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Application of 3-indoleacetonitrile in the preparation of drugs for inhibiting novel coronavirus sars-cov-2

A technology of indole acetonitrile and sars-cov-2, applied in antiviral agents, drug combinations, pharmaceutical formulations, etc., can solve problems such as storms, reduce the mortality rate of new crowns, and have no anti-SARS-CoV-2, etc., to achieve weight loss Degree of decline, large clinical therapeutic potential, effect of reducing viral load

Active Publication Date: 2022-04-01
HUAZHONG AGRI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Pauline Maisonnasse et al. (2020, Hydroxychloroquine use against SARS-CoV-2 infection in non-humanprimates, nature) published a study in Nature, which showed that hydroxychloroquine (HCQ) has a wide range of antiviral effects based on previous studies, so it is used in many HCQ is included in the anti-SARS-CoV-2 drug screening projects. When evaluating the antiviral effect of hydroxychloroquine (HCQ) in vitro, it is proved that it does have anti-SARS-CoV-2 efficacy in vitro; combined with existing literature reports HCQ can be used as an immune modulator. The use of HCQ in lupus patients can reduce the level of inflammatory cytokines, and there is also a cytokine storm problem in the treatment of patients with COVID-19; based on these characteristics, HCQ is considered to be able to treat COVID-19, And it has been used globally for thousands of patients infected with SARS-CoV-2 causing COVID-19, however, so far there is no clear data showing that HCQ is effective in the treatment of COVID-19
Therefore, Pauline Maisonnasse et al. established a model of non-human primate (NHP) animal infection with SARS-CoV-2, which can be used for the analysis and evaluation of the early stage of human infection with SARS-CoV-2. After the primate model cynomolgus monkeys were infected with SARS-CoV-2, the antiviral effect and therapeutic effect of HCQ were also evaluated in vitro against SARS-CoV-2. The results showed that HCQ showed a positive effect in VERO E6 cells Anti-SARS-CoV-2 viral activity, but no anti-SARS-CoV-2 effect in the reconstituted human airway epithelial model; in cynomolgus monkey animal models, compared with placebo, cynomolgus monkeys infected with SARS-CoV- After 2, no matter in the early stage or the middle and late stage of infection, HCQ used alone or in combination with azithromycin had no significant effect on the viral load in the tissue, and there was no obvious clinical effect; and, in SARS-CoV- 2 Pre-infection, HCQ as prophylaxis also fails to provide protection against SARS-CoV-2 infection
[0004] In 2020, the WHO announced the launch of a global clinical trial called the Solidarity Trial, and selected four drugs that were most likely to reduce the mortality rate of the new crown at that time, namely remdesivir, hydroxychloroquine, lopinavir and interference Gene β1a, after nearly a year of trials, more than 400 hospitals and more than 10,000 patients in more than 30 countries around the world participated, but the results of the trials were not ideal, because there is no evidence that hydroxychloroquine and lopinavir can reduce mortality , the WHO halted trials of the two drugs in June and August, respectively.
[0006] Studies have shown that indole compounds can effectively inhibit bacterial pathogens such as Escherichia coli, and indole and its derivatives are regarded as potential resistance compounds for antibiotic-resistant pathogens. -Related reports on CoV-2 virus

Method used

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  • Application of 3-indoleacetonitrile in the preparation of drugs for inhibiting novel coronavirus sars-cov-2
  • Application of 3-indoleacetonitrile in the preparation of drugs for inhibiting novel coronavirus sars-cov-2
  • Application of 3-indoleacetonitrile in the preparation of drugs for inhibiting novel coronavirus sars-cov-2

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Toxicity test of 3-indoleacetonitrile to cells

[0050] Use Caco-2 cell among the present invention, inoculate 96 well plate, treat that cell density reaches 80%, with 3-indole acetonitrile (final concentration is: 0 μ M, 3.5 μ M, 7 μ M, 17.5 μ M, 35 μ M, 70 μ M, 175 μ M, 350 μ M, 700 μM) to incubate the cells for 48 hours. Cell viability was measured using TransDetect cell counting box, and the absorbance at OD450nm was measured according to the instructions of the kit. The specific implementation process is as follows:

[0051] 1. Cell culture

[0052] The frozen and revived Caco-2 cells were subcultured twice, and expanded with DMEM medium containing 10% fetal bovine serum and double antibodies (penicillin 100 U / ml, streptomycin 100 ug / ml).

[0053] 2. Toxicity test of 3-indoleacetonitrile to cells

[0054] Well-grown Caco-2 cells were taken for digestion and passage, and the cell density was adjusted to 2×10 with cell growth medium (DMEM medium + 10% fetal bovin...

Embodiment 2

[0059] Inhibitory effect of 3-indoleacetonitrile on novel coronavirus at the cellular level:

[0060] Western Blot and plaque forming unit (plaque forming unit) were used to detect the influence of 3-indoleacetonitrile on the proliferation of SARS-COV-2 virus (WBP-1) at the cellular level, and the specific steps were as follows:

[0061] 1. 3-indoleacetonitrile treated cells and infected the new coronavirus WBP-1

[0062] 1) The Caco-2 cells in good growth state were digested and passaged, and the cell density was adjusted to 1×10 with cell culture medium. 5 / ml, 1ml per well was inoculated in a 12-well plate to grow to a monolayer.

[0063] 2) Add different amounts of 3-indoleacetonitrile, the final concentrations of 3-indoleacetonitrile are 0 μM, 75 μM, 150 μM, and 300 μM, respectively, and the working concentration of 0 μM is the no drug control.

[0064] 3) After being treated with different concentrations of 3-indoleacetonitrile for 24 hours, the cells were infected wit...

Embodiment 3

[0088] Evaluation of antiviral effect of 3-indoleacetonitrile in lethal infection model of mice

[0089] Mouse experiment steps:

[0090] 1) The 6-week-old female BALB / c mice were randomly divided into 2 large groups. The first large group was the non-infected new coronavirus group, which were the control group (PBS) (5 mice), the 3-indoleacetonitrile group ( 5 rats); the second largest group is the SARS-CoV-2 virus infection group, respectively PBS+SARS-CoV-2 infection group (10 rats), 3-indoleacetonitrile+SARS-CoV-2 infection group (10 rats ).

[0091] 2) 3-indoleacetonitrile was prepared as a 4 mg / mL aqueous solution, and each mouse was injected with 100 μL of PBS or 3-indoleacetonitrile solution through the tail vein each time.

[0092] 3) 2 hours before infection with SARS-CoV-2, inject 3-indoleacetonitrile (3-indoleacetonitrile+SARS-CoV-2 infection group) or PBS (PBS+SARS-CoV-2 infection group) once into the tail vein, and then Carry out intranasal infection 5 median ...

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Abstract

The invention belongs to the field of biological preparations, and in particular relates to the application of 3-indoleacetonitrile in the preparation of drugs for inhibiting novel coronavirus SARS-CoV-2. The present invention finds for the first time that 3-indoleacetonitrile can inhibit the new coronavirus at the cell and animal levels, and can relieve the body's adverse symptoms caused by the new coronavirus infection. 2. It is effective in the infection model, which can significantly reduce the virus content in the lung tissue of mice, reduce the degree of weight loss of mice, and improve the survival rate of mice, which makes 3-indoleacetonitrile have great potential for clinical treatment.

Description

technical field [0001] The invention belongs to the field of biological preparations, and in particular relates to the application of 3-indoleacetonitrile in the preparation of drugs for inhibiting novel coronavirus SARS-CoV-2. Background technique [0002] The new type of coronavirus pneumonia (coronavirus disease 19, COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) has seriously endangered human health and public health safety, and has brought great harm to the world community. and a huge burden on the economy. Many domestic and foreign scholars speculate that the new coronavirus may be similar to influenza virus and coexist with humans for a long time. However, so far, there is no recognized effective treatment for new coronary pneumonia or anti-SARS-CoV-2 virus method. Therefore, it is of great significance to research and develop new anti-SARS-CoV-2 preparations or drugs. [0003] Up to n...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/404A61P11/00A61P31/14
CPCA61K31/404A61P11/00A61P31/14
Inventor 金梅林回显锋杨丽黄坤张宇飞赵雪锦盛锋张强孙小美钟鸣杨欢欢
Owner HUAZHONG AGRI UNIV
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