Application of BET inhibitor BMS-986158 in preparation of anti-AIDS medicine

1. BMS-9861658, inhibitor technology, applied in the field of biomedicine

Active Publication Date: 2021-11-30
KUNMING INST OF ZOOLOGY CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, there is no research report that this compound can be used for the

Method used

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  • Application of BET inhibitor BMS-986158 in preparation of anti-AIDS medicine
  • Application of BET inhibitor BMS-986158 in preparation of anti-AIDS medicine
  • Application of BET inhibitor BMS-986158 in preparation of anti-AIDS medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1 BMS-986158 activates the expression of latent HIV-1

[0040] The effect of BMS-986158 on the activation of latent HIV-1 in three HIV-1 latent cell lines (J-Lat, ACH2 and OM10.1) All three cell lines of J-Lat, ACH2 and OM10.1 are human T lymphocyte lines , the culture condition is RPMI-1640 medium plus 10% FBS.

[0041] In the activation experiment of J-Lat cells, 2×10 5 Each well of J-Lat cells was spread in a 48-well cell culture plate, and 5-fold serial dilutions of BMS-986158 (500, 100, 20, 4, 0.8 nM) were added to different wells, and JQ1 was used as a positive drug control. A 5-fold serial dilution concentration (5000, 1000, 200, 40, 8 nM) was set, and a DMSO control group was set at the same time. 5% CO at 37°C 2 After culturing in a humidified incubator for 48 hours, the cells in each well were collected, and the percentage of GFP-positive cells in each well was analyzed by flow cytometry. After treating J-Lat cells with BMS-986158 100nM and JQ1 1μM...

Embodiment 2

[0046] Example 2 Toxicity test of BMS-986158 on human PBMC and J-Lat cells

[0047] Peripheral blood mononuclear cells (PBMC) were obtained by extracting 10 ml of peripheral blood from normal donors by density gradient centrifugation [approved by the Life Science Ethics Committee of Kunming Institute of Zoology, Chinese Academy of Sciences, number: SWYX-2013016]. Resuspend the isolated PBMCs in an appropriate volume of 1640 (10% FBS) in 5×10 5 The amount of cells per well was added to a 96-well plate containing different concentrations of BMS-986158 (concentration: 100, 20, 4, 0.8, 0.16, 0.032 μM); for J-Lat cells, 4 × 10 4 The amount of cells per well was added to a 96-well plate containing different concentrations of BMS-986158 (concentration: 200, 40, 8, 1.6, 0.32, 0.064 μM). After culturing in the incubator for 2 days, add 20 μl to each well MTT solution, after culturing in the incubator for 4 hours, discard 100 μl of the supernatant, and then add 100 μl of 12% SDS-50% DM...

Embodiment 3

[0048] Example 3 Effect of BMS-986158 on cells

[0049] 3.1 Effect of BMS-986158 on T cell activation

[0050] BMS-986158 is less toxic to cell lines as well as PBMC. Existing studies have shown that: some latent activators can cause extensive T cell activation, and sustained immune activation is a major obstacle in the course of HIV-1 therapy, especially with CD8 + Cell depletion is closely related (Xing and Siliciano 2013). In order to further evaluate the effect of BMS-986158 on immune cells, the present invention respectively detected the effect of BMS-986158 on CD4 + and CD8 + Effects on the expression of T cell activation markers (cell surface receptors CD25, CD69 and HLA-DR). After treating PBMCs with BMS-986158 for 48 hours, collect the cells, wash with PBS, add a master mix containing specific antibodies for the three receptors of CD25, CD69 and HLA-DR, incubate on ice for 30 minutes, add a large volume of PBS to wash, and then The cells were resuspended in 300 μ...

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Abstract

The invention relates to application of a BET inhibitor BMS-986158, in particular to application of the BET inhibitor BMS-986158 in preparation of an anti-HIV-1 medicine. Researches show that the BET inhibitor BMS-986158 can be used for remarkably activating expression of HIV-1 in an HIV-1 latent cell line J-Lat, OM10.1 and ACH2 cells; when the the BET inhibitor BMS-986158 is combined with other types of latent activators, a synergistic effect is shown; the activation effect is not influenced by anti-HIV drugs, and activities of the anti-HIV drugs can be improved; and in peripheral blood mononuclear cells separated from a body of an HIV-1 patient receiving ART treatment for a long time, the BMS-986158 also shows a remarkable latent activation effect. Toxicity experiment of the BMS-986158 on PBMC shows that CC50 is greater than 100 [mu] M, indicating that the BMS-986158 less toxic to cells. The BMS-9861658 has low toxicity and high latent activation HIV-1 activity, and can enhance an antiviral effect of an anti-viral drug in vitro. Therefore, the BMS-9861658 can be used for preparing an anti-HIV-1 latency medicine and can be combined with an anti-HIV medicine to be used for treating the AIDS, and a new intervention way and strategy are provided for thoroughly curing AIDS.

Description

technical field [0001] The invention relates to the technical field of biomedicine, and provides a new application of BET inhibitor BMS-986158, especially in the preparation of anti-AIDS drugs. Background technique [0002] Although today's anti-HIV drugs can well inhibit the replication of the virus, can reduce the level of plasma HIV-1 to below the clinical detection line, significantly improve the quality of life of patients, and enable them to obtain a life span close to normal, but patients must take drugs for a long time , once the drug is stopped, the virus will rebound quickly, and the viral load will quickly return to the level before treatment. Studies have shown that an important reason why HIV-1 is difficult to be completely eliminated in the body is the existence of virus latent reservoirs. Resting CD4 + The composition of T cells, in addition to dendritic cells and macrophages, etc., there are two main ways of its formation: one is cells activated by HIV-1 in...

Claims

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Application Information

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IPC IPC(8): A61K31/437A61K45/06A61K31/167A61K31/22A61P31/18
CPCA61K31/437A61K45/06A61K31/167A61K31/22A61P31/18A61K2300/00
Inventor 黄旭升郑永唐田仁荣罗荣华杨柳萌马梦迪
Owner KUNMING INST OF ZOOLOGY CHINESE ACAD OF SCI
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