CN113975267B - Application of 6 alpha-hydroxyeyeurycommactone in preparation of anti-dengue virus drugs - Google Patents
Application of 6 alpha-hydroxyeyeurycommactone in preparation of anti-dengue virus drugs Download PDFInfo
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- CN113975267B CN113975267B CN202111249591.2A CN202111249591A CN113975267B CN 113975267 B CN113975267 B CN 113975267B CN 202111249591 A CN202111249591 A CN 202111249591A CN 113975267 B CN113975267 B CN 113975267B
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- 238000011144 upstream manufacturing Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a picrasma quassioides bitter compound 6 alpha-hydroxyeyeurycoma alactone:
Description
Technical Field
The invention relates to application of a quassia bitter compound 6 alpha-hydroxyeurycoma actanone in preparation of an anti-dengue virus preparation, belonging to the technical field of pharmaceutical chemistry antiviral.
Background
6 alpha-hydroxyeyuromolactanone belongs to the picrin class of compounds which are characteristic components of the quassiaceae plant. Studies have shown that picrin compounds are capable of significantly inhibiting replication of a variety of viruses, such as human immunodeficiency virus, human herpesvirus and tobacco mosaic virus (Bioorganic & Medicinal ChemLett, 1996:701-706;Bull Chem Soc Jpn,1999,72 (4): 751-756; JAGricFoodchem,2010,58 (3): 1572-1577), but no pharmacological effect study of such compounds has been reported so far.
6 alpha-hydroxyeyuromolactanone belongs to the picrin class of compounds which are characteristic components of the quassiaceae plant. Studies have shown that picrin compounds are capable of significantly inhibiting replication of a variety of viruses, such as human immunodeficiency virus, human herpesvirus and tobacco mosaic virus (Bioorganic & Medicinal Chem Lett,1996,6:701-706;Bull Chem Soc Jpn,1999,72 (4): 751-756;J Agric Food Chem,2010,58 (3): 1572-1577), but no pharmacological effect studies on dengue viruses have been reported so far for such compounds.
However, there is a lack of specific antiviral drugs against dengue virus in clinic at present, and due to the characteristics of more virus serotypes, antibody dependence enhancement (anti-dependent enhancement, ADE) and the like, stable and effective vaccines against DENV are difficult to obtain, and dengue fever can only be mainly improved by symptoms such as fever, hemorrhage and the like, which brings great impediment to clinical treatment of dengue fever. Therefore, the discovery of active molecules against dengue virus is of great biological research and practical significance.
Disclosure of Invention
In order to solve the technical problems, one of the purposes of the invention is to provide the application of 6 alpha-hydroxyeylyuromamactone in preparing the drugs for resisting dengue viruses, and the invention discovers that 6 alpha-hydroxyeylyuromamactone has antiviral effect through in vitro experiments and can obviously inhibit replication of dengue viruses.
The anti-dengue virus drug preparation comprises a therapeutically effective amount of 6α -hydroxyeyeurycommalone, and also comprises pharmaceutical excipients or other compatible drugs.
The pharmaceutical excipients refer to one or two of the combination of the conventional pharmaceutical excipients, such as solvents, disintegrants, flavoring agents, preservatives, coloring agents and adhesives.
The other compatible medicines refer to that 6 alpha-hydroxyurea with effective dose is taken as a medicine raw material, and other natural medicines or chemicals with anti-inflammatory, immunity enhancing or antiviral activities are matched.
Wherein the anti-inflammatory drug is selected from the group consisting of: (1), acetylsalicylates, including aspirin and the like; (2) Non-acetylsalicylates, including magnesium salicylate, sodium salicylate, choline magnesium salicylate, diflunisal (diflunisal), bissalicylate; (3) Non-salicylates, including ibuprofen, indomethacin (indomethacin), flurbiprofen, phenoxyibuprofen, naproxen, nabumetone (naproxen), piroxicam (piroxicam), phenylbutazone, diclofenac, fenprofen, ketoprofen, ketorolac, tetrachlorofenamic acid, sulindac, tolmetin, and the like.
The immunopotentiator is selected from the group consisting of: levamisole (LMS), interleukin 2 (cell growth factor, t cell growth factor, TCGF), interferon (IFN), transfer factor factor, TF, thymosin (thymosin), aminocyclosporin (cycliosporin a), extracts from ginseng, astragalus, schisandra, wolfberry, codonopsis pilosula, cordyceps, ganoderma lucidum and tremella, and the like.
The antiviral active drug is selected from: (1) Non-ring-opening nucleosides, including Zidovudine (Zidovudine), stavudine (Stavudine), lamivudine (Lamivudine), zalcitabine (Zalcitabine), and the like; (2) Ring-opened nucleosides, including acyclovir (Aciclovir), ganciclovir (Ganciclovir), penciclovir (Penciclovir), famciclovir, 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 (Amantadine Hydrochloride), rimantadine hydrochloride (Rimantadine Hydrochloride), sodium phosphonoformate, oseltamivir phosphate (Oseltamivir Phosphate), and the like.
The dengue virus resistant pharmaceutical preparation comprises a plurality of clinical pharmaceutical dosage forms, such as capsules, granules, tablets, injections, liposome nanoparticles, sustained release agents, controlled release agents or dispersible tablets, and the like.
It is a further object of the present invention to provide a pharmaceutical composition.
Specifically, the pharmaceutical composition refers to a composition containing 6α -hydroxyeurycommalone, pharmaceutically acceptable salt thereof or solvate thereof as an active ingredient, and a pharmaceutically acceptable carrier, excipient or diluent.
The medicinal excipient comprises one or more than two of solvent, disintegrating agent, correctant, antiseptic, colorant and binder.
Compared with the prior art, the invention has the following advantages and technical effects:
the 6 alpha-hydroxyeurycommalone of the invention has strong in-vitro anti-dengue virus activity, is obviously superior to positive drug ribavirin, and indicates that the compound has good medicinal prospect.
Drawings
FIG. 1 is a graph showing the toxicity of various doses of 6α -hydroxyuromycomalone to BHK-21 cells;
FIG. 2 is a graph showing the result of inhibition of BHK-21 cells infected with DENV-2 by 6α -hydroxyuromycomalone to induce cytopathy;
FIG. 3 is a graph showing the results of inhibition of BHK-21 cell death induced by 6α -hydroxyuromycomactone following DENV-2 infection;
FIG. 4 is a graph showing the result of inhibition of viral RNA synthesis by 6α -hydroxyuromycomactone after infection of BHK-21 cells with DENV-2.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but embodiments of the present invention are not limited thereto.
The 6 alpha-hydroxyeurycommalone used in the embodiment of the invention is prepared by separation from plant Eurya longifolia (authenticated by university of south medical college), the structure is identified by a UV, MS, NMR and other spectral methods, and the purity is more than 98 percent measured by an HPLC-DAD peak area normalization method.
The invention adopts a DENV-2 infected cell model to evaluate the influence of 6 alpha-hydroxyeurycommalone on DENV-2 induced cytopathy, death and viral RNA synthesis.
EXAMPLE 1 6 toxicity of alpha-hydroxyeurycommactone on BHK-21 cells
Experimental method
1. Taking BHK-21 cells in logarithmic growth phase at 1×10 5 Cell density of each/mL was inoculated in 96-well plates and cultured at 37℃for 24 hours.
2. A control group and a drug group with different concentrations were set, and a maintenance solution (2% serum) containing the drug with the corresponding concentration was added to the mixture, and the mixture was incubated at 37℃for 4 d.
3. mu.L of MTT solution (5 mg/ml) was added to each well and incubation was continued at 37℃for 4h. After 4. 4h, the medium in the wells was discarded and 150. Mu.L of dimethyl sulfoxide was added to each well. The absorbance of each well was measured at the microplate reader OD 490 nm.
The test results in fig. 1 show that: the half-inhibitory concentration of 6α -hydroxyuromamactone on BHK-21 cells was μM, and was not substantially toxic to cells at a concentration of 1 μM.
Example 26 inhibition of type II dengue virus induced cytopathy by alpha-hydroxyeurycomatoctone
Experimental method
1. Taking BHK-21 cells in logarithmic growth phase at 1×10 5 Cell density of each mL was inoculated in 6-well plate and cultured at 37℃for 24 hours.
2. The supernatant was aspirated, washed 2-3 times with PBS, infected with 1 mL of 200 PFU/mL DENV-2 virus, and incubated at 37℃for 1 h.
3. The virus solution is sucked, washed for 2 to 3 times by PBS, added with 2 mL of maintenance solution containing 6α -hydroxyeurycommalone (EL-1,0.25, 0.5, 1 μM) or 20 μM Ribavirin (RV), and incubated for 4 to 5 days at 37 ℃.
4. The cytopathic effect of each well was observed under a microscope and recorded by photographing.
The test results in fig. 2 show that: 6 alpha-hydroxyeurycommactone is capable of dose-dependently inhibiting DENV-2 induced cytopathy.
Example 3 6 inhibition of type II dengue virus induced cell death by alpha-hydroxyeurycommactone
Experimental method
1. Taking BHK-21 cells in logarithmic growth phase at 1×10 5 Cell density of each/mL was inoculated in 96-well plates and cultured at 37℃for 24 hours.
2. The supernatant was aspirated, washed 2-3 times with PBS, and infected with 100. Mu.L of 200 PFU/mL DENV-2 virus, and incubated at 37℃for 1 h.
3. The virus solution is sucked out, PBS is used for cleaning for 2 to 3 times, 200 mu L of maintenance solution containing 6 alpha-hydroxyeurycommalone (0.625 to 20 mu M) or 20 mu M Ribavirin (RV) is added, and the mixture is incubated for 4 to 5 days at 37 ℃.
4. mu.L of CCK-8 solution (Biyun Biotechnology Co., shanghai) was added to each well and incubation was continued for 30 min at 37 ℃. The absorbance of each well was measured at the microplate reader OD 450 nm to detect cell death.
The test results in fig. 3 show that: 6. Alpha. -hydroxyeurycommactone is effective in inhibiting DENV-induced cell death at a half-effective concentration of 0.39.+ -. 0.02. Mu.M.
Example 4 6 inhibition of type II dengue virus-induced viral RNA synthesis by alpha-hydroxyeurycommactone
The experimental method comprises the following steps:
1. taking BHK-21 cells in logarithmic growth phase at 1×10 5 Cell density of each mL was inoculated in 6-well plate and cultured at 37℃for 24 hours.
2. The supernatant was aspirated, washed 2-3 times with PBS, infected with 1 mL of 200 PFU/mL DENV-2 virus, and incubated at 37℃for 1 h.
3. The virus solution was aspirated, washed 2 to 3 times with PBS, and added with 2 mL maintenance solution containing 6α -hydroxyeurycommalone (EL-1,0.25, 0.5, 1 μM) or 20 μM Ribavirin (RV), and incubated at 37℃for 48 h.
4. Collecting cell total RNA: 1 mL RNAios reagent (Takara, japan) was added to each well, and after 5 minutes at room temperature, the supernatant was aspirated into a 1.5mL EP tube. Adding 0.2. 0.2 mL chloroform into each tube, sufficiently shaking and uniformly mixing, incubating for 15min at room temperature, centrifuging at 12000rpm at 4 ℃, sucking the upper liquid phase, transferring into another 1.5mL EP tube, adding 0.5mL isopropanol, shaking, incubating for 10min at room temperature, and centrifuging at 12000rpm at 4 ℃ for 15min. The supernatant was removed by pipetting, adding 75% ethanol 1 mL, washing the pellet, centrifuging at 12000rpm at 4℃for 15min and removing the supernatant. The precipitate was dried at room temperature for several minutes, and an appropriate amount of RNase-free water was added to dissolve the precipitate. The ultraviolet spectrophotometer detects the absorbance ratio of 260/280, and calculates the concentration of RNA.
5. Reverse transcription: the reaction system: RNA 500 ng, 5X PrimeScript RT Master Mix (TAKARA, japan) 2. Mu.L, ddH 2 O was made up to a total volume of 10. Mu.L. And (3) after the uniform mixing point is separated, the mixture is sent to a PCR instrument, and the program is set at 37 ℃ for 15min and 85 ℃ for 5 s.
6. Real-time fluorescent quantitative PCR detects RNA levels of viral envelope protein (E) and nonstructural protein 1 (Non-structural protein 1, ns 1): cDNA template 1. Mu.L, qPCR Master Mix (DBI Bioscience, germany) 5. Mu.L, upstream and downstream primers 0.4. Mu.L, probe 0.2. Mu.L, ddH 2 O was added to the total volume to 10. Mu.L to constitute the reaction system. And (3) after mixing and separating, carrying out PCR amplification by a qPCR instrument by a two-step method, wherein the specific program is set as follows: pre-denaturation at 95℃for 2min, PCR reaction at 95℃for 10 s,60℃for 30 s for 40 cycles.
7. And (3) calculating: RNA copy numbers of the samples were calculated from the Cq values of the samples in combination with a standard curve.
The test results of fig. 4 show that: 6 alpha-hydroxyeurycommactone has obvious inhibition effect on RNA synthesis of virus E protein and NS1 protein induced by DENV-2.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (3)
- Use of 6α -hydroxyuromamactone as sole active ingredient for the preparation of a medicament for the treatment of dengue virus.
- 2. The use according to claim 1, wherein the medicament comprises a therapeutically effective amount of 6α -hydroxyeurycommalone and pharmaceutically acceptable excipients.
- 3. The use according to claim 1, wherein the anti-dengue virus drug is selected from the group consisting of capsules, granules, tablets, injections.
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| 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 |
| CN110612981A (en) * | 2019-10-18 | 2019-12-27 | 广东省农业科学院果树研究所 | Application of quassin compounds in killing ants |
| CN112136824A (en) * | 2020-10-14 | 2020-12-29 | 广东省农业科学院果树研究所 | Application of quassin compounds in preventing and treating plant fungal diseases |
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| 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 |
| CN110612981A (en) * | 2019-10-18 | 2019-12-27 | 广东省农业科学院果树研究所 | Application of quassin compounds in killing ants |
| CN112136824A (en) * | 2020-10-14 | 2020-12-29 | 广东省农业科学院果树研究所 | Application of quassin compounds in preventing and treating plant fungal diseases |
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