Identification of the First PPAR alpha/gamma Dual Agonist Able To Bind to Canonical and Alternative Sites of PPAR gamma and To Inhibit Its Cdk5-Mediated Phosphorylation
| العنوان: | Identification of the First PPAR alpha/gamma Dual Agonist Able To Bind to Canonical and Alternative Sites of PPAR gamma and To Inhibit Its Cdk5-Mediated Phosphorylation |
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| المؤلفون: | Antonio Lavecchia, Roberta Montanari, Franck Peiretti, Giorgio Pochetti, Maurizio Crestani, Fulvio Loiodice, Antonio Laghezza, Marco Giudici, Luca Piemontese, Carmen Cerchia, Davide Capelli, Paolo Tortorella |
| المساهمون: | Università degli studi di Bari, Istituto di Cristallografia (IC), Consiglio Nazionale delle Ricerche (CNR), Centre recherche en CardioVasculaire et Nutrition (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laghezza, Antonio, Piemontese, Luca, Cerchia, Carmen, Montanari, Roberta, Capelli, Davide, Giudici, Marco, Crestani, Maurizio, Tortorella, Paolo, Peiretti, Franck, Pochetti, Giorgio, Lavecchia, Antonio, Loiodice, Fulvio, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), University degli Studi di Bari 'Aldo Moro' H96J15001610005, Università degli studi di Bari Aldo Moro (UNIBA) |
| المصدر: | Journal of Medicinal Chemistry Journal of Medicinal Chemistry, 2018, 61 (18), pp.8282-8298. ⟨10.1021/acs.jmedchem.8b00835⟩ Journal of Medicinal Chemistry, American Chemical Society, 2018, 61 (18), pp.8282-8298. ⟨10.1021/acs.jmedchem.8b00835⟩ Journal of medicinal chemistry (Online) (2018). doi:10.1021/acs.jmedchem.8b00835 info:cnr-pdr/source/autori:Laghezza A., Piemontese L., Cerchia C., Montanari R., Capelli D., Giudici M., Crestani M., Tortorella P., Peiretti F., Pochetti G., Lavecchia A., Loiodice F/titolo:Identification of the first PPARa%2Fg able to bind to canonical and alternate sites of PPARg and to inhibit its Cdk-5-mediated phosphorylation/doi:10.1021%2Facs.jmedchem.8b00835/rivista:Journal of medicinal chemistry (Online)/anno:2018/pagina_da:/pagina_a:/intervallo_pagine:/volume |
| بيانات النشر: | HAL CCSD, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Models, Molecular, 0301 basic medicine, Agonist, Protein Conformation, medicine.drug_class, [SDV]Life Sciences [q-bio], nuclear receptors, Crystallography, X-Ray, Partial agonist, Serine, Mice, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Transactivation, 0302 clinical medicine, 3T3-L1 Cells, Adipocyte, Drug Discovery, medicine, Animals, Humans, Structure–activity relationship, PPAR alpha, PPARa PPARg, Enzyme Inhibitors, Phosphorylation, Molecular Structure, Chemistry, Cyclin-Dependent Kinase 5, Hep G2 Cells, 3. Good health, Cell biology, PPAR gamma, 030104 developmental biology, 030220 oncology & carcinogenesis, Molecular Medicine, Propionates, PPAR modulators, drug discovery, X-ray crystallography, Structure activity relationship, Molecular docking, Type 2 diabetes, Rosiglitazone, medicine.drug |
| الوصف: | A new series of derivatives of the PPAR alpha/gamma dual agonist 1 allowed us to identify the ligand (S)-6 as a potent partial agonist of both PPAR alpha and gamma subtypes. X-ray studies in PPAR gamma revealed two different binding modes of (S)-6 to the canonical site. However, (S)-6 was also able to bind an alternative site as demonstrated by transactivation assay in the presence of a canonical PPAR gamma antagonist and supported from docking experiments. This compound did not activate the PPAR gamma-dependent program of adipocyte differentiation inducing a very less severe lipid accumulation compared to rosiglitazone but increased the insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Finally, (S)-6 inhibited the Cdk5-mediated phosphorylation of PPAR gamma at serine 273 that is currently considered the mechanism by which some PPAR gamma partial agonists exert antidiabetic effects similar to thiazolidinediones, without showing their typical side effects. This is the first PPAR alpha/gamma dual agonist reported to show this inhibitory effect representing the potential lead of a new class of drugs for treatment of dyslipidemic type 2 diabetes. |
| اللغة: | English |
| تدمد: | 0022-2623 1520-4804 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e5a1c950da701c703e15bad5955f4e70Test https://hal-amu.archives-ouvertes.fr/hal-02068142Test |
| حقوق: | RESTRICTED |
| رقم الانضمام: | edsair.doi.dedup.....e5a1c950da701c703e15bad5955f4e70 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00222623 15204804 |
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