CN112294806B - Application of 1-formyl-beta-carboline derivative in preparation of anti-newcastle disease virus drugs - Google Patents
Application of 1-formyl-beta-carboline derivative in preparation of anti-newcastle disease virus drugs Download PDFInfo
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Abstract
The 1-formyl-beta-carboline derivative is applied to preparing the anti-newcastle disease virus medicine. The molecular structure of the related 1-formyl-beta-carboline derivative is shown as formulas (I), (II) and (III); in-vitro experimental research proves that the derivative can play an obvious inhibiting role in both the early and later stages of Newcastle disease virus proliferation, can play an antiviral role in related cell lines, can obviously inhibit the proliferation of NDV (Newcastle disease virus) with 3 different genotypes, and has higher inhibition rate along with the increase of concentration; meanwhile, the compound has low cytotoxicity to DF-1 and has the potential of being applied to resisting Newcastle disease virus alone or in combination with other medicines.
Description
Technical Field
The invention belongs to a new antiviral application of 3 1-formyl-beta-carboline derivatives, and particularly relates to an application of the derivatives in preparation of a medicament for resisting Newcastle disease viruses.
Background
Newcastle Disease Virus (NDV), a member of the family paramyxoviridae, a enveloped, non-segmented, single-stranded negative-strand RNA Virus that infects a variety of hosts, including humans. Among them, hendra virus (HeV) and Nipah virus (NiV) cause extremely high mortality after infecting humans, posing a great threat to human health.
Newcastle Disease virus can infect poultry and over 200 birds, and Newcastle Disease (ND) caused by the Newcastle Disease virus is one of the most important diseases endangering the poultry industry and is listed as an epidemic Disease which must be reported by the world animal health Organization (OIE). China is the country with the largest number of chickens in the world, and the development of poultry industry in China is seriously harmed by Newcastle disease.
The beta-carboline alkaloid is widely present in plants, animals and microorganisms, and has good biological activity. Deyan Chen et al (2015) reported that harmine inhibits enterovirus type 71 activity; veranica m.quintana et al (2016) reported the activity of harmine and its derivatives to inhibit dengue virus; paromita Bag et al (2014) reported that beta-carboline alkaloids inhibit replication of herpes simplex virus type I.
Disclosure of Invention
Based on the new research findings of the inventor, the invention provides the application of the 1-formyl-beta-carboline derivatives in preparing the anti-newcastle disease virus drugs, wherein the structures of the 1-formyl-beta-carboline derivatives are shown as formulas (I), (II) and (III):
preferably, the concentration of the 1-formyl-beta-carboline derivatives in the medicine is 5-30 mu M.
Further, the 1-formyl-beta-carboline derivatives can be used alone or in combination with other drugs.
Furthermore, the 1-formyl-beta-carboline derivatives can resist the multiplication of the Newcastle disease virus by directly inhibiting the adsorption effect of the Newcastle disease virus.
On the other hand, the invention also provides a medicament for resisting the Newcastle disease virus, and the effective component of the medicament provided by the invention comprises one or more than two compositions of the compounds shown in the structural formulas (I), (II) and (III).
The 1-formyl-beta-carboline derivatives have the highest inhibition rate of over 95 percent on the Newcastle disease virus, and have no cell specificity in antiviral action; after the 3 derivatives are treated, the virus titer in the cell supernatant and the virus mRNA in the cells are obviously reduced; and the compound can play an inhibiting role in the early and later stages of the proliferation of the Newcastle disease virus.
The 1-formyl-beta-carboline derivative can be used as an NDV adsorption inhibitor to directly inhibit the adsorption effect of Newcastle disease viruses, so that the virus proliferation is inhibited at an early stage, and the inhibition rate is 33-45%.
Drawings
Figure 1 shows that the derivative can significantly inhibit the expression of NDV P mRNA after being treated.
Figure 2 shows that the addition of the derivatives to different cell lines significantly inhibited NDV proliferation.
FIG. 3 shows that the derivatives can be added at different times after NDV vaccination to significantly inhibit the proliferation of Newcastle disease virus, and FIGS. 3A, 3B, and 3C show the antiviral effects of compounds I, II, and III, respectively.
FIG. 4 shows that the derivatives inhibit the adsorption of Newcastle disease virus.
FIG. 5 is a graph of the results associated with the inability of comparative compounds 1-9 to inhibit NDV proliferation (F48E 9).
FIG. 6 is a graph showing the results associated with the inability of comparative compounds 1-9 to inhibit NDV proliferation (PPMV-1/SX-01/Ch/15).
Detailed Description
The technical solution of the present invention is further explained by the following description, and the examples provided are only illustrative of the method of the present invention, and do not limit the remaining relevant contents of the present disclosure in any way.
The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby. Unless otherwise specified, the examples follow conventional experimental conditions.
The compounds I to III and the compounds 1 to 9 used in the following examples were synthesized by the inventors themselves according to the methods which have been disclosed in the prior art. Other experimental materials were purchased from commercial products.
Example 1
This example demonstrates in vitro anti-NDV EC for compounds (I) - (III) 50 The values were determined:
four strains of Newcastle disease viruses (provided by animal medical college at northwest university of agriculture and forestry) with different virulence and different genotypes are respectively used as Blackbird/China/08, PPMV-1/SX-01/Ch/15, la Sota and F48E9, and the EC is tested by a plaque test 50 The value is obtained.
Inoculating DF-1 cells (purchased from American ATCC) into a 12-well plate, infecting the cells with four strains of Newcastle disease virus respectively (MOI = 0.01) after the cells grow to 70-80%, adding DMEM culture solution (purchased from Gibco company in America) containing different concentrations of compounds I, II and III after the virus infection, and continuing incubation and culture for 24h;
collecting cell supernatant, diluting in gradient, and performing plaque test: BHK-21 cells (purchased from ATCC in USA) were cultured in 12-well plates, and after 70-80% of the cells were infected with the diluted sample at 37 ℃ for 1h, the supernatant was discarded, and a fresh medium containing methylcellulose (1%) was added, and the results were observed after 72 h.
Calculating EC according to the statistical result by applying GraphPad Prism software 50 Values, results are shown in table 1. EC of said compound 50 The values are all lower than 16 mu M, the compound can play a better role in resisting virus under the concentration without cytotoxicity, and has better inhibition effect on 3 genotypes and strains with different virulence.
TABLE 1 EC of Compounds (I) to (III) against 4 NDV strains 50 Value (μ M)
Comparative example:
this example performed an in vitro anti-NDV activity assay on compounds 1-9, and the results showed that none of compounds 1-9 had anti-NDV activity:
the specific method comprises the following steps: inoculating DF-1 cells into a 12-well plate, infecting the cells with F48E9 or PPMV-1/SX-01/Ch/15 (MOI = 0.01) after the cells grow to 70-80%, adding culture solution containing different compounds 1-9 with different concentrations after virus infection, and continuing incubation and culture for 24h; collecting cell supernatant, diluting in gradient, and performing plaque test: BHK-21 cells were cultured in 12-well plates, and after 70-80% growth, the cells were infected with the diluted sample at 37 ℃ for 1h, the supernatant was discarded, and fresh medium containing methylcellulose (1%) was added, and the results were observed after 72 h. The results are shown in FIG. 5 (F48E 9) and FIG. 6 (PPMV-1/SX-01/Ch/15).
Example 2:
this example is a related assay for cytotoxicity of compounds (i) - (iii):
the cytotoxic effect of the compound on DF-1 cells was tested using a CCK-8 kit (purchased from Shanghai ceramic Biotechnology Co., ltd.); DF-1 cells were cultured in a 96-well plate, and after the cells grew to 70-80%, 100. Mu.L of DMEM medium containing compounds I, II, III (5. Mu.M, 10. Mu.M, 20. Mu.M, 30. Mu.M, 50. Mu.M, 75. Mu.M, 100. Mu.M, 150. Mu.M and 200. Mu.M) at different concentrations was added, and 5 wells were repeated at each concentration, and after culturing was continued for 48 hours, 10. Mu.L of CCK-8 reagent was added to each well. At 37 ℃,5% CO 2 After culturing for 1h in the dark, the absorbance at 450nm was measured. And calculating the inhibition rate according to the absorbance value. The inhibition rate calculation formula is as follows:
cytostatic rate (%) =1- [ A (dosed) -A (blank) ]/[ A (0 dosed) -A (blank) ] × 100%
CC was calculated from inhibition using GraphPad Prism software 50 The values, results are shown in Table 2. Shows the Compound CC 50 The values are all higher than 50 mu M, and the toxicity is low.
TABLE 2 CC of Compounds (I) - (III) in DF-1 cells 50 Value (μ M)
Example 3
This example demonstrates that compounds (i) - (iii) significantly inhibit NDV P mRNA expression:
inoculating DF-1 cells into a 12-well plate, infecting by using F48E9 (MOI = 0.01) after the cells grow to 70-80%, adding culture solutions containing compounds I, II and III with different concentrations (5 mu M, 10 mu M and 20 mu M) after virus infection, and continuing incubation and culture for 24h;
adding TRIzol (purchased from Takara Bio), extracting RNA according to the instruction, and reverse transcribing the RNA into cDNA using StarScript II First-strand cDNA Synthesis Kit-II Kit (purchased from Genstar);
finally, the 2 XRealStar green power mixture kit (purchased from Genstar) was used to detect the expression level of NDV P mRNA by real-time fluorescent quantitative PCR (qPCR) according to the instructions.
The results of figure 1 show that the compounds I-III can obviously inhibit NDV P mRNA expression, and the inhibition effect is better with the increase of the compound concentration, and can reach more than 95 percent at most.
Example 4:
this example demonstrates that compounds (i) - (iii) significantly inhibit NDV P mRNA expression on different cell lines:
inoculating Hela, vero or BHK-21 cells (purchased from ATCC in USA) into a 12-well plate, infecting with F48E9 (MOI = 0.01) after the cells grow to 70-80%, adding culture solution containing compounds I, II and III with concentration of 20 μ M after virus infection, incubating and culturing for 24h, and collecting cell samples; after RNA extraction and reverse transcription, NDV P mRNA expression was detected using qPCR. The results in fig. 2 show that the compound can significantly inhibit the expression of NDV P mRNA in different cell lines, and the inhibition rate of 3 compounds is more than 90% at the concentration.
Example 5:
this example demonstrates that compounds (i) - (iii) inhibit NDV proliferation when added at various stages of NDV proliferation:
DF-1 cells are inoculated on a 12-hole plate, after the cells grow to 70-80%, compounds (I) - (III) are respectively added for 6h and 2h before inoculation of virus or for 2h, 4h, 8h and 12h after inoculation of virus (F48E 9;0.01 MOI), cell supernatants are collected 24h after inoculation of virus, and after gradient dilution, the virus titer is detected by a plaque test, and the result is shown in 3.
FIGS. 3A, 3B, and 3C show the antiviral effects of compounds (I), (II), (III), respectively, and the results show that the addition of the compounds in both early and late stages of Newcastle disease Virus propagation exerts an inhibitory effect, with the best effect of adding the derivatives as soon as possible after Newcastle disease Virus infection.
Example 6:
this example demonstrates that compounds (i) - (iii) significantly inhibit virus-adsorbed cells:
BHK-21 cells are inoculated in a 12-well plate, and after the cells grow to 70-80%, the plate is placed in a 4 ℃ precooling mode for 1h, then F48E9 is used for infection (200 PFU), and meanwhile, compounds I, II and III (20 mu M) are respectively added; after incubation at 4 ℃ for 1h, the supernatant was discarded, washed three times with precooled PBS, and then fresh medium containing methylcellulose (1%) was added, and the results were observed after 72 h.
The results are shown in FIG. 4, which demonstrates that the compound can directly inhibit the adsorption of the Newcastle disease virus to BHK-21 cells, and the inhibition rates of the compounds (I) - (III) are 43.5%, 44.5% and 33%, respectively.
Claims (4)
1.1-formyl-beta-carboline derivatives are used for preparing a medicament for resisting Newcastle disease viruses, and the structures of the 1-formyl-beta-carboline derivatives are shown as formulas (I), (II) and (III):
2. the use of claim 1, wherein the concentration of the 1-formyl- β -carboline derivative in the medicament is 5-30 μ M.
3. The use of claim 1, wherein the 1-formyl- β -carboline derivative is administered alone or in combination with other drugs.
4. The use according to claim 1, wherein the 1-formyl- β -carboline derivative is resistant to the proliferation of newcastle disease virus by directly inhibiting the adsorption of newcastle disease virus.
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| EP2422790A1 (en) * | 2007-02-09 | 2012-02-29 | Emory University | Paramyxovirus family inhibitors and methods of use thereof |
| CN101850110A (en) * | 2009-03-30 | 2010-10-06 | 天津泽世德生物医药有限公司 | Novel medicinal composition and preparation method |
| US20120022048A1 (en) * | 2010-07-22 | 2012-01-26 | Franco Lori | Anti-proliferative substituted pyrazolo[3,4-d]pyrimidines derivatives (SPP) to inhibit immune activation, virus replication and tumor growth |
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| WO2006077427A2 (en) * | 2005-01-21 | 2006-07-27 | Mnl Pharma Limited | Antiviral drug combinations |
| JP2010215533A (en) * | 2009-03-13 | 2010-09-30 | Kagoshima Univ | Antiviral agent containing diphenylmethane derivative as active ingredient |
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