CN113975268A - Application of 5, 6-dehydrourogalactone in preparation of anti-dengue virus drugs - Google Patents
Application of 5, 6-dehydrourogalactone in preparation of anti-dengue virus drugs Download PDFInfo
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- CN113975268A CN113975268A CN202111250221.0A CN202111250221A CN113975268A CN 113975268 A CN113975268 A CN 113975268A CN 202111250221 A CN202111250221 A CN 202111250221A CN 113975268 A CN113975268 A CN 113975268A
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- dengue virus
- dehydrourogalactone
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- dengue
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- 230000000405 serological effect Effects 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
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- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- FQCQGOZEWWPOKI-UHFFFAOYSA-K trisalicylate-choline Chemical compound [Mg+2].C[N+](C)(C)CCO.OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O FQCQGOZEWWPOKI-UHFFFAOYSA-K 0.000 description 1
- DFHAXXVZCFXGOQ-UHFFFAOYSA-K trisodium phosphonoformate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)P([O-])([O-])=O DFHAXXVZCFXGOQ-UHFFFAOYSA-K 0.000 description 1
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Abstract
The invention provides a picrasma quassioides kusnezoffm type compound 5, 6-dehydrouromycolactone:
Description
Technical Field
The invention relates to application of quassinoid 5, 6-dehydrouromycolactinone in preparation of a dengue virus resistant drug, and belongs to the technical field of pharmaceutical chemistry antiviral.
Background
5, 6-dehydrouromycolactone belongs to quassin compounds, which are characteristic components of plants in the family of quassiaceae. Studies show that the picrorhizine compound can obviously inhibit the replication of various viruses, such as human immunodeficiency virus, human herpes virus and tobacco mosaic virus (Bioorganic & Medicinal Chem Lett, 1996, 6: 701-706; Bull Chem Soc Jpn, 1999, 72 (4): 751-756; J age Food Chem, 2010, 58 (3): 1572-1577), but no research report on the anti-dengue virus pharmacological action of the compound exists so far.
Dengue virus (DENV) belongs to a member of the flaviviridae family of the flaviviridae genus, and members of the same genus include: japanese encephalitis virus, West Nile virus, St.Louis encephalitis virus, yellow fever virus, etc. The virus has an RNA genome capsid in the shape of a dumbbell, rod or sphere with a diameter of 40-50 nm. Can be cultured and propagated in brain and tissue cells of mice, and is most sensitive to Aedes albopictus pure cell strain (C6/36). Dengue virus has 1-4 serotypes, wide serological cross reaction exists among the serotypes, and abnormal secondary infection can cause the phenomenon of antibody-dependent infection enhancement (ADE).
Dengue virus (DENV) infection is the most prevalent arbovirus disease in humans today. According to WHO estimates that 25-30 million people worldwide face the risk of Dengue virus infection, about 5 million to 1 million Dengue Fever (DF) cases occur each year, and patients show symptoms of high fever, headache, myalgia, arthralgia and rash, of which 50 million cases develop more serious Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS), with a mortality rate of 5% -10%. The virus is transmitted from person to person primarily through aedes aegypti and aedes albopictus. The virus is mainly prevalent in more than one hundred countries and regions, such as southeast Asia, America, eastern Mediterranean, Africa, etc.
According to the estimation of the world health organization, about 5 million to 1 hundred million people worldwide infect dengue fever virus to cause dengue fever, and the clinical symptoms are mainly shown as follows: fever, rash, headache and myalgia; dengue virus infectors may develop more serious conditions, dengue hemorrhagic fever and dengue shock syndrome, with about 25 to 50 million people statistically expressing dengue hemorrhagic fever every year worldwide.
Along with the change of global climate, the acceleration of urbanization process, frequent communication of personnel and the increase of labor personnel in dengue epidemic areas in China, the threat of dengue virus epidemic still exists, and the climate and environment of partial areas in China are suitable for the survival of the transmission medium of the dengue virus, thereby providing conditions for the transmission of the virus.
At present, no effective vaccine or drug is available for preventing and treating diseases caused by dengue virus, so that the search for effective anti-dengue virus drugs is of great significance.
Disclosure of Invention
In order to solve the above technical problems, an object of the present invention is to provide a use of 5, 6-dehydrourogalactone in the preparation of a drug for resisting dengue virus, and the present invention finds that 5, 6-dehydrourogalactone has an antiviral effect and can significantly inhibit the replication of dengue virus.
The invention also aims to provide an anti-dengue virus medicinal preparation which contains 5, 6-dehydrourogalactone with effective treatment amount and also contains pharmaceutic adjuvant or other compatible medicaments.
The pharmaceutical adjuvant refers to conventional pharmaceutical excipient, such as one or two of solvent, disintegrant, correctant, antiseptic, colorant and binder.
The other compatible medicines are prepared by taking 5, 6-dehydrouromycolone with effective dose as a medicine raw material and then adding other natural medicines or chemicals with anti-inflammatory, immune enhancement or antiviral activities.
Wherein the anti-inflammatory drug is selected from: (1) acetylsalicylates including aspirin and the like; (2) non-acetylsalicylate including magnesium salicylate, sodium salicylate, choline magnesium salicylate, diflunisal (diflunisal), salsalate; (3) non-salicylates including ibuprofen, indomethacin (indomethacin), flurbiprofen, phenoxyibuprofen, naproxen, nabumetone (naproxone), piroxicam (piroxicam), phenylbutazone, diclofenac, fenprofen, ketoprofen, ketorolac, tetrachlorofenamic acid, sulindac, tolmetin, and the like.
The immune enhancing drug is selected from: levamisole (LMS), interleukin 2 (cell growth factor, t cell growth factor, TCGF), Interferon (IFN), transfer factor (TF factor, TF), thymosin (thymosin), cyclosporine (cyclosporine, cyclosporine a), and extracts from ginseng, astragalus, schisandra, wolfberry, codonopsis pilosula, cordyceps sinensis, ganoderma lucidum and tremella, etc.
The antiviral active agent is selected from: (1) non-ring-opening nucleosides including Zidovudine (Zidovudine), Stavudine (Stavudine), Lamivudine (Lamivudine), Zalcitabine (Zalcitabine), and the like; (2) open-ring nucleosides including acyclovir (Aciclovir), Ganciclovir (Ganciclovir), Penciclovir (Penciclovir), Famciclovir (Famcclovir), Adefovir Dipivoxil (Adefovir Dipivoxil); (3) non-nucleosides including Nevirapine (Nevirapine), Efavirenz (Efavirenz); (4) protease inhibitors including Saquinavir (Saquinavir), Indinavir (Indinavir), Nelfinavir (Nelfinavir); (4) other types, including Ribavirin (Ribavirin), Amantadine Hydrochloride (Hydrochloride), Rimantadine Hydrochloride (Hydrochloride), foscarnet sodium, and Oseltamivir Phosphate (Oseltamivir Phosphate), among others.
The dengue virus resistant pharmaceutical preparation comprises a plurality of clinical pharmaceutical formulations, such as capsules, granules, tablets, injections, liposome nanoparticles, sustained release agents, controlled release agents or dispersible tablets and the like.
It is another object of the present invention to provide a pharmaceutical composition.
The pharmaceutical composition contains 5, 6-dehydrourogalactone, pharmaceutically acceptable salts thereof or solvates thereof as an active ingredient, and a pharmaceutically acceptable carrier, excipient or diluent.
The medicinal excipient comprises one or more of solvent, disintegrant, correctant, antiseptic, colorant and binder.
Compared with the prior art, the invention has the following advantages and technical effects:
the 5, 6-dehydrouromycolactinone has strong in-vitro anti-dengue virus activity, is obviously superior to a positive medicament ribavirin, and has good medicinal prospect.
Drawings
FIG. 1 shows that 5, 6-dehydrourogalactone has no toxicity to BHK-21 cells at 20. mu.M concentration, as measured by MTT method.
FIG. 2 is a microscopic (40-fold) observation of the pathological effect of cells, showing that 5, 6-dehydrourogalactone inhibits dengue virus type 2 induced cytopathic effect.
FIG. 3 is a diagram of the CCK8 method for detecting cell death, which shows that 5, 6-dehydrourogalactone can inhibit dengue virus type 2 induced cell death.
FIG. 4 shows the expression level of virus RNA detected by real-time fluorescent quantitative PCR method, and shows that 5, 6-dehydrourogalactone can inhibit the synthesis of virus RNA induced by dengue virus type 2.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
The 5, 6-dehydrourogalactanone used in the examples of the present invention was prepared by separating from Eurycoma longifolia (certified by medical college of Jinnan university), the structure of the 5, 6-dehydrourogalactanone was identified by spectroscopic methods such as UV, MS, NMR, etc., and the purity was more than 98% by HPLC-DAD peak area normalization.
According to the invention, a cell model infected by the type 2 dengue virus is adopted, and the influence of 5, 6-dehydrourogalactone on type 2 dengue virus induced cytopathic effect, death and virus RNA synthesis is evaluated.
Example 15 toxicity of 6, 6-dehydrourogalactone to BHK-21 cells
Test method BHK-21 cells in logarithmic growth phase were taken at 1X 105The cell density of each/mL is inoculated in a 96-well plate, each well is 100 mu L, a control group and a drug group with different concentrations are arranged, and the cytotoxicity is detected by adopting an MTT method after 4 days.
The test results in fig. 1 show that: the half inhibitory concentration of 5, 6-dehydrourogalactone on BHK-21 cells was 37.63. mu.M, and there was substantially no toxicity to cells at a concentration of 20. mu.M.
Example 25 inhibitory Effect of 6-dehydrourogalactone on dengue virus type 2 induced cytopathic Effect
Test method BHK-21 cells in logarithmic growth phase were taken at 1X 105Cells were seeded at a density of 2 mL/mL in 6-well plates and infected with 200 PFU type 2 dengue virus (DENV-2) for 1 h, treated with 5, 6-dehydrourogalactone (EL-2, 2.5, 5, 10. mu.M) or 20. mu.M Ribavirin (RV), and the cytopathic effect was observed under a microscope and photographed 4 d later.
Figure 2 the test results show: 5, 6-dehydrourogalactone dose-dependently inhibited dengue virus type 2-induced cytopathic effects.
Example 35 inhibition of dengue virus type 2 induced cell death by 6, 6-dehydrourogalactanone
Test method BHK-21 cells in logarithmic growth phase were taken at 1X 105The cells are inoculated in a 96-well plate at the cell density of 100 mu L per well, and after being infected with 200 PFU 2 type dengue virus for 1 h, 5, 6-dehydrourogalactone (0.625-20 mu M) or 20 mu M RV is given for treatment, and after 4 d, the cell death condition is detected by a CCK8 method.
FIG. 3 shows the results of the test: 5, 6-dehydrourogalactone was effective in inhibiting dengue virus type 2 induced cell death at a half effective concentration of 4.67. mu.M.
Example 45 inhibition of viral RNA Synthesis induced by dengue virus type 2 by 6-dehydrourogalactanone
Test method BHK-21 cells in logarithmic growth phase were taken at 1X 105The cells are inoculated in a 6-well plate at the cell density of 2 mL per well, and after being infected with 200 PFU 2 type dengue virus for 1 h, 5, 6-dehydrouromycolactone (2.5, 5 and 10 mu M) or 20 mu M RV is given for treatment, and after 2 d, the expression conditions of virus E protein and NS1 protein are detected by a real-time fluorescent quantitative PCR method.
Fig. 4 shows the test results: 5, 6-dehydrourogalactone has obvious inhibiting effect on RNA synthesis of virus E protein and NS1 protein induced by type 2 dengue virus.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (6)
- Use of 5, 6-dehydrourogalactone in the preparation of a medicament for resisting dengue virus.
- 2. The use according to claim 1, wherein the medicament comprises a therapeutically effective amount of 5, 6-dehydrourogalactone and pharmaceutically acceptable excipients.
- 3. The use according to claim 2, wherein the pharmaceutical formulation further comprises a drug compatible with 5, 6-dehydrourogalactone.
- 4. The use according to claim 1, wherein the anti-dengue virus drugs are all formulated as capsules, granules, tablets, injections, liposomal nanoparticles, sustained release agents, controlled release agents or dispersible tablets.
- 5. A pharmaceutical composition characterized by containing 5, 6-dehydrourogalactone, a pharmaceutically acceptable salt thereof, or a solvate of either thereof according to claim 1 as an active ingredient, together with a pharmaceutically acceptable carrier, excipient, or diluent.
- 6. The composition of claim 5, wherein the pharmaceutically acceptable excipient comprises one or a combination of two or more of a solvent, a disintegrant, a flavoring agent, a preservative, a coloring agent, and a binder.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106999522A (en) * | 2014-09-04 | 2017-08-01 | 马来西亚热带生物有限公司 | Eurycoma longifolia extract product and its for strengthen and/or stimulating immune system purposes |
| CN109479881A (en) * | 2018-11-09 | 2019-03-19 | 广东省农业科学院果树研究所 | 6 α-hydroxyeurycomalactone are in insect antifeedant activity and inhibit the application developed |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106999522A (en) * | 2014-09-04 | 2017-08-01 | 马来西亚热带生物有限公司 | Eurycoma longifolia extract product and its for strengthen and/or stimulating immune system purposes |
| CN109479881A (en) * | 2018-11-09 | 2019-03-19 | 广东省农业科学院果树研究所 | 6 α-hydroxyeurycomalactone are in insect antifeedant activity and inhibit the application developed |
Non-Patent Citations (1)
| Title |
|---|
| KATSUNORI MIYAKE ET AL: ""Cytotoxic Activity of Quassinoids from Eurycoma longifolia"", 《NATURAL PRODUCT COMMUNICATIONS》, vol. 5, no. 7, pages 1009 - 1012 * |
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