CN116115604A - New application of mevastatin - Google Patents
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- CN116115604A CN116115604A CN202310075853.0A CN202310075853A CN116115604A CN 116115604 A CN116115604 A CN 116115604A CN 202310075853 A CN202310075853 A CN 202310075853A CN 116115604 A CN116115604 A CN 116115604A
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Abstract
The invention discloses a new application of mevastatin, relates to the technical field of medicines, and in particular relates to an application of mevastatin or pharmaceutically acceptable salts thereof in preparing medicines for treating diseases caused by respiratory syncytial virus. The invention discovers that the mevastatin compound shown as the formula (I) can inhibit the proliferation of respiratory syncytial virus and infect host cells for the first time, and can be used for treating diseases in respiratory syncytial virus infection. Mevastatin is a small molecule compound, CC thereof 50 62.61. Mu.M, capable of dose-dependent inhibition of respiratory syncytial virus replication, IC 50 (half inhibitory concentration) 0.67. Mu.M, a Selection Index (SI) of about 93, indicates that mevastatin is a low-toxicity, highly potent anti-respiratory syncytial virus drug.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a new application of mevastatin, and especially relates to an application of mevastatin or pharmaceutically acceptable salts thereof in preparing medicines for treating diseases caused by respiratory syncytial virus.
Background
Respiratory syncytial virus (Respiratory syncytial virus, RSV) belongs to the Pneumovirus genus (Pneumovirus) of the paramyxoviridae family, with only one serotype. The virus is spherical, has a diameter of 120-300 nm, has an envelope, and has a genome of non-segmented single negative strand RNA. Mainly causes lower respiratory tract infection such as bronchiolitis and pneumonia of infants below 6 months, and upper respiratory tract infection such as rhinitis and common cold of older children and adults. Up to now, no specific medicine is available for curing lower respiratory tract infection of infants with bronchiolitis, pneumonia and the like caused by respiratory syncytial virus for less than 6 months. Therefore, the development of corresponding anti-respiratory syncytial virus drugs is also critical to completely combat the new coronavirus.
Mevastatin, english name: mevastatin, CAS:73573-88-3, which has the structural formula shown in the following formula (I),
mevastatin is a potent, competitive and selective HMG-CoA (HMG CoA) reductase inhibitor that competes with the substrate HMG-CoA binding site (Ki=1 nM) 10000 times more avidly than the HMG-CoA substrate itself. Mevastatin induces cell cycle arrest, which results in cell cycle arrest in the early G0/G1 and late G2/M, accompanied by down-regulation of cdk4, cdk6 and cyclin D1, and up-regulation of the cell cycle inhibitors p21 and p 27. Mevastatin also induced apoptosis and inhibited TNF-induced NF- κB activation (IC 50 approximately 17 μM). In addition, mevastatin can inhibit isoprenoid biosynthesis and reduce cholesterol levels in plasma, and thus can be used as a potential drug for the treatment of coronary heart disease and atherosclerosis, and the study of cardiovascular diseases. However, no report on respiratory syncytial virus resistance is found.
Disclosure of Invention
The invention provides application of mevastatin or pharmaceutically acceptable salts thereof in preparing medicaments for treating diseases caused by anti-respiratory syncytial virus, which aims to solve the problems in the prior art.
In order to achieve the technical purpose, the invention mainly adopts the following technical scheme:
in a first aspect, the present invention provides the use of mevastatin or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease caused by an anti-respiratory syncytial virus.
Further, the mevastatin or a pharmaceutically acceptable salt thereof inhibits respiratory syncytial virus proliferation.
Further, the mevastatin or a pharmaceutically acceptable salt thereof inhibits respiratory syncytial infection of host cells.
In a second aspect, the present invention provides a medicament for the treatment of a disease caused by respiratory syncytial virus, which comprises mevastatin or a pharmaceutically acceptable salt thereof.
Further, the medicament comprises mevastatin or pharmaceutically acceptable salts thereof and pharmaceutically acceptable auxiliary materials.
Further, the pharmaceutical dosage form is selected from the group consisting of tablets, capsules, oral liquids, oral granules, oral powders, and injections.
In a third aspect, the present invention provides a method of preparing a medicament for the treatment of a disease caused by respiratory syncytial virus, by mixing an effective amount of mevastatin or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.
In a fourth aspect, the present invention provides a method of inhibiting respiratory syncytial virus proliferation, comprising administering to a subject in need thereof an effective amount of mevastatin or a pharmaceutically acceptable salt thereof.
In a fifth aspect, the present invention provides a method of inhibiting infection of a host cell by respiratory syncytial virus, comprising administering to a subject in need thereof an effective amount of mevastatin or a pharmaceutically acceptable salt thereof.
Compared with the prior art, the invention has the following beneficial effects:
the invention discovers that the mevastatin compound shown as the formula (I) can inhibit the proliferation of respiratory syncytial virus and infect host cells for the first time, and can be used for treating diseases in respiratory syncytial virus infection.
Mevastatin is a small molecule compound, CC thereof 50 62.61. Mu.M, capable of dose-dependent inhibition of respiratory syncytial virus replication, IC 50 (half inhibitory concentration) 0.67. Mu.M, a Selection Index (SI) of about 93, indicates that mevastatin is a low-toxicity, highly potent anti-respiratory syncytial virus drug.
Drawings
Fig. 1 is a schematic diagram of a mevastatin cytotoxicity assay provided in an embodiment of the invention;
FIG. 2 is a graph showing the level of dose-dependent inhibition of respiratory syncytial virus replication of a compound of formula (I) in Hela cells according to the invention;
FIG. 3 is a graph showing the level of dose-dependent inhibition of respiratory syncytial virus replication of a compound of formula (I) in the supernatant of Hela cell culture broth according to the example of the present invention;
FIG. 4 is a graph showing the level of dose-dependent inhibition of respiratory syncytial virus replication of a compound of formula (I) in Hela cells, as provided by the examples of the present invention;
FIG. 5 is a graph showing the level of dose-dependent inhibition of respiratory syncytial virus replication by a compound of formula (I) outside of HeLa cells, as provided by the examples of this invention.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
The embodiment of the invention relates to the following steps:
use of mevastatin or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease caused by anti-respiratory syncytial virus.
In some embodiments, the mevastatin or a pharmaceutically acceptable salt thereof inhibits respiratory syncytial virus proliferation.
In some embodiments, the mevastatin or a pharmaceutically acceptable salt thereof inhibits respiratory syncytial infection of a host cell.
The invention provides a medicament for treating diseases caused by respiratory syncytial virus, which comprises mevastatin or pharmaceutically acceptable salts thereof.
In some embodiments, the medicament comprises mevastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant.
It will be appreciated that the medicament of the embodiments of the present invention may be formulated with different pharmaceutically acceptable excipients to produce suitable clinical dosage forms including, but not limited to, the following: tablets (including but not limited to coated tablets), capsules, oral liquids, oral granules, oral powders, injections (including but not limited to lyophilized powder injection or emulsion for injection). Such pharmaceutically acceptable excipients include, but are not limited to, diluents, wetting agents, binders, disintegrants, lubricants, color and flavor modulators, solvents, solubilizers, co-solvents, emulsifiers, antioxidants, metal complexing agents, inert gases, preservatives, topical analgesics, pH modifying agents, isotonic or isotonic agents and the like. Further: diluents such as starches, sucrose, celluloses, inorganic salts and the like; wetting agents such as water, ethanol, and the like; binders such as starch slurry, dextrin, sugar, cellulose derivatives, gelatin, povidone, polyethylene glycol, and the like; disintegrants such as starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium dicarboxymethyl cellulose, crospovidone, surfactants, running disintegrants, etc.; lubricants such as talc, calcium stearate, magnesium lauryl sulfate, silica gel micropowder, polyethylene glycol, etc.; color, flavor, taste, and smell modifiers such as coloring matter, perfume, sweetener, mucilage, and corrigent, specifically such as fuchsin and xylitol; solvents such as water, oil, ethanol, glycerol, propylene glycol, polyethylene glycol, dimethyl sulfoxide, liquid paraffin, fatty oil, ethyl acetate, etc.; solubilizers such as tweens, sellers, polyoxyethylene fatty alcohol ethers, soaps, sulphates, sulphonates and the like; cosolvents such as organic acids (e.g., citric acid) and salts thereof, amides and amines, inorganic salts, polyethylene glycol, povidone, glycerin, and the like; emulsifying agents such as span, tween, herba Euphorbiae Helioscopiae, benzyl, glycerin fatty acid ester, higher fatty acid salt, sulfate, sulfonate, acacia, tragacanth, gelatin, pectin, phospholipid, agar, sodium alginate, hydroxide, silica, bentonite, etc.; suspending agents such as glycerin, syrup, acacia, tragacanth, agar, sodium alginate, cellulose derivatives, povidone, carbopol, polyvinyl alcohol, thixotrope and the like; antioxidants such as sulfite, metabisulfite, bisulfite, ascorbic acid, gallic acid, esters thereof, and the like; metal complexing agents such as disodium edetate, polycarboxylic acid compounds, and the like; inert gases such as nitrogen, carbon dioxide, and the like; preservatives, such as nipagins, organic acids and salts thereof (e.g., sodium benzoate), quaternary ammonium compounds, chlorhexidine acetate, alcohols, phenols, volatile oils, and the like; local analgesics such as benzyl alcohol, chlorobutanol, lidocaine, procaine and the like; pH adjusting agents such as hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, acetic acid, sodium hydroxide, sodium bicarbonate, ethylenediamine, meglumine, phosphate, acetate, citric acid, citrate, etc.; isotonic or isotonic agents, such as glucose, sodium chloride, sodium citrate, sorbitol, xylitol, and the like. It will be appreciated that the diluents described in the examples of the present invention may also be referred to as fillers, which may also function the same in pharmaceutical formulations; the water in the embodiment of the invention is water meeting the requirements of medicaments, such as water for injection, purified water and the like, and the oil is oil for injection; the preservative provided by the embodiment of the invention can also be called an antibacterial agent, and plays roles in inhibiting the growth of microorganisms, prolonging the shelf life and the like in the preparation; the lubricant of the embodiment of the invention contains a glidant, an anti-sticking agent and the like; the sugar in the embodiment of the invention can be powdered sugar or syrup, and the type of the sugar is not limited to glucose; perfumes according to embodiments of the present invention include, but are not limited to, fragrances.
It will be appreciated that the medicaments according to the embodiments of the present invention may be formulated in different dosage forms based on different excipients, and accordingly, the mode of administration may also be varied.
The invention also provides a method for preparing the medicine for treating diseases caused by respiratory syncytial virus, which comprises the step of mixing an effective amount of mevastatin or pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.
The present invention also provides a method for inhibiting the proliferation of respiratory syncytial virus, which comprises administering to a subject in need thereof an effective amount of mevastatin or a pharmaceutically acceptable salt thereof.
The present invention also provides a method of inhibiting respiratory syncytial virus infection in a host cell, comprising administering to a subject in need thereof an effective amount of mevastatin or a pharmaceutically acceptable salt thereof.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods. The experimental procedure, which does not address the specific conditions in the examples below, is generally followed by routine conditions such as Sambrook et al, molecular cloning: conditions described in the laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989) or as recommended by the manufacturer.
At present, a cell culture model for in-vitro screening of anti-respiratory syncytial virus drugs is the most commonly used screening model, and has the advantages that: the method can provide a large number of cells with the same genetic character as research objects, is convenient to operate, can eliminate the influence of other external factors, can detect the effective concentration and the therapeutic index of the medicine, and provides more foundation for the later mechanism research. The invention adopts a cell culture screening method to detect the influence of the mevastatin compound shown in the formula (I) on the infection of Hela cells by respiratory syncytial virus, and quantitatively analyzes the activity of the compound shown in the formula (I) on resisting respiratory syncytial virus based on the detection of the copy numbers of the viral nucleic acid in the supernatant and the cells.
Example 1: evaluation of anti-respiratory syncytial Virus Activity of the Compound of formula (I) (mevastatin)
1. Experimental materials
1.1 cells, viruses and pharmaceuticals
HeLa cells were purchased from ATCC (cat# HTB-037).
The compound of formula (I) (CAS: 73573-88-3) was purchased from Sigma.
1.2 reagents
DMEM medium and FBS were purchased from GIBCO company; c (C)CK8 cell Activity assay kit was purchased from Thermofisher company; SYBR mixed solution (iTaq) TM Universal
Green Supermix) was purchased from Bio-Rad corporation.
1.3 laboratory apparatus
Quantitative RCP instrument (Bio-Rad CFX96 Touch) TM Real-Time PCR detection system) was purchased from Bio-Rad company. Multi-label microplate readers are available from PerkinElmer corporation.
Type 1.0R cryocentrifuge and cell incubator are available from Thermofisher company.
2. Experimental methods and results
2.1 cell culture
37℃，5％ CO 2 Culturing in a humidifying incubator. DMEM medium containing 10% fbs, 100U/mL penicillin and streptomycin was used. Cells were passaged to 90% confluence at a passaging ratio of 1/3-1/4.
2.2 Virus culture
200 μl/tube was divided and stored frozen at-70deg.C for use.
2.3 cytotoxicity assays of Compounds of formula (I)
HeLa cells at 6X 10 3 Cells/well (100 μl) were inoculated into 96-well cell culture plates and the cells were attached for use; the drug was treated with cell maintenance fluid (dmem+2% serum) at a maximum concentration of 100.0 μm in a total of 6 gradients (100 μm,50 μm,25 μm,12.5 μm,6.25 μm,3.125 μm) with 2-fold gradient dilutions, 3 multiplex wells per gradient. After 48 hours of culture, the culture supernatant was discarded, 10. Mu.l of a CCK 8-containing reagent was added to each well, and the culture was continued in a cell incubator for 1 hour, and after 1 hour, the absorbance at 450nm was measured by a microplate reader, and the cell viability was calculated.
The results show that, as shown in FIG. 1, the compound of formula (I) mevastatin versus Hela cells CC 50 Is 62.61. Mu. Mol/l. The complete lack of cytotoxicity to HeLa cells in the range of less than 6.25. Mu.M, indicates a safer application of the compound of formula (I), i.e., the compound of formula (I)The dosage of the drug is 0.25-4.0 mu M according to the cell experiment dosage.
2.4 detection of the efficiency of the compounds of formula (I) in inhibiting the replication of respiratory syncytial virus based on fluorescent quantitative PCR.
2.4.1. The following experiments were all performed in BSL-2 laboratory:
HeLa cells were cultured at 1.0X10 4 The cells/holes are inoculated in a 48-hole cell culture plate, and after the cells are cultured in a 37 ℃ cell culture box for 14 to 18 hours, the cells are grown into a monolayer for standby. The culture medium in the well plate was discarded, and after washing twice with PBS, 1.0MOI virus solution and 500. Mu.l of each concentration gradient drug were added and cultured in a 37℃cell incubator. The drug was diluted in 2-fold gradients for 5 gradients with 4.0 μm as starting concentration, 3 duplicate wells per gradient. After 120h of culture, RNA is extracted from the supernatant of each experimental hole and cells, the RNA is reversely transcribed into cDNA, and then fluorescent quantitative PCR detection is carried out. The experiments set up a blank control group (ribavirin), a negative control group (no drug treatment after viral infection) and an experimental drug group.
2.4.2.120h, and the cell supernatant and cells were collected with Trizol, and brought out of the biosafety secondary (BSL-2) laboratory after virus inactivation. For RNA extraction.
2.4.3 extraction of RNA from samples according to the instructions of the apathy technologies TR205-50 kit.
2.4.4 RNA obtained was reverse transcribed into cDNA according to the bang ZR102 reverse transcription kit.
2.4.5 detection of genome replication levels by the genome quantitative PCR method (QPCR). The quantitative RCR primer is directed against the N gene sequence of respiratory syncytial virus, and is as follows:
5'-TGACAGCAGAAGAACTAGGGC-3'；
5'-TGGGTGATGTGAATTTGCCCT-3'。
the housekeeping gene GADPH was selected as a corrected reference control gene and the quantitative RCR primers for GADPH were as follows:
5'-GCTCCCTCTTTCTTTGCAGCAAT-3'；
5'-TACCATGAGTCCTTCCACGATAC-3'。
2.4.6 quantitative Ct values were checked by reference Gene (GAPDH), and the data of each group were normalized by using the group as the standard group, and the calculation formula was: viral replication inhibition = 1-drug/negative control group x 100%. The results were averaged, standard deviation and IC50 calculated by GraphPad Prism 8 software.
2.4.7A graph of the results of inhibition of respiratory syncytial virus replication by the compound of formula (I) is drawn using the results of the calculations in step (2.4.6). The results are shown in fig. 2 and 3.
The results of fig. 2 show that: in Hela cells, the compound of formula (I) inhibits replication levels of respiratory syncytial virus, IC for replication of respiratory syncytial virus 50 (half inhibition concentration) was 0.67. Mu. Mol/liter.
The results of fig. 3 show that: in the supernatant of Hela cell culture fluid, the compound of formula (I) can inhibit the replication level of respiratory syncytial virus in a dose-dependent manner, and the compound of formula (I) has IC (integrated circuit) for replication of respiratory syncytial virus 50 (half inhibitory concentration) was 0.75. Mu. Mol/liter.
2.5 detection of the efficiency of the compounds of formula (I) in inhibiting the replication of respiratory syncytial virus based on enzyme-linked immunosorbent assay (ELISA).
2.5.1. The following experiments were all performed in BSL-2 laboratory:
HeLa cells were cultured at 1.0X10 4 The cells/holes are inoculated in a 48-hole cell culture plate, and after the cells are cultured in a 37 ℃ cell culture box for 14 to 18 hours, the cells are grown into a monolayer for standby. The culture medium in the well plate was discarded, and after washing twice with PBS, 1.0MOI virus solution and 500. Mu.l of each concentration gradient drug were added and cultured in a 37℃cell incubator. The drug was diluted in 2-fold gradients for 5 gradients with 4.0 μm as starting concentration, 3 duplicate wells per gradient. After 120h of culture, the supernatant of each experimental hole and cells are taken for detection by enzyme-linked immunosorbent assay (ELISA). The experiments set up a blank control group (ribavirin), a negative control group (no drug treatment after viral infection) and an experimental drug group.
2.5.2.120h later, the cell supernatant and cells were collected and brought out of the biosafety secondary (BSL-2) laboratory after virus inactivation.
2.5.3. To the harvested cells, 100. Mu.l of cell lysate (50 mM Tris,0.5% NP-40,1mM EDTA and 100mM NaCl) was added, and the cells were lysed on a shaker at 4℃for 1 hour, transferred to a 1.5 ml EP tube, and then centrifuged at 12000rpm for 10 minutes at 4℃on a centrifuge, to collect the supernatant.
2.5.4. The cell supernatants and cell lysate supernatants were assayed according to instructions of SEK11049, baiji shenzhou (respiratory syncytial virus antigen assay kit).
2.5.5. OD measured in the previous step 450 The value is calculated according to the formula: viral replication inhibition (%) =1-drug group OD 450 Value/negative control OD 450 The value was 100%. Results inhibition curves were plotted by GraphPad Prism 8 software.
2.5.6A graph of the results of inhibition of respiratory syncytial virus replication by the compound of formula (I) is drawn using the results of the calculations in step (2.5.5). The results are shown in fig. 4 and 5.
The results of fig. 4 and 5 show that: within Hela cells and outside cells, the compounds of formula (I) are able to inhibit the replication level of respiratory syncytial virus dose-dependently.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (9)
1. Use of mevastatin or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease caused by anti-respiratory syncytial virus.
2. Use according to claim 1, characterized in that: the mevastatin or a pharmaceutically acceptable salt thereof inhibits respiratory syncytial virus proliferation.
3. Use according to claim 1, characterized in that: the mevastatin or a pharmaceutically acceptable salt thereof inhibits respiratory syncytial infection of host cells.
4. A medicament for treating diseases caused by respiratory syncytial virus, which is characterized in that: the medicament comprises mevastatin or a pharmaceutically acceptable salt thereof.
5. The medicament for treating diseases caused by respiratory syncytial virus according to claim 4, wherein: the medicine comprises mevastatin or pharmaceutically acceptable salts thereof and pharmaceutically acceptable auxiliary materials.
6. The medicament for treating diseases caused by respiratory syncytial virus according to claim 4, wherein: the pharmaceutical dosage form is selected from tablets, capsules, oral liquid, oral granules, oral powder or injection.
7. A method for preparing a medicament for treating diseases caused by respiratory syncytial virus, comprising the steps of: an effective amount of mevastatin or a pharmaceutically acceptable salt thereof is admixed with a pharmaceutically acceptable carrier.
8. A method of inhibiting respiratory syncytial virus proliferation, comprising: an effective amount of mevastatin or a pharmaceutically acceptable salt thereof is administered to a subject in need of inhibition.
9. A method of inhibiting infection of a host cell by respiratory syncytial virus, comprising: administering to a subject in need of prevention of infection an effective amount of mevastatin or a pharmaceutically acceptable salt thereof.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020142940A1 (en) * | 2000-10-17 | 2002-10-03 | Graham Barney Scott | Method of inhibiting viral infection using HMG-COA reductase inhibitors and isoprenylation inhibitors |
| US20050085528A1 (en) * | 2003-10-17 | 2005-04-21 | Pfizer Inc. | Parmaceutical |
| WO2021226479A1 (en) * | 2020-05-07 | 2021-11-11 | The Regents Of The University Of California | Inhaled statins for treatment of viral respiratory diseases |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020142940A1 (en) * | 2000-10-17 | 2002-10-03 | Graham Barney Scott | Method of inhibiting viral infection using HMG-COA reductase inhibitors and isoprenylation inhibitors |
| US20050085528A1 (en) * | 2003-10-17 | 2005-04-21 | Pfizer Inc. | Parmaceutical |
| WO2021226479A1 (en) * | 2020-05-07 | 2021-11-11 | The Regents Of The University Of California | Inhaled statins for treatment of viral respiratory diseases |
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