition program
- PROS.IT project [CTN01_00230_413096]
- Ricerca di base grant program of the University of Perugia
- NIH [R01 CA127231, CA 161879, CA222469, CA098468, CA207416]
- Department of Defense Partnering PI [W81XWH17-1-0479, PR160167]
- [R01 ES030197]
- [R43DK105694]
- [P30DK041296]
Pregnane X receptor (PXR) is a master xenobiotic-sensing transcription factor and a validated target for immune and inflammatory diseases. 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 garcinoic acid as a selective and efficient PXR agonist. The properties of this natural molecule as a specific PXR agonist were demonstrated by the screening on a panel of nuclear receptors, the assessment of the physical and thermodynamic binding affinity, and the determination of the PXR-garcinoic acid complex crystal structure. Cytotoxicity, transcriptional, and functional properties were investigated in human liver cells, and compound activity and target engagement were confirmed in vivo in mouse liver and gut tissue. In conclusion, garcinoic acid is a selective natural agonist of PXR and a promising lead compound toward the development of new PXR-regulating modulators.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据