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Application of compound and analogue thereof as ROR gamma regulator

A technology of compounds and analogs, applied in the field of medicine, can solve the problems of unclear target signaling pathways, difficult to distinguish beneficial and harmful components of active monomers, affecting development and use, etc.

Inactive Publication Date: 2021-08-17
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0028] Although ginseng preparations are widely used in clinical and health care all over the world, because ginseng preparations are crude extracts with complex components, including polysaccharides, proteins, saponins, etc.
The components of ginseng, such as ginsenoside, can further hydrolyze many products, and the relevant target signaling pathways are not clear, and it is difficult to distinguish active monomers, beneficial and harmful components, which affects the further development and use of the functions of these compounds

Method used

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  • Application of compound and analogue thereof as ROR gamma regulator
  • Application of compound and analogue thereof as ROR gamma regulator
  • Application of compound and analogue thereof as ROR gamma regulator

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1 proves that Panaxadiol or its analogs can effectively regulate RORγ recruitment co-regulators, and is a regulator of RORγ.

[0067] figure 1 In order to use the AlphaScreen biochemical method, the final concentration of 1 μM Panaxadiol (Panaxadiol) or its analogues was determined to promote the interaction between coactivator (SRC2-3 and SRC3-3) and co-repressor factor (NCoR-2) motifs and RORγ . The analogs are panaxatriol, protopanaxadiol ((20R)-Protopanaxadiol) and protopanaxatriol ((20S)-Protopanaxatriol). All experiments were performed independently in triplicate. The coregulator polypeptide sequence with an N-terminal biotinylation tag is:

[0068] SRC2-3: QEPVSPKKKENALLRYLLDKDDTKD;

[0069] SRC3-3: PDAASKHKQLSELLRGGSG;

[0070] NCoR-2: GHSFADPASNLGLEDIIRKALMGSF.

[0071] Protein purification: the human RORγLBD (amino acid residue number 262-507) gene was constructed in the pET24a vector containing the 6 polyhistidine fusion tag of Novagen Company....

Embodiment 2

[0077] Example 2 proves that Panaxadiol (Panaxadiol) and its analogues effectively inhibit the transcriptional activation of the RORγ reporter gene, and are inhibitors of RORγ at the cellular level.

[0078] AlphaScreen technology shows that at the biochemical level, panaxadiol and its analogs can simultaneously promote the recruitment of various coactivators and co-inhibitors by RORγ, and the combined effect at the cellular level ultimately affects the activation or inhibition of the compound on the expression of RORγ target genes. We used two general methods of Gal4 reporter gene and IL-17 reporter gene to detect the activation or inhibition of RORγ target gene expression by intracellular compounds, respectively. The Gal4 reporter gene is mainly used to determine the extent to which RORγ regulators regulate the overall transcriptional activity of RORγ target genes, while the IL-17 reporter gene is mainly used to measure the regulation of transcriptional activity of a specific...

Embodiment 3

[0080] Example 3 demonstrates the analysis of the crystal structure of the complex of Panaxadiol (Panaxadiol) and RORγ.

[0081] In order to reveal the molecular mechanism of mutual recognition and binding of panaxadiol and RORγ from the atomic level, the crystal structure of the complex formed by panaxadiol and RORγ was analyzed by conventional methods ( image 3 ). Obtain RORγ protein as in Example 1, add panaxadiol 5 times the amount of purified RORγLBD protein, and coactivator SRC2-2 polypeptide (KHKILHRLLQDSS) 2 times the amount of RORγLBD protein, and incubate on ice for 1 h Then, concentrate to 10mg / mL. The crystallization screening kit from Hampton Company was used for crystallization, and the sample complex was mixed with the screening buffer 1:1 and screened by hanging drop crystallization. The crystal grows best at room temperature for about 48 hours, and the best crystallization buffer conditions are: 0.1M BIS-TRIS pH 5.5, 3.0M Sodium chloride. The crystals were...

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Abstract

The invention discloses application of a compound and an analogue thereof as an ROR gamma regulator, and relates to the technical field of medicines. The compound is panaxadiol and analogues thereof, and the analogues comprise panaxatriol, protopanaxadiol, protopanaxatriol and a newly synthesized analogue. The newly synthesized analogue is a novel panoxadiol analogue which is designed and synthesized on the basis of a combination mode of panoxadiol and an ROR gamma three-dimensional crystal structure. The compound can be applied to preparation of drugs for treating or preventing diseases related to ROR gamma regulation. The compound can be applied to preparation of drugs for treating or preventing interleukin 17 regulation related diseases. The invention also discloses application of the compound or the pharmaceutically acceptable salt thereof in preparation of a pharmaceutical preparation for preventing or treating and regulating ROR gamma related diseases. The invention also relates to application of the compound in preparation of pharmaceutical compositions used in combination with other pharmaceutical preparations for preventing or treating and regulating ROR gamma-related diseases.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to the application of Panaxadiol and its analogs as retinoic acid receptor-related orphan receptor RORγ regulators. Background technique [0002] The therapeutic effect of compound drugs can be exerted by binding to one or more protein "targets", thereby activating or inhibiting them to regulate the function and signal transduction of these "targets". Thus, the identification of a drug's protein target provides the basis for understanding the action of a drug's action. The elucidation of the role of these drug target proteins will provide theoretical support for the effective treatment of diseases and an effective means for the development of important new drugs. [0003] Nuclear receptors are a group of transcription factor proteins regulated by small molecule ligands. Ligands Small molecule compounds play an important role in modulating the activity of nuclear receptors. Induc...

Claims

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Application Information

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IPC IPC(8): C07J17/00A61K31/58A61P37/00A61P19/02A61P19/00A61P17/06A61P17/00A61P1/00A61P21/00A61P11/06
CPCC07J17/00A61P37/00A61P19/02A61P19/00A61P17/06A61P17/00A61P1/00A61P21/00A61P11/06
Inventor 李勇田思雨
Owner XIAMEN UNIV
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