PDF(Pubmed)
Abstract：
No therapeutic drugs are currently available for nonalcoholic steatohepatitis (NASH) that progresses from nonalcoholic fatty liver via oxidative stress-involved pathways. Three cognate peroxisome proliferator-activated receptor (PPAR) subtypes (PPARα/δ/γ) are considered as attractive targets. Although lanifibranor (PPARα/δ/γ pan agonist) and saroglitazar (PPARα/γ dual agonist) are currently under investigation in clinical trials for NASH, the development of seladelpar (PPARδ-selective agonist), elafibranor (PPARα/δ dual agonist), and many other dual/pan agonists has been discontinued due to serious side effects or little/no efficacies. This study aimed to obtain functional and structural insights into the potency, efficacy, and selectivity against PPARα/δ/γ of three current and past anti-NASH investigational drugs: lanifibranor, seladelpar, and elafibranor. Ligand activities were evaluated by three assays to detect different facets of the PPAR activation: transactivation assay, coactivator recruitment assay, and thermal stability assay. Seven high-resolution cocrystal structures (namely, those of the PPARα/δ/γ-ligand-binding domain (LBD)-lanifibranor, PPARα/δ/γ-LBD-seladelpar, and PPARα-LBD-elafibranor) were obtained through X-ray diffraction analyses, six of which represent the first deposit in the Protein Data Bank. Lanifibranor and seladelpar were found to bind to different regions of the PPARα/δ/γ-ligand-binding pockets and activated all PPAR subtypes with different potencies and efficacies in the three assays. In contrast, elafibranor induced transactivation and coactivator recruitment (not thermal stability) of all PPAR subtypes, but the PPARδ/γ-LBD-elafibranor cocrystals were not obtained. These results illustrate the highly variable PPARα/δ/γ activation profiles and binding modes of these PPAR ligands that define their pharmacological actions.
摘要：
目前尚无治疗药物可用于非酒精性脂肪性肝炎（NASH），该非酒精性脂肪肝通过涉及氧化应激的途径发展。三种同源过氧化物酶体增殖物激活受体（PPAR）亚型（PPARα/δ/γ）被认为是有吸引力的靶标。尽管目前在NASH的临床试验中正在研究羊膜（PPARα/δ/γpan激动剂）和saroglitazar（PPARα/γ双重激动剂），Seladelpar（PPARδ选择性激动剂）的发展，纤维膜（PPARα/δ双重激动剂），和许多其他双/泛激动剂已经停止，由于严重的副作用或很少/没有疗效。这项研究旨在获得对效力的功能和结构见解，功效,以及三种当前和过去的抗NASH研究药物对PPARα/δ/γ的选择性：羊毛膜，seladelpar,还有Elafibranor.通过三个测定来评估配体活性以检测PPAR激活的不同方面:反式激活测定,共激活剂募集试验，和热稳定性测定。七个高分辨率共晶结构(即PPARα/δ/γ-配体结合域（LBD）-羊毛膜，PPARα/δ/γ-LBD-seladelpar，和PPARα-LBD-纤维膜）通过X射线衍射分析获得，其中六个代表蛋白质数据库中的第一个沉积物。发现Lanifibranor和seladelapar结合到PPARα/δ/γ-配体结合袋的不同区域，并在三种测定中以不同的效力和功效激活所有PPAR亚型。相比之下,纤维膜诱导所有PPARAR亚型的反式激活和共激活因子募集（非热稳定性），但未获得PPARδ/γ-LBD-纤维共晶体。这些结果说明了这些PPAR配体的高度可变的PPARα/δ/γ激活谱和结合模式，这定义了它们的药理作用。
