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Garcinoic Acid Is a Natural and Selective Agonist of Pregnane X Receptor.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-03-20 , DOI: 10.1021/acs.jmedchem.0c00012 Desirée Bartolini 1 , Francesca De Franco 2 , Pierangelo Torquato 1 , Rita Marinelli 1 , Bruno Cerra 1 , Riccardo Ronchetti 1 , Arne Schon 3 , Francesca Fallarino 4 , Antonella De Luca 5 , Guido Bellezza 5 , Ivana Ferri 5 , Angelo Sidoni 5 , William G Walton 6 , Samuel J Pellock 6 , Matthew R Redinbo 6 , Sridhar Mani 7 , Roberto Pellicciari 2 , Antimo Gioiello 1 , Francesco Galli 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-03-20 , DOI: 10.1021/acs.jmedchem.0c00012 Desirée Bartolini 1 , Francesca De Franco 2 , Pierangelo Torquato 1 , Rita Marinelli 1 , Bruno Cerra 1 , Riccardo Ronchetti 1 , Arne Schon 3 , Francesca Fallarino 4 , Antonella De Luca 5 , Guido Bellezza 5 , Ivana Ferri 5 , Angelo Sidoni 5 , William G Walton 6 , Samuel J Pellock 6 , Matthew R Redinbo 6 , Sridhar Mani 7 , Roberto Pellicciari 2 , Antimo Gioiello 1 , Francesco Galli 1
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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.
中文翻译：
石榴皮酸是Pregnane X受体的天然选择性激动剂。
孕烷X受体（PXR）是异种生物感知的主要转录因子，也是免疫和炎性疾病的有效靶标。仍然非常需要鉴定用于研究受体的治疗相关性的化学探针。实际上，当前可用的PXR配体不是高度选择性的，并且可以表现出毒性和/或潜在的脱靶效应。在这项研究中，我们确定了藤黄酸是一种选择性和有效的PXR激动剂。通过在一组核受体上的筛选，对物理和热力学结合亲和力的评估以及对PXR-海藻酸复合物晶体结构的确定，证明了这种天然分子作为特异性PXR激动剂的特性。研究了人类肝细胞的细胞毒性，转录和功能特性，并在小鼠肝脏和肠道组织中证实了化合物的活性和靶标的参与。总之，藤黄酸是PXR的选择性天然激动剂，也是开发新型PXR调节剂的有前途的先导化合物。
更新日期：2020-03-21
中文翻译：
石榴皮酸是Pregnane X受体的天然选择性激动剂。
孕烷X受体（PXR）是异种生物感知的主要转录因子，也是免疫和炎性疾病的有效靶标。仍然非常需要鉴定用于研究受体的治疗相关性的化学探针。实际上，当前可用的PXR配体不是高度选择性的，并且可以表现出毒性和/或潜在的脱靶效应。在这项研究中，我们确定了藤黄酸是一种选择性和有效的PXR激动剂。通过在一组核受体上的筛选，对物理和热力学结合亲和力的评估以及对PXR-海藻酸复合物晶体结构的确定，证明了这种天然分子作为特异性PXR激动剂的特性。研究了人类肝细胞的细胞毒性，转录和功能特性，并在小鼠肝脏和肠道组织中证实了化合物的活性和靶标的参与。总之，藤黄酸是PXR的选择性天然激动剂，也是开发新型PXR调节剂的有前途的先导化合物。
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