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Application of Obatoclax in preparation of HIV-1 latent infection reversal agent

A technology of HIV-1 and latent infection, applied in the field of medicine, can solve the problems of restricting wide application, poor specificity of action, large toxic and side effects, etc., and achieve the effect of promoting death and preventing supplementation

Active Publication Date: 2020-03-24
SOUTHERN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Unfortunately, the above-mentioned candidate LRAs for the treatment of HIV latent infection are still only in the clinical trial stage, and breakthrough progress has not yet been made. They have more or less certain defects, which limit their wide application in clinical practice.
The main issues are as follows: 1) Some epigenetic therapy drugs can also cause many side effects while activating the virus. For example, the mechanism of HDAC inhibitors is controversial, and nausea, vomiting, and blood system abnormalities have also been reported in clinical practice. and affect the normal function of genes, etc.; 2) PKC activators can affect the transcription factor signaling pathway of normal T cell activation, resulting in complex immune and chemical drug clearance leading to the latent virus reservoir; 3) Some drugs have poor specificity and Extensive, high toxicity and side effects, not suitable for long-term application, etc.
4) Many of the above-mentioned LRAs are still in the clinical trial stage, and even some drugs have only been confirmed to activate latent viruses in in vitro cell experiments, and there is still a long way to go before widespread clinical application
[0013] Obatoclax is generally used for the treatment of lung cancer and has entered phase III clinical trials of advanced small cell lung cancer, but no studies have reported the pharmacological activity of Obatoclax in the treatment of other diseases

Method used

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  • Application of Obatoclax in preparation of HIV-1 latent infection reversal agent
  • Application of Obatoclax in preparation of HIV-1 latent infection reversal agent
  • Application of Obatoclax in preparation of HIV-1 latent infection reversal agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] In Example 1, the effect of Obatoclax on the expression of P24 protein in HIV-1 latent infection cell model J-Lat 10.6 and Ach2 cells was studied, and it was proved that Obatoclax can effectively promote the expression of P24 protein in J-Lat 10.6 and Ach2 cells. The specific process is as follows:

[0032] (1) Culture and activation of HIV-1 latently infected cell lines

[0033] 1) Collect J-Lat 10.6 and Ach2 cell liquid in a centrifuge tube, centrifuge at 800rpm for 5min, discard the supernatant, and keep the cell pellet.

[0034] 2) Add 5ml of culture medium, blow the cells evenly, pipette 20μl of cell fluid into the cell counting plate, and count.

[0035] 3) Adjust the cell concentration to 1×10 6 cells / ml, spread in 6-well plate at 2ml / well.

[0036] 4) Add serial dilutions of different concentrations of Obatoclax (0-2.5 μM) and the corresponding positive drug Prostratin.

[0037] 5) At 37°C, with 5% CO 2 After incubation in the incubator for 48 h, the cells ...

Embodiment 2

[0060] The present embodiment detects the effect of Obatoclax on the HIV-1p24 protein expression of HIV-1 latently infected cell model ACH2 cells by enzyme-linked immunosorbent assay (ELISA), and the specific test process is as follows:

[0061] 1) Collect the ACH2 cell liquid in a centrifuge tube, centrifuge at 800rpm for 5min, discard the supernatant, and keep the cell pellet.

[0062] 2) Add 5ml of culture medium, blow the cells evenly, pipette 20μl of cell fluid into the cell counting plate, and count.

[0063] 3) Adjust the cell concentration to 1×10 6 cells / ml, spread in 96-well plate at 100 μl / well.

[0064] 4) Add serially diluted different concentrations of Obatoclax (0.01-2.5 μM).

[0065] 5) At 37°C, 5% CO 2 After incubation in the incubator for 48 hours, 100 μl of cell culture supernatant was collected and placed in another 96-well plate, an equal volume of 5% Triton X-100 was added, and incubated overnight at 4°C.

[0066] 6) Use ELISA p24 protein detection re...

Embodiment 3

[0069] In this example, the cytotoxicity of Obatoclax to J-Lat 10.6, ACH2, and J-Lat A2 latently infected cell lines was analyzed by the MTT method. The specific operations are as follows:

[0070] 1) Collect J-Lat 10.6, ACH2, J-Lat A2 cell fluid in a centrifuge tube at 1×10 6 Each / ml, 100μl / well was added to a 96-well cell culture plate;

[0071] 2) Add Obatoclax prepared in serially diluted blank culture medium, 100 μl / well.

[0072] 3) At 37°C, 5% CO 2 After incubating in the incubator for 48h, add MTT solution (5mg / ml, prepared in PBS, pH=7.4) 20μl / well, continue at 37°C, 5%CO 2 Incubate for 4h. Centrifuge at 3000rpm for 5min, carefully discard the culture supernatant in the well, add 100μl DMSO to each well, and shake for 15min to dissolve the crystals;

[0073] 4) Use a microplate reader to detect the absorbance at 570 nm in each well.

[0074] The result is as Figure 4~6 , which in turn represent the cytotoxicity of Obatoclax to J-Lat 10.6, ACH2, J-Lat A2 cells, ...

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Abstract

The invention provides an application of Obatoclax and a pharmaceutically acceptable derivative thereof in preparation of an HIV-1 latent infection reversal agent. The Obatoclax has good activity of activating an HIV-1 latent cell bank, is an inhibitor of Bcl-2 family protein, can prevent supplement of the HIV latent cell bank and promote death of reactivated cells, and is expected to realize realfunctional healing of HIV.

Description

technical field [0001] The invention belongs to the technical field of medicine, relates to new applications of existing compounds, in particular to the application of Obatoclax in preparing HIV-1 latent infection reversal agents. Background technique [0002] AIDS is caused by human immunodeficiency virus (human immunodeficiency virus, HIV), the most serious single-cause disease in humans, characterized by severe damage to the systemic immune system. As of 2018, the number of people infected with HIV worldwide has reached 36.9 million, seriously threatening human health and survival. In 1996, the successful application of highly active antiretroviral therapy (HAART) or combination antiretroviral therapy (cART) transformed AIDS from a fatal disease to a chronic and manageable disease , greatly prolonging the survival time of AIDS patients. As of 2018, 21.7 million people worldwide have received cART treatment. However, since the development of cART, it also has its insurm...

Claims

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Application Information

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IPC IPC(8): A61K31/404A61P31/18
CPCA61K31/404A61P31/18
Inventor 李琳周晨亮梁太珍赖芳圆郑腾羿陈佩李楚玉刘叔文
Owner SOUTHERN MEDICAL UNIVERSITY
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