Application of trifluridine in preparation of HIV-1 drug

A technology of HIV-1 and trifluridine, applied in the field of HIV-1, can solve the problems of activation and killing obstacles, toxic and side effects, etc., and achieve good activation effect, low toxicity and good safety

Inactive Publication Date: 2021-03-30
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These activators were demonstrated in in vitro latency models as well as in CD4 latently infected in vitro + There is a strong activation effect in T cells, but when it is applied clinically, it may cause the activation of the whole cell level to trigger a severe immune response, or have strong toxic side effects on the body (Wang Haipeng, et al., HIV latent infection activator 2017.33(02):p.293-302.), up to now, no clinically effective and safe activators have been found, which is the largest application of the "activation and killing" strategy. hinder

Method used

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  • Application of trifluridine in preparation of HIV-1 drug
  • Application of trifluridine in preparation of HIV-1 drug
  • Application of trifluridine in preparation of HIV-1 drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 3

[0031] Example 1 Degradation experiment of CHAF1A by trifluridine in J-Lat 10.6 cell line.

[0032] The inventor's previous research has found that the host protein CHAF1A is a key factor in the formation and maintenance of HIV-1 latency, and is a safe and effective HIV-1 latent infection activation target. Therefore, the degradation effect of different concentrations of trifluridine on CHAF1A was detected to confirm the most appropriate drug concentration.

[0033] 1. Experimental method

[0034] Take an appropriate amount of well-growing J-Lat 10.6 cells and plate them. The medium used: 1640 medium, 10% fetal bovine serum and 1% penicillin-streptomycin mixed solution, culture condition: 5% carbon dioxide, 37°C.

[0035] Add final concentrations of 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.125 μM, 1.5625 μM, 0.78125 μM, 0.390625 μM trifluridine into the medium to treat the cells, and the PBS treatment group was used as a control, and the samples were collected for Western Blot dete...

Embodiment 2 3

[0038] Example 2 The activation effect of trifluridine on latent infection in J-Lat 10.6 cell line

[0039] 1. Experimental method

[0040] 1) Well-grown J-Lat 10.6 cells were plated, the medium used: 1640 medium, 10% fetal bovine serum and 1% penicillin-streptomycin mixed solution, culture conditions: 5% carbon dioxide, 37°C.

[0041] 5 cells per well in a 2-well clear plate; add trifluridine at a final concentration of 50 μM, 25 μM, 12.5 μM, 6.25 μM, and 3.125 μM, respectively, use PBS as a negative control, and take TNF-α treatment group and JQ-1 treatment group as positive control group.

[0042] 2) Cultivate for 48 hours, collect the cells by centrifugation, discard the supernatant, wash once with PBS, discard the supernatant, and then resuspend with PBS;

[0043] 3) Use a flow cytometer to detect the GFP expression level of the corresponding cells, and make a statistical graph to analyze the results.

[0044] 2. Experimental results

[0045] Experimental results such...

Embodiment 3

[0046] Example 3 Fluoxuridine Activation of HIV-1 in Clinical Samples of Infected Persons

[0047] 1. Experimental method

[0048] 1) Well-grown J-Lat cells were plated, the medium used: 1640 medium, 10% fetal bovine serum and 1% penicillin-streptomycin mixed solution, culture conditions: 5% carbon dioxide, 37°C. Different concentrations of trifluridine were added, and the final concentrations were: 100 μM, 25 μM, 6.25 μM, 1.5625 μM, .0390625 μM, 0.097656 μM, 0.024414 μM, 0.006104 μM, 0.001526 μM, 0.000381 μM, 0 μM.

[0049] 2) Cultivate for 48 hours, collect the cells by centrifugation, discard the supernatant, wash once with PBS, discard the supernatant, and then resuspend with PBS;

[0050] 3) Use a flow cytometer to detect the GFP expression level of the corresponding cells, and make a statistical graph to analyze the results.

[0051] 2. Experimental results

[0052] Experimental results such as Figure 4 shown. It can be seen from the experimental results that the E...

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Abstract

The invention discloses an application of trifluridine in preparation of an HIV-1 drug, and provides a new application of trifluridine as an HIV-1 latent infection activator, and the trifluridine hasa very good activation effect on HIV-1 latent infection. As trifluridine is a clinically used drug, trifluridine is low in toxicity and good in safety, but the related application of trifluridine serving as an HIV-1 latent infection activator is not reported yet at present. Trifluridine has important research and development value and development significance in the aspect of activation of HIV-1 latent infection.

Description

technical field [0001] The present invention relates to the technical field of HIV-1, more specifically, relates to the application of trifluridine in the preparation of HIV-1 medicine. Background technique [0002] Combined antiretroviral therapy (combined antiretroviral therapy, cART) can effectively control the virus in HIV-1 infected patients in the treatment of HIV-1 (human immunodifficiency virus type 1). Patients must take drugs to suppress the virus for life. Once the drug is stopped, the viremia in the infected person will explode rapidly in a short period of time. This is the main reason why HIV-1 is difficult to completely cure so far. [0003] In order to achieve a functional cure for HIV-1 and restore the patient's immune system to a normal level without receiving combined antiretroviral therapy, scientists have proposed three treatment strategies, namely: "activation and killing" strategy, permanent silencing strategies, partial or complete replacement of immu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7072A61P31/18
CPCA61K31/7072A61P31/18
Inventor 张辉阳涛张旭
Owner SUN YAT SEN UNIV
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