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Application of bromine structural domain protein inhibitor to preparation of anti-HIV-1 latency drugs

A bromodomain protein, HIV-1 technology, which is applied in the field of preparing anti-HIV-1 latent therapeutic drugs to achieve the effect of accelerating clearance

Inactive Publication Date: 2017-01-04
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, there is still no report about OTX015, RVX-208, PFI-1 and Bromosporine having anti-HIV-1 latent therapeutic effect

Method used

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  • Application of bromine structural domain protein inhibitor to preparation of anti-HIV-1 latency drugs
  • Application of bromine structural domain protein inhibitor to preparation of anti-HIV-1 latency drugs
  • Application of bromine structural domain protein inhibitor to preparation of anti-HIV-1 latency drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1B

[0034] Example 1 BET inhibitor activates the dose-effect relationship experiment of latent HIV-1

[0035] 2×10 per hole 4 Plant C11 and A10.6 cells in a 96-well plate, add 100uL 1640 medium (Gibco) containing 10% FBS (Gibco) to each well, and add different concentrations of BET inhibitors according to the ratio of drug to medium 1:200 ;After 48 hours of drug treatment, observe the expression of GFP in the cells under a fluorescent microscope, and collect the cells for flow cytometry detection, and analyze the proportion of fluorescent cells;

[0036] The results showed that with the increase of BET inhibitor concentration, the number of cells expressing green fluorescence increased; HIV-1 latently infected cell C11 was treated with OTX015, the proportion of green fluorescent positive cells was as high as 88.4%, and the positive cells after RVX-208 treatment The ratio was as high as 85.4%, the ratio of positive cells was as high as 94.3% after being treated with PFI-1, and the...

Embodiment 2B

[0037] Example 2 BET inhibitor activates time-effect relationship of latent HIV-1

[0038] 2×10 per hole 4 Plant C11 and A10.6 cells in a 96-well plate, add 100uL 1640 medium (Gibco) containing 10% FBS (Gibco) to each well, and add different concentrations of BET inhibitors according to the ratio of drug to medium 1:200 . After 24h, 48h, and 72h of drug-treated cells, the expression of GFP in the cells was observed under a fluorescent microscope, and the cells were collected for flow cytometry detection, and the proportion of fluorescent cells was analyzed to obtain the kinetic characteristics of drug-activated latent HIV-1;

[0039] The results showed that when BET inhibitors were treated with HIV-1 latent infection cell models, the number of green fluorescent positive cells gradually increased with time, and the best activation effect was basically achieved after 48 hours on C11 cells; the results suggested that OTX015, RVX- 208, PFI-1 and Bromosporine have a time-effect r...

Embodiment 3B

[0040] Example 3 Effects of BET Inhibitors on Systemic T Cell Activation

[0041] Isolate CD4 T cells from normal human peripheral blood, press 10 per well 6Cells were planted in a 24-well plate, and 500uL of 1640 medium (Gibco) containing 10% FBS (Gibco) was added to each well, and OTX015, RVX-208, PFI-1, Bromosporine and Prostratin were added to make the final concentration of 1uM respectively. , 50uM, 5uM, 2.5uM and 1uM, the cells were collected after 48h of drug treatment. Wash once with 1mL PBS, then resuspend the cells with 100uL PBS, add 1uL of antibodies CD69-FITC and CD25-PE (BD-Biosciences) respectively, incubate on ice for 45min, wash with PBS three times, and then resuspend the cells with 500uL PBS, The expression levels of CD25 and CD69 were analyzed by flow cytometry;

[0042] The results showed that compared with Prostratin activated CD25 28.78% and CD69 80.9%, the BET inhibitor group was almost similar to the blank control group, and did not cause a significa...

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Abstract

The invention belongs to the medicine field and relates to the application of a bromine structural protein BET inhibitor to anti-HIV-1 latency treatment. Experiments prove that the chemical has an HIV-1 latent cell activation induction effect without causing activation of T cells of the whole body, can achieve synergetic activation after being combined with a protein kinase c agonist or cytokines, and can kill activated latent infected cells after being combined with antiretroviral drugs, so as to accelerate the elimination of a latent virus storage. Furthermore, the bromine structural domain protein inhibitor can be used for preparing anti-HIV-1 latency drugs and can provide a new interventional way and strategy for complete cure of AIDS.

Description

technical field [0001] The invention belongs to the field of medicine and relates to the use of bromodomain protein (BET) inhibitors in the preparation of anti-HIV-1 latent therapeutic drugs Background technique [0002] Research has disclosed that AIDS, Acquired Immunodeficiency Syndrome (AIDS) is an infectious disease that seriously affects human physical and mental health caused by human immunodeficiency virus (Human Immunodeficiency Virus, HIV-1) infection of the immune system. According to statistics, in 2012, about 35.3 million people were infected with HIV-1 in the world, of which 2.3 million were newly infected and 1.6 million died. AIDS has become a serious public health and social problem in the world today. At present, the clinical treatment of AIDS is mainly High Active Antiretroviral Treatment (HAART), which can reduce the plasma HIV-1 level below the clinical detection line, significantly improve the quality of life of patients, and enable them to obtain Nearl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/5517A61P31/18A61K31/517A61K31/519A61K31/22
Inventor 朱焕章陆盼盼曲喜英
Owner FUDAN UNIV
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