CN111138499B - Anderson polyacid and application thereof in resisting ADV7 virus - Google Patents

Anderson polyacid and application thereof in resisting ADV7 virus Download PDF

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CN111138499B
CN111138499B CN201911378303.6A CN201911378303A CN111138499B CN 111138499 B CN111138499 B CN 111138499B CN 201911378303 A CN201911378303 A CN 201911378303A CN 111138499 B CN111138499 B CN 111138499B
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adv7
virus
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polyacid
anderson polyacid
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王龙胜
王悦
魏艳红
李妮
朱茂春
郭超
袁子月
冯治坤
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Hubei University of Technology
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    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
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Abstract

The invention discloses Anderson polyacid and application thereof in resisting ADV7 virus. Research experiments on inhibiting the activity of the ADV7 virus show that the compound A0 can inhibit cytopathic effect (CPE) of the ADV7 virus on host Hela cells, enhance the cell survival rate and reduce the yield of progeny virus, and has potential application in preparing anti-ADV 7 virus medicaments.

Description

Anderson polyacid and application thereof in resisting ADV7 virus
Technical Field
The invention relates to the technical field of antiviral drugs, in particular to Anderson polyacid and application thereof in resisting ADV7 virus.
Background
Adenoviruses (ADV) are a widely distributed group of DNA viruses. There are 52 known adenovirus types, designated ADVl to ADV52, in two genera, for a total of about 100 serotypes. About 1/3 of the known serotypes of human adenoviruses are associated with human disease. Adenovirus can invade various tissues and organs such as respiratory tract, eye conjunctiva, gastrointestinal tract and urinary tract, mainly respiratory tract infection, severe cases can cause infantile pneumonia, and can accumulate all systems of the whole body. Adenovirus pneumonia caused by adenovirus infection is one of the most serious types of infantile pneumonia. The adenovirus types associated with respiratory diseases are mainly ADV7, ADV3 and ADV4, wherein ADV7 can cause severe or fatal lower respiratory tract infection of infants and is easy to cause epidemic outbreak. At present, no effective preventive vaccine and therapeutic medicine exist clinically aiming at the infection caused by the virus, and symptomatic treatment is mainly adopted.
Polyoxometalates (polyoxometalates) are polyanion clusters having specific structures and compositions, which are formed by condensing oxygen-containing metal salts of early transition metals such as vanadium, molybdenum, tungsten, niobium, tantalum and the like under certain conditions, and are also referred to as Polyacids (POMs) for short. Due to the wide variety of polyacid, the polyacid has rich and variable compositions, peculiar physical, chemical, physiological and pharmacological activities, rich and variable optical, electrical, magnetic and other physical properties, and has wide application prospects in the fields of nano science, materials, catalysis and medicinal chemistry. In 1971, raynaud et al reported [ SiW ] 12 O 40 ] 4- Inhibitory activity against Murine Leukemia Sarcoma Virus (MLSV) (M.Raynaud, et.al.C.R.Acad.Sci.Hebd.Seancesacacad.Sci.D1971, 272, 347). In 1985, french scientists found (NH) 4 ) 17 Na[NaSb 9 W 21 O 86 ](HPA-23) has an inhibitory effect on HIV reverse transcriptase (DormontD., et. Al. Ann. Inst. Pasours/Virol, 1985,136E, 75). In 1988, professor YAMASE of Japan found (i-PrNH) 3 ) 6 [Mo 7 O 24 ]·3H 2 O (PM-8) exhibits good antitumor activity (ToshihiroYamase, inorg. Chem. Acta.1988,151, 15-18).
Disclosure of Invention
The present invention has been made in view of the above-mentioned situation, and an object of the present invention is to provide Anderson polyacid [ (N (C) 4 H 9 ) 4 )] 3 [MnMo 6 O 18 ((OCH 2 ) 3 CNH 2 ) 2 ](A0) As a screening compound against ADV7 virus.
The invention relates to the antipodal polyacid [ (N (C) 4 H 9 ) 4 )] 3 [MnMo 6 O 18 ((OCH 2 ) 3 CNH 2 ) 2 ](A0) The inhibitory activity of ADV7 virus was evaluated.
The object of the invention is achieved in that Anderson polyacid A0 is tested for activity by standard viral activity test methods.
In order to achieve the purpose, the scheme of the invention is as follows:
in a first aspect, the present invention provides an anderson polyacid, characterized in that:
the Anderson polyacid refers to a compound A0: [ (N (C) 4 H 9 ) 4 )] 3 [MnMo 6 O 18 ((OCH 2 ) 3 CNH 2 ) 2 ]；
The cation of A0 is tetrabutylammonium cation, and the anion structure is as follows:
Figure BDA0002341606740000021
in a second aspect, the present invention provides a use of the andresonide polyacid described above in resisting ADV7 virus, wherein the use comprises: the compound A0 has anti-ADV-7 activity.
Preferably, when the compound A0 is at 200. Mu.g/mL, the inhibition rate of ADV7 is 65.9%.
Further, after pharmaceutically acceptable auxiliary materials and carriers are added into the compound A0, the compound A is used for preparing a preparation for resisting the ADV7 virus.
Further, the preparation is any one of granules, tablets, pills, capsules, injections or dispersing agents.
In the scheme of the invention, through a large number of biological experiments, anderson polyacid A0 is found to have the activity of inhibiting ADV7 virus. The specific expression is that the cell pathological effect caused by the ADV7 virus can be inhibited, the survival rate of infected cells is enhanced, the replication and proliferation of the ADV7 virus in the cells are inhibited, and the yield of progeny virus is reduced. Therefore, the compound has potential to prepare specific treatment medicines for resisting ADV7 infection and has better clinical application prospect.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. the compounds have simple synthesis process, are economical and quick, and are easy to produce and popularize on a large scale.
2. The polyacid is a non-nucleoside drug and is not easy to generate drug resistance.
Drawings
FIG. 1 is a graph of the effect of Anderson polyacid A0 on Hela cell viability of ADV7 action.
FIG. 2 is a graph showing the inhibitory effect of Anderson polyacid A0 on CPE in Hela cells caused by ADV 7.
FIG. 3 is a graph of the inhibitory effect of Anderson polyacid A0 on the yield of ADV7 progeny virus.
Detailed Description
The invention is further described in detail below with reference to the figures and specific examples.
Anderson polyacid (TBA) for use in the invention 3 [MnMo 6 O 18 ((OCH 2 ) 3 CNH 2 ) 2 ]According to the method of Eur.J.Inorg.chem. (2003, 2406-2412), tris (hydroxymethyl) aminomethane is reacted with octamolybdic acid and manganese acetate under reflux, and then the reaction solution is cooled and filtered to remove insoluble impurities, and the obtained filtrate is diffused by ether to obtain the corresponding Anderson polyacid.
The application of the Anderson polyacid serving as the anti-ADV 7 virus can inhibit the cytopathic effect (CPE) generated by the ADV7 in host cells Hela and enhance the cell survival rate. Inhibit the replication and proliferation of ADV7 virus in cells, and reduce the yield of progeny virus. These studies indicate that this compound has the potential to be developed into a drug effective in the treatment of ADV7 infection.
[ example 1 ] Anderson polyacid Compound A0 Activity against ADV7 study experiment
In this example, the compounds were tested for their activity against ADV7 as follows:
1. the test contents are as follows:
compound anti-ADV 7 activity assay: the invention combines the cytopathic effect analysis and MTT determination cell survival rate detection method to evaluate the ADV7 activity of Anderson polyacid.
2. The test method comprises the following steps:
2.1.1 toxicity of Compounds on host Hela cells
Plating Hela cells on a 96-well plate, 5% CO at 37% 2 After the culture box is cultured to grow a monolayer, cell culture solution is discarded, cell maintenance solutions containing compounds with different concentrations are respectively added for continuous culture, the cytotoxicity is visually observed and respectively recorded by a microscope after 48 hours, and the cell survival rate is measured by an MTT method. The SPSS11.5 software calculates the median toxic concentration of the drug to the cells (CC 50). Cell survival rate = (drug group mean OD) 492 Value/cell control mean OD 492 Value) × 100%.
2.1.2 inhibitory Activity of Compounds on ADV7
Plating Hela cells in a 96-well plate, at 37 deg.C, 5% 2 After the culture box is used for culturing full monolayers, culture solution is discarded, cells are infected by 100TCID50 ADV7 virus solution for 1.5h, and test compounds (ribavirin serving as a positive control drug) with different concentrations are added to incubate the cells. After the culture is continued for about 48 hours, the cytopathic effect (CPE) is observed under a microscope when about 90% of CPE lesions appear in the virus control wells. Observation and recording method of CPE: the cell-free lesions are marked as-less than 25% of the cell lesions are marked as +,25% -50% of the cell lesions are marked as + + +,50% -75% of the cell lesions are marked as + + +, and more than 75% of the cell lesions are marked as + + +.
After CPE observation is finished, the inhibition rate of the medicine on ADV7 is detected by using an MTT method. The method comprises the following specific steps: MTT 50. Mu.L (5 mg. Multidot.mL) was added to each well -1 ) After incubation for 3-4h, the supernatant was removed and an equal volume of DMSO was added to dissolve the pellet. The absorbance (OD) at 492nm was read with a microplate reader 492 Value). The inhibition rate of the drug against ADV7 was calculated using the following formula. The half effective concentration of the drug (Concentrationfor 50% of maximail, EC 50) was calculated using SPSS11.5 software.
Figure BDA0002341606740000051
2.1.3 Therapeutic Index (TI) of drug
TI = CC50/EC50. A higher therapeutic index indicates greater antiviral potential.
3. Results of the experiment
TABLE 1 cytotoxicity and anti-ADV 7 Activity of Anderson polyacid
Figure BDA0002341606740000052
The cytotoxicity and anti-ADV 7 activity of the compounds are shown in Table 1. The effect of concentration-dependent anderson polyacid (A0) on Hela cell viability for ADV7 action is shown in figure 1. The invention detects that the Anderson polyacid A0 has certain inhibitory activity on ADV7, and the inhibitory rate of 200 mug/mLA 0 on adenovirus reaches 65.9%. The effect of compound A0 in inhibiting CPE of Hela cells caused by ADV7 is shown in figure 2, the ADV7 infected Hela cells become round and are separated from the cell plate wall, and the treatment of 200 mug/mLA 0 has obvious inhibition effect on the pathological effect.
Example 2 test for inhibitory Effect of Anderson polyacid Compound A0 on ADV7 progeny Virus production
In this example, the activity of ADV7 resistance was intensively studied in anderson polyacid, and an inhibitory effect test of compound A0 on the yield of ADV7 progeny virus was performed, as follows:
1. content of the experiment
The inhibitory effect of compound A0 on the production of ADV7 progeny virus was examined after ADV7 infection of Hela cells.
2. Test method
Hela cells in logarithmic growth phase are plated on 24-hole plates and grow into 100TCID after a monolayer 50 ADV7 infected cells, 37 degrees C were incubated for 1.5h after removing virus liquid, PBS washing three times, adding containing 200 u g/mLA0 cell maintenance liquid. Collecting cells and supernatant culture solution after 48h, freeze thawing and cracking at-20 deg.C and 37 deg.C for three times, and performing TCID 50 Methods determine ADV7 virus titers.
3. Test results
As shown in fig. 3, the virus titer of the A0-treated Hela cells was significantly reduced compared to the virus control group, and was reduced by approximately 6.0log compared to the virus control group.
In conclusion, the Anderson polyacid A0 has stronger activity of inhibiting ADV7, can inhibit Hela cell apoptosis caused by the ADV7 virus, reduces the yield of progeny virus, and has potential for preparing a medicament for effectively resisting the ADV7 infection clinically.

Claims (4)

1. The application of Anderson polyacid in preparing ADV7 virus resisting medicine is characterized in that:
the Anderson polyacid refers to a compound A0: [ (N (C) 4 H 9 ) 4 )] 3 [MnMo 6 O 18 ((OCH 2 ) 3 CNH 2 ) 2 ]；
The cation of A0 is tetrabutylammonium cation, and the anion structure is as follows:
Figure FDA0003782033110000011
the compound A0 has anti-ADV-7 activity.
2. The use of the anderson polyacid of claim 1 in the preparation of a medicament against the ADV7 virus, wherein: when compound A0 was at 200. Mu.g/mL, the inhibition of ADV7 was 65.9%.
3. Use of the anderson polyacid of claim 1 or 2 in the preparation of a medicament against the ADV7 virus, characterized in that: after pharmaceutically acceptable auxiliary materials and carriers are added into the compound A0, the compound A is used for preparing an ADV7 virus resistant preparation.
4. The use of the anderson polyacid of claim 3 in the preparation of a medicament against the ADV7 virus, wherein: the preparation is any one of granules, tablets, pills, capsules or injections.
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