ArticleDiabetologia2013
Identification of the antibiotic ionomycin as an unexpected peroxisome proliferator-activated receptor γ (PPARγ) ligand with a unique binding mode and effective glucose-lowering activity in a mouse model of diabetes.
Article in Diabetologia, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 28 citations in OpenAlex.
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- Review
- The Role of Transcription Factor PPAR-γ in the Pathogenesis of Psoriasis, Skin Cells, and Immune Cells.International journal of molecular sciences · 2022Review
- DEPP Deficiency Contributes to Browning of White Adipose Tissue.International journal of molecular sciences · 2022Article
- Structural overview and perspectives of the nuclear receptors, a major family as the direct targets for small-molecule drugs.Acta biochimica et biophysica Sinica · 2022Article
- Identification and structural insight of an effective PPARγ modulator with improved therapeutic index for anti-diabetic drug discovery.Chemical science · 2020Article
- The PPARPPAR research · 2020Review
- PPARγ Transcription Deficiency Exacerbates High-Fat Diet-Induced Adipocyte Hypertrophy and Insulin Resistance in Mice.Frontiers in pharmacology · 2020Article
- TNFα induces CaJournal of experimental & clinical cancer research : CR · 2018Article
- Signaling Mechanisms of Selective PPARPPAR research · 2018Review
- Deciphering the Roles of PPARγ in Adipocytes via Dynamic Change of Transcription Complex.Frontiers in endocrinology · 2018Review
- Screening for PPAR Non-Agonist Ligands Followed by Characterization of a Hit, AM-879, with Additional No-Adipogenic and cdk5-Mediated Phosphorylation Inhibition Properties.Frontiers in endocrinology · 2018Article
- Identification of a novel selective PPARγ ligand with a unique binding mode and improved therapeutic profile in vitro.Scientific reports · 2017Article
- Targeting nuclear receptors with marine natural products.Marine drugs · 2014Review
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Authors and funding
9 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
aims/hypothesisExisting thiazolidinedione (TZD) drugs for diabetes have severe side effects. The aim of this study is to develop alternative peroxisome proliferator-activated receptor γ (PPARγ) ligands that retain the benefits in improving insulin resistance but with reduced side effects.
methodsWe used AlphaScreen assay to screen for new PPARγ ligands from compound libraries. In vitro biochemical binding affinity assay and in vivo cell-based reporter assay were used to validate ionomycin as a partial ligand of PPARγ. A mouse model of diabetes was used to assess the effects of ionomycin in improving insulin sensitivity. Crystal structure of PPARγ complexed with ionomycin revealed the unique binding mode of ionomycin, which elucidated the molecular mechanisms allowing the discrimination of ionomycin from TZDs.
resultsWe found that the antibiotic ionomycin is a novel modulating ligand for PPARγ. Both the transactivation and binding activity of PPARγ by ionomycin can be blocked by PPARγ specific antagonist GW9662. Ionomycin interacts with the PPARγ ligand-binding domain in a unique binding mode with properties and epitopes distinct from those of TZD drugs. Ionomycin treatment effectively improved hyperglycaemia and insulin resistance, but had reduced side effects compared with TZDs in the mouse model of diabetes. In addition, ionomycin effectively blocked the phosphorylation of PPARγ at Ser273 by cyclin-dependent kinase 5 both in vitro and in vivo. CONCLUSIONS/
interpretationOur studies suggest that ionomycin may represent a unique template for designing novel PPARγ ligands with advantages over current TZD drugs.
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