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Application of dibenzyl tetrahydroisoquinoline derivative in preparation of anti-coronavirus drug

A coronavirus and application technology, applied in the field of biomedicine, can solve the problems of lack of small molecule drugs, high price, large side effects, etc., and achieve good application prospects and excellent inhibitory activity.

Active Publication Date: 2021-03-19
CHONGQING MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, the anti-HIV drug Kaletra (lopinavir and ritonavir) has poor efficacy and side effects in clinical trials for the treatment of new coronavirus pneumonia
Although antibodies, small proteins, and lipopeptides targeting the spike S protein can effectively block coronaviruses from invading cells, they are expensive, and effective small molecule drugs are still very scarce

Method used

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  • Application of dibenzyl tetrahydroisoquinoline derivative in preparation of anti-coronavirus drug
  • Application of dibenzyl tetrahydroisoquinoline derivative in preparation of anti-coronavirus drug
  • Application of dibenzyl tetrahydroisoquinoline derivative in preparation of anti-coronavirus drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: Compound is to the inhibitory activity, specificity and cytotoxicity of SARS-CoV-2 pseudovirus infection on HEK293T cells

[0038] 1. Fake virus packaging

[0039] Will 2×10 7 A HEK293T cell was seeded in a 10cm culture dish (80%-90% density),

[0040]Transfection was carried out 12 hours later (refer to the instruction manual of Lipo8000), and the transfection ratio was Opti-MEM500μl+Lipo8000 18μl+the following plasmids:

[0041] pNL4-3-Luc-R-E: VSVG=5:1 (10 μg, 2 μg);

[0042] pNL4-3-Luc-R-E: pCMV3-SARS-CoV-2.Spike (D614) = 1:1 (6 μg, 6 μg);

[0043] pNL4-3-Luc-R-E: pCMV3-SARS-CoV-2.Spike (G614) = 1:1 (6 μg, 6 μg);

[0044] pNL4-3-Luc-R-E: pCMV3-SARS-CoV.Spike=1:1 (6 μg, 6 μg);

[0045] pNL4-3-Luc-R-E:pCMV3-MERS-CoV.Spike=1:1 (6 μg, 6 μg)

[0046] The medium was changed 12 hours after transfection, and the supernatant was collected after 48 hours and 72 hours of normal culture, centrifuged for 5 minutes (4°C, 4000 rpm), and the virus supernatant wa...

Embodiment 2

[0061] Embodiment 2: The inhibitory activity of compound on different cells to SARS-CoV-2 pseudovirus infection

[0062] 1. Inhibitory activity test of the compound to be tested against pseudovirus infection

[0063] The antiviral infection activity of the target compound on different cells was tested by luciferase activity, and stepherine and tetrandrine were used as positive controls. HEK293T, Calu-3 or A549 cells (2x10 4 cells / well) were incubated with gradient concentrations of various compounds for 1 hour, and the same amount of pseudovirus SARS-CoV-2 (S-G614) (50 μL, 3.8×10 4 copy) infection. The medium was replaced with fresh DMEM 8 h after infection. 72 hours after infection, the cells were collected and lysed with 30 μl lysis buffer (Promega), and the RLU value was measured with luciferase assay reagent (Promega) according to the product description, and the effect of the test compound on SARS-CoV-2 (S-G614) pseudovirus was calculated. Infectious median effective ...

Embodiment 3

[0068] Embodiment 3: Compound is to the inhibitory activity of different coronavirus infection

[0069] 1. Experimental method

[0070] HEK293T cells were treated with (1×10 4 / well) density was inoculated into 96-well plate, 12h later, the compound to be tested (50μM to 32.7nM) was diluted with a 2.5-fold gradient concentration and incubated with an equal volume of virus supernatant at 37°C for 30min, and then added to the cells. Add the virus control group, the solvent blank control group, stepherine and tetrandrine as positive controls, and each group has 3 replicate wells, and culture at 37°C for 48h. Then add 30 μl 1× cell lysate to each well to lyse the cells, lyse at room temperature for 15 minutes, centrifuge to collect 15 μl supernatant, add 15 μl detection substrate, mix thoroughly, and immediately detect luciferase activity with a microplate reader. According to the inhibition rate of different concentrations of drugs to coronavirus, the half effective concentrati...

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Abstract

The invention discloses an application of a dibenzyl tetrahydroisoquinoline derivative in preparation of an anti-coronavirus drug. The structure of the bibenzyl tetrahydroisoquinoline derivative is shown as a formula I, and the bibenzyl tetrahydroisoquinoline derivative can effectively inhibit the infection ability of various coronaviruses to cells, and especially has excellent inhibitory activityto SARS-CoV-2 (S-D614), SARS-CoV-2 (S-G614), SARS-CoV, MERS-CoV coronavirus infection. The bibenzyl tetrahydroisoquinoline derivative disclosed by the invention has a good application prospect in preparation of anti-coronavirus medicines and medicines for preventing and / or treating diseases caused by coronavirus infection.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to the use of a class of bisbenzyl tetrahydroisoquinoline derivatives in the preparation of anti-coronavirus drugs and drugs for treating diseases caused by coronavirus infection. Background technique [0002] There are currently 7 types of coronaviruses that can infect humans: HcoV-229E, HcoV-NL63, HcoV-HKU1, HcoV-OC43, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus ( MERS-CoV), 2019 novel coronavirus (2019-nCoV, SARS-CoV-2). Among them, the first four (HcoV-229E, HcoV-NL63, HcoV-HKU1, HcoV-OC43) coronaviruses are seasonally prevalent in the population worldwide, causing mild respiratory disease in most patients; SARS-CoV The mortality rate caused by infection with MERS-CoV is very high; SARS-CoV-2 is a new type of β-coronavirus, which belongs to single-stranded RNA virus, which is highly infectious and generally susceptible to the...

Claims

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Application Information

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IPC IPC(8): A61K31/4748A61K31/4725A61P31/14A61P11/00
CPCA61K31/4748A61K31/4725A61P31/14A61P11/00
Inventor 黄露义唐霓汪凯黄爱龙何长龙
Owner CHONGQING MEDICAL UNIVERSITY
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