ArticleAntioxidants (Basel, Switzerland)2023
Functional and Structural Insights into the Human PPARα/δ/γ Targeting Preferences of Anti-NASH Investigational Drugs, Lanifibranor, Seladelpar, and Elafibranor.
Article in Antioxidants (Basel, Switzerland), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
26 citing papers in PubMed.
- Seladelpar in patients with primary biliary cholangitis and compensated cirrhosis: Efficacy and safety from RESPONSE and ASSURE studies.Hepatology communications · 2026Trial
- Stable simulations do not guarantee functional engagement: a case study of off-target prediction for Seladelpar and Zanamivir.Journal of computer-aided molecular design · 2026Article
- Crystal structure of seladelpar, CActa crystallographica. Section E, Crystallographic communications · 2026Article
- The Latest Therapeutic Targets and New Drug Research of Metabolic Dysfunction-Associated Steatotic Liver Disease.Clinical pharmacology and therapeutics · 2026Review
- Review
- From dual to quintuple agonism for next-generation pharmacology to treat obesity and type 2 diabetes: synergistic incretin and nuclear receptor signaling.Cardiovascular diabetology. Endocrinology reports · 2026Article
- Review Article: Targeting Peroxisome Proliferator-Activated Receptors in Primary Biliary Cholangitis.Alimentary pharmacology & therapeutics · 2026Review
- The context-dependent roles of PPAR-γ in adipocyte differentiation and obesity: a master regulator with dual functions.Frontiers in nutrition · 2026Review
- PPAR-mediated reduction of lipid accumulation in hepatocytes involves the autophagy-lysosome-mitochondrion axis.Annals of medicine · 2025Article
- Peroxisome Proliferator-Activated Receptor Agonist IVA337 Alleviates Inflammation and Fibrosis in MASH by Restoring Lipid Homeostasis.The American journal of pathology · 2025Article
- Long-Term Efficacy and Safety of Selective PPARδ Agonist Seladelpar in Primary Biliary Cholangitis: ASSURE Interim Study Results.The American journal of gastroenterology · 2025Article
- Game Changers: Blockbuster Small-Molecule Drugs Approved by the FDA in 2024.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Competitive Ligand-Induced Recruitment of Coactivators to Specific PPARα/δ/γ Ligand-Binding Domains Revealed by Dual-Emission FRET and X-Ray Diffraction of Cocrystals.Antioxidants (Basel, Switzerland) · 2025Article
- Highlights on U.S. FDA-approved halogen-containing drugs in 2024.European journal of medicinal chemistry · 2025Review
- Elafibranor: A promising therapeutic approach for liver fibrosis and gut barrier dysfunction in alcohol-associated liver disease.World journal of gastroenterology · 2025Review
- Prospects of elafibranor in treating alcohol-associated liver diseases.World journal of gastroenterology · 2025Article
- Therapeutic Targeting of PPARγ in Nonalcoholic Fatty Liver Disease: Efficacy, Safety, and Drug Development.Drug design, development and therapy · 2025Review
- Waterless structures in the Protein Data Bank.IUCrJ · 2024Article
- Dual peroxisome proliferator-activated receptor α/δ agonists: Hope for the treatment of alcohol-associated liver disease?World journal of gastroenterology · 2024Article
- ACAD9 treatment with bezafibrate and nicotinamide riboside temporarily stabilizes cardiomyopathy and lactic acidosis.Mitochondrion · 2024Article
Corrections and comments
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Authors and funding
13 authors.
Funding
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.
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