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Compound serving as PPAR gamma ligand and application thereof

A technology of ligands and uses, applied to PPARγ ligands, ionomycin (ionomycin) and its derivatives, in the field of treatment of PPARγ-mediated diseases, can solve the problems of side effects restricting use, increasing heart attack rates, weight gain, etc.

Inactive Publication Date: 2013-01-16
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

TZDs can significantly improve a series of symptoms of type 2 diabetes by improving insulin sensitivity and reducing blood sugar concentration, but clinical use has found that it has serious side effects, such as edema, weight gain, and increased heart attack rate [Micahael et al. , Cell, 2005, 123:993-999]
The adverse effect of side effects of TZDs drugs has greatly limited the clinical use of TZDs-based PPARγ ligand drugs

Method used

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  • Compound serving as PPAR gamma ligand and application thereof
  • Compound serving as PPAR gamma ligand and application thereof
  • Compound serving as PPAR gamma ligand and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0130] Example 1, proves that ionomycin is a ligand of PPARγ with high specificity and low transcription activity.

[0131] To prove that ionomycin can specifically bind to PPARγ, we co-transfected Cos7 cells with a Gal-4 driven reporter gene and a plasmid containing the target gene of different nuclear receptor LBD fragments. It is obvious that after 10μMionomycin treatment, only cells transfected with PPARγLBD have increased reporter gene activity, which reflects the high specificity of ionomycin as a PPARγ ligand (attached figure 1 A). In addition, ionomycin-mediated transcriptional activity of PPARγ can be inhibited by the PPARγ antagonist 1μM GW9662, which once again confirmed that ionomycin is a ligand of PPARγ (attached figure 1 B).

[0132] The 3T3-L1 preadipocyte oil red staining experiment showed that the ability of 10μM ionomycin to induce adipocyte differentiation was significantly lower than that of 1μM rosiglitazone, that is, the ability of ionomycin to activate PPA...

Embodiment 2

[0134] Example 2, The molecular structure verification experiment of the complex of PPARγ ligand binding region fragment and ionomycin

[0135] In order to detect the high affinity of ionmycin and PPARγ at the molecular level, we solved the Protein crystal structure of the PPARγ / ionomcyin complex with the co-activator SRC1-2 LXXLL motif. The structure shows that the combination of ionomycin and PPARγ ligand binding domain conforms to the classical conformation, and the overall structure of the complex is strongly conserved with most regions of PPARγ / rosiglitazone (attached figure 2 A). However, due to the huge difference in molecular weight and structure of ionomycin and rosiglitazone, the difference in the spatial position of the two in the ligand binding pocket and the resulting change in the relative position of the surrounding peptides (attached) figure 2 D). The molecular weight of Ionomycin is about twice that of rosiglitazone, and the structure diagrams of the two overl...

Embodiment 3

[0136] Example 3. Ionomcyin unique binding site in the PPARγ ligand binding pocket

[0137] In order to verify that the ligand pocket residues are binding to ionomycin, we mutated some of the key residues in contact with ionomycin, and then tested the transcriptional activity of these mutant PPARγ to determine the importance of the mutant residues.

[0138] Y473 has been confirmed to play a key role in the formation of stable hydrogen bonds between the complete activator and PPARγH12 and rosiglitazone, while ionomycin and Y473 have only weak hydrophobic effects. Y473F disrupts the formation of hydrogen bonds. Transient transfection experiments have confirmed that Y473F reduces the transcriptional activity of rosiglitazone on PPARγ and promotes the transcriptional activity of ionomycin on PPARγ. This indicates that the structural difference between ionomycin and rosiglitazone leads to its regulation. PPARγ activity produced corresponding changes. (Attached image 3 F)

[0139] R288 ...

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Abstract

The invention relates to a compound serving as PPAR gamma ligand and the application thereof, and discovers that antibiotic ionomycin relates to novel ligand which can be bound with PPAR gamma with high affinity binding and specificity. The ligand has similar capability to traditional PPAR gamma activating agent, such as rogridone, on terms of restraining CDK5 to perform phosphorylation to PPAR gamma, has the property of adjusting blood sugar metabolic balance through PPAR gamma and further improving the low sensibility of II type diabetes insulin, and can better improve a series of iconic indexes of diabetes. In addition, ionomycin has low transcriptional activation capability and obviously lower side effects, such as lipogenesis and weight gain inducing, than that of rogridone-the ligand of PPAR gamma. The compound provides a three dimensional crystal structure of ionomycin and PPAR gamma which are mutually bound through X-ray crystal diffraction and reveals a special binding model of ionomycin in a PPAR gamma ligand binding domain at the atomic level, and the structure is obviously different from rogridone / PPAR gamma protein complex belonging to thiazolidinedione.

Description

Technical field [0001] The present invention relates to a novel and effective PPARγ ligand, and relates to ionomycin (ionomycin) and its derivatives for the treatment of diseases mediated by PPARγ. The invention belongs to the fields of structural biology, biochemistry and medicinal chemistry. Background technique [0002] PPARγ (Peroxisome Proliferator Activated Receptor γ) is an important nuclear receptor, which plays a key role in regulating blood sugar balance and adipocyte differentiation. Synthetic PPARγ ligand rosiglitazone (Avandia) TM ) And pioglitazone (Actos TM ) Are thiazolidinedione derivatives (TZDs), which are widely used in the treatment of type 2 diabetes, which are characterized by low insulin sensitivity rather than insulin secretion dependence. TZDs can significantly improve a series of symptoms of type 2 diabetes by improving insulin sensitivity and lowering blood glucose concentration, but clinical use has found that it has serious side effects, such as ede...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/341C07D405/14C07D307/12A61P3/10A61P35/00
Inventor 李勇郑伟莉金利华冯需辉
Owner XIAMEN UNIV
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