New FDA Drug Approvals for 2024: Synthesis and Clinical Application

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер 285, С. 117241 - 117241

Опубликована: Янв. 5, 2025

Язык: Английский

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Design, Synthesis, and Biological Evaluation of Imidazolidinone Derivatives as Potent PPARα/δ Agonists for the Treatment of Cholestatic Liver Diseases

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер 286, С. 117284 - 117284

Опубликована: Янв. 16, 2025

Язык: Английский

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Drugs targeting peroxisome proliferator-activated receptors

Drug Discovery Today, Год журнала: 2025, Номер unknown, С. 104318 - 104318

Опубликована: Фев. 1, 2025

Язык: Английский

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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, Год журнала: 2025, Номер 14(4), С. 494 - 494

Опубликована: Апрель 20, 2025

Peroxisome proliferator-activated receptors (PPARs), composed of the α/δ/γ subtypes, are ligand-activated nuclear receptors/transcription factors that sense endogenous fatty acids or therapeutic drugs to regulate lipid/glucose metabolism and oxidative stress. PPAR forms a multiprotein complex with retinoid X receptor corepressor in an unliganded/inactive state, ligand binding induces replacement coactivator initiate transcription various genes, including metabolic antioxidant ones. We investigated processes by which is replaced two coactivators compete for PPARα/δ/γ-ligand-binding domains (LBDs) using single- dual-emission fluorescence resonance energy transfer (FRET) assays. Single-FRET revealed respective PPARα/δ/γ-selective agonists (pemafibrate, seladelpar, pioglitazone) induced dissociation peptides, NCoR1 NCoR2, from PPARα/δ/γ-LBDs recruitment CBP TRAP220. Meanwhile, dual-FRET demonstrated these simultaneous four CBP, TRAP220, PGC1α, SRC1, were competitively recruited different preferences upon activation. Furthermore, five newly obtained cocrystal structures X-ray diffraction, PPARα-LBDs–NCoR2/CBP/TRAP220/PGC1α PPARγ-LBD–NCoR2, co-analyzed those our previous studies. This illustrates bound same PPARα-LBD loci via their consensus LXXLL motifs liganded state; NCoR1/NCoR2 corepressors IXXXL sequences within LXXXIXXXL unliganded activation AF-2 helix 12 formation interfered created space coactivator. These PPARα/γ-related biochemical physicochemical findings highlight coregulator dynamics on limited loci.

Язык: Английский

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New therapies for primary biliary cholangitis usher in a personalised approach to treatment

Drugs & Therapy Perspectives, Год журнала: 2024, Номер unknown

Опубликована: Дек. 16, 2024

Язык: Английский

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