WO2023239175A1 - Composition for preventing or treating alphaherpesvirus, gammaherpesvirus or norovirus infectious disease comprising extract of tsuga sieboldii, potentilla discolor bunge, potentilla nivea l., hydrocotyle yabei makino, or anthriscus sylvestris - Google Patents
Composition for preventing or treating alphaherpesvirus, gammaherpesvirus or norovirus infectious disease comprising extract of tsuga sieboldii, potentilla discolor bunge, potentilla nivea l., hydrocotyle yabei makino, or anthriscus sylvestris Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K10/00—Animal feeding-stuffs
- A23K10/30—Animal feeding-stuffs from material of plant origin, e.g. roots, seeds or hay; from material of fungal origin, e.g. mushrooms
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- 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
- A61K36/13—Coniferophyta (gymnosperms)
- A61K36/15—Pinaceae (Pine family), e.g. pine or cedar
-
- 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)
- A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
-
- 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)
- A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
-
- 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
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
Definitions
- the present invention relates to a natural product extract that exhibits antiviral activity against gammaherpesvirus, alphaherpesvirus, or norovirus.
- a composition for treating or preventing diseases caused by gammaherpes virus infection comprising extracts of hemlock, hemlock, chinensis, or Jeju capsicum;
- a composition for treating or preventing diseases caused by alphaherpesvirus infection comprising extracts of Euphorbia chinensis, Euphorbia chinensis, or Jeonho;
- it relates to a composition for treating or preventing diseases caused by norovirus infection, comprising extracts of Euphorbia chinensis or Euphorbia chinensis.
- Viruses are microorganisms that cannot replicate on their own, and thousands of types of viruses currently exist on Earth. Some of these viruses infect humans, and these viral infections are currently on the rise worldwide due to global warming and globalization.
- Herpesviridae is an enveloped virus with a relatively large and complex structure whose viral genome is double-stranded DNA of 120 to 230 kbp in size.
- the above virus family has evolved to be able to infect the host throughout its life by evading the host's immune system and forming a latent infection in addition to lytic infection, in which progeny viruses replicate, and alpha according to differences in biological characteristics. It is classified into three groups: Alpha herpesvirinae , Beta herpesvirinae , and Gamma herpesvirinae .
- herpes viruses have a high infection rate of over 70-90% in Korea. Once infected, they form a latent infection in the human body and are chronic viruses that remain infectious throughout life by repeating latent infection and reactivation in the host, affecting immune function. They are representative opportunistic infection pathogens that cause various diseases through reactivation or congenital infection due to degradation and have a fatal infection prognosis depending on the patient's immune status. Control of reactivated herpes virus infections due to decreased immunity, such as the increase in organ transplants and hematopoietic stem cell transplants and human immunodeficiency virus (HIV-1) infections, is becoming an important issue. The decline in immunity of the elderly population due to persistent infections is acting as an important health and socioeconomic burden in countries that are entering aging societies at the fastest rate.
- HIV-1 human immunodeficiency virus
- Herpes simplex virus I Herpes simplex virus II
- HSV-II Herpes simplex virus II
- VZV Varicella zoster virus
- HCMV Human cytomegalovirus
- Human herpesvirus 6 Human herpesvirus 7, Epstein-barr virus (EBV), and Kaposi's sarcoma-associated herpesvirus (KSHV), of which Epstein-Barr virus (EBV) and Kaposi's sarcoma herpesvirus (KSHV) belong to gammaherpesviruses.
- ESV Epstein-barr virus
- KSHV Kaposi's sarcoma-associated herpesvirus
- EBV Epstein-Barr virus
- KSHV Kaposi's sarcoma herpesvirus
- gammaherpesvirus has distinct cell tropism and has the characteristic of causing persistent infection in the host through latency in lymphocytes. It causes benign or malignant tumors in infected hosts, affecting 90% of the world's population.
- EBV causes Burkitt's lymphoma, gastric carcinoma, nasopharyngeal carcinoma, post-transplant B cell lymphomas, and Hodgkin's lymphoma
- KSHV contributes to the formation of tumors such as Hodgkin's disease
- KSHV is the cause of Kaposi's sarcoma, primary effusion lymphoma, and multicentric castleman's disease.
- Herpes simplex virus-1 (HSV-1), a type 1 human infectious herpes virus, is an alphaherpesvirus that forms a latent infection in the nervous system. It continues to infect the host for life and is reactivated and proliferates due to decreased immunity, etc., infecting the skin and skin. Herpes that appears around the mouth, lips, eyes, or genitals can cause herpes simplex, cold sores, stomatitis, and herpes simplex keratitis, as well as meningitis and encephalitis. In newborns, it can cause fatal encephalitis.
- VZV Varicella-Zoster virus
- Varicella a type 3 human infectious herpesvirus
- DRG dorsal root ganglia
- shingles which causes extreme pain.
- Reactivation of VZV causes shingles that occurs in the chest, optic ganglion, and facial nerve areas, and can also cause herpes zoster (zoster sine herpete), which causes abnormal skin sensation or radiating pain even without skin herpes.
- PPN postherpetic neuralgia
- PZV postherpetic neuralgia
- 'Postherpetic neuralgia (PHN)' the most common complication after shingles caused by reactivated VZV, causes varying degrees of pain for each patient, and usually occurs when pain persists for at least 4 months or more after the rash. It is classified as posterior neuralgia. This chronic pain causes not only physical pain but also psychological anxiety, depression, and insomnia in patients, which has a significant negative impact on the patient's quality of life. Therefore, rapid control of VZV reactivation and infection is very important. It is important.
- Human norovirus is a norovirus belonging to the Caliciviridae family that has positive single-stranded RNA as its genome, and accounts for the highest percentage of non-bacterial gastroenteritis, the main cause of enteritis in winter worldwide. Human norovirus enters the environment through the feces or aerosolized vomit of infected patients, and is contracted by consuming food or drinking water contaminated with the virus. There are reports that shedding of human norovirus can be observed for up to eight weeks even after symptoms such as diarrhea have stopped. In addition, since infection is possible with less than 100 virus particles, it is highly contagious, and a small amount of virus contamination can cause widespread mass enteritis, making it an important pathogen that must be controlled to improve public health. In particular, prevention and treatment for norovirus is urgent because it is easy to spread in facilities where many immunocompromised people live together, such as nursing homes, and symptoms can worsen to severe cases.
- MNVs Murine noroviruses
- MNV-1 mouse norovirus
- feline calicivirus 9 (FCV-9), which belongs to the caliciviridae family, was once accepted as an alternative virus to human norovirus, but after the discovery of mouse norovirus, the transmission route and pathogenic characteristics changed. It is not used because it is different. While human norovirus and mouse norovirus are transmitted through feces through gastrointestinal infection, feline calicivirus is a virus transmitted through respiratory infection and has many different properties, so mouse norovirus is accepted as a more appropriate alternative virus system. .
- the present inventors studied the effect of natural products on virus activity and completed the present invention by developing natural product extracts that can effectively inhibit infection by norovirus, alphaherpesvirus, and gammaherpesvirus.
- the purpose of the present invention is to provide a composition with antiviral activity containing extracts of hemlock, hemlock, euphorbia, or Jeju mantle as an active ingredient, which can treat or prevent diseases caused by gammaherpesvirus infection.
- the purpose of the present invention is to provide a composition with antiviral activity containing extracts of Euphorbia or Euphorbia as an active ingredient, which can prevent or treat diseases caused by norovirus infection.
- the purpose of the present invention is to provide a composition with antiviral activity containing as an active ingredient extracts of Euphorbia chinensis, Euphorbia chinensis, or Jeonho chinensis, which can prevent or treat diseases caused by alphaherpesvirus infection.
- the present invention provides a composition containing extracts of hemlock, hemlock, euphorbia, or Jeju mantle.
- the composition may be a pharmaceutical composition, food composition, or animal feed composition.
- the composition may be used to prevent, treat, or improve gammaherpes virus infectious disease.
- the composition may be for preventing, treating, or improving Kaposi's sarcoma herpes virus infectious disease.
- the composition is capable of reducing the expression of the lytic protein of Kaposi's sarcoma herpes virus.
- the infectious disease may be one or more diseases selected from the group consisting of Kaposi's sarcoma, primary exudative lymphoma, and multicentric Castleman's disease.
- the composition may be for preventing, treating, or ameliorating Epstein-Barr virus infectious disease.
- the composition is capable of reducing expression of the lytic protein of Epstein Barr virus.
- the infectious disease may be one or more diseases selected from the group consisting of Burkitt's lymphoma, gastric carcinoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, and post-transplant B cell lymphoma.
- the present invention provides a pharmaceutical composition for the prevention or treatment of norovirus infectious diseases, comprising as an active ingredient one or more extracts selected from the group consisting of Prickly pear and Prickly pear extracts.
- the pharmaceutical composition may include one or more extracts selected from the group consisting of Lilium vulgaris and Lilium vulgaris extracts, or may include an extract extracted from a mixture selected from the group consisting of Lilium vulgaris and Lilium vulgaris extracts.
- the norovirus may be a human norovirus.
- the norovirus infectious disease may be non-bacterial gastroenteritis.
- the Euphorbia chinensis extract may be fractionated with one or more solvents selected from the group consisting of hexane, chloroform, butanol, ethyl acetate, and water.
- the Euphorbia chinensis extract may be a hexane fraction or a chloroform fraction.
- the present invention provides a food composition for preventing or improving norovirus infectious diseases, comprising as an active ingredient one or more extracts selected from the group consisting of Prickly pear and Prickly pear extracts.
- the norovirus infectious disease may be non-bacterial gastroenteritis.
- the present invention provides a feed composition for animals for preventing or ameliorating norovirus infectious diseases, comprising as an active ingredient one or more extracts selected from the group consisting of Prickly pear and Prickly pear extracts.
- the norovirus infectious disease may be non-bacterial gastroenteritis.
- the present invention provides a pharmaceutical composition for the prevention or treatment of alphaherpesvirus infectious diseases, comprising as an active ingredient one or more extracts selected from the group consisting of Euphorbia chinensis, Euphorbia chinensis and Jeonho extract.
- the pharmaceutical composition comprises one or more extracts selected from the group consisting of extracts of Corolla, Corolla, and Corolla extracts, or comprises an extract extracted from a mixture selected from the group consisting of extracts of Corolla, Corolla, and Corolla extracts. can do.
- the alphaherpesvirus may be herpes simplex virus or varicella-zoster virus.
- the herpes simplex virus infectious disease may be one or more diseases selected from the group consisting of herpes simplex, cold sores, stomatitis, meningitis, and encephalitis.
- the varicella-zoster virus infectious disease may be one or more diseases selected from the group consisting of varicella-zoster virus shingles and Zoster Sine Herpete.
- the Euphorbia chinensis extract may be fractionated with one or more solvents selected from the group consisting of hexane, chloroform, butanol, ethyl acetate, and water.
- the Euphorbia chinensis extract may be a hexane fraction or a chloroform fraction, and preferably may be a hexane fraction.
- the present invention provides a food composition for preventing or ameliorating alphaherpesvirus infectious disease, comprising as an active ingredient one or more extracts selected from the group consisting of Euphorbia flower, Euphorbia chinensis and Jeonho extract.
- the alphaherpesvirus may be herpes simplex virus or varicella-zoster virus.
- the present invention provides a feed composition for animals for preventing or ameliorating alphaherpesvirus infection disease, which contains as an active ingredient one or more extracts selected from the group consisting of Euphorbia chinensis, Euphorbia chinensis and Jeonho extract.
- the alphaherpesvirus may be herpes simplex virus or varicella-zoster virus.
- a composition containing extracts of Hemlock, Hemlock, Euphorbia, or Jeju mantle according to the present invention has an antiviral effect against KSHV and EBV. Therefore, the composition of the present invention can treat or prevent diseases caused by gammaherpesvirus infection.
- the Prickly pear and Prickly pear extracts of the present invention have an excellent effect of inducing inhibition of the proliferation of norovirus. Accordingly, the extracts of Prickly pear and Prickly pear of the present invention can be used for the prevention or treatment of norovirus infectious diseases.
- the extracts of the present invention such as euphorbia vulgaris, euphorbia vulgaris, and jeonho, have an excellent effect of inducing inhibition of the proliferation of alphaherpesvirus. Therefore, the composition of the present invention can be used for the prevention or treatment of alphaherpesvirus infectious diseases.
- Figure 1 shows the level of GFP expression when 86 natural product-derived mixtures were treated with the BC-3-G cell line.
- Figure 2 shows the level of GFP expression when 86 natural product-derived mixtures were treated with the BC-3-G cell line, with the negative control group designated as 0.
- Figure 3 shows GFP positive cells in flow cytometry when BC-3-G cell line was treated with six types of natural product-derived mixtures.
- Figure 4 shows the expression levels of RTA and K8 when BC-3-G cell line was treated with six types of natural product-derived mixtures.
- Figure 5 shows the expression levels of RTA and K8 when BC-3 cell line was treated with three mixtures derived from natural products at different concentrations.
- Figure 6 shows the expression levels of RTA and K8 when BC-3-G cell line was treated with three mixtures derived from natural products at different concentrations.
- Figure 7 shows the expression levels of RTA and K8 when BCBL-1 cell line was treated with three mixtures derived from natural products at different concentrations.
- Figure 8 shows the expression level of ZTA when Raji cell line was treated with six types of natural product-derived mixtures.
- Figure 9 shows the expression levels of EA-D and ZTA when Akata (+) cell line was treated with three types of natural product-derived mixtures.
- Figure 10 shows the expression levels of EA-D and ZTA when the Akata (+) cell line was treated with three mixtures derived from natural products at different concentrations.
- Figure 11 shows the expression levels of RTA and K8 when nine types of natural product extracts were treated with BC-3-G cell line.
- Figure 12 shows the expression levels of RTA and K8 when nine types of natural product extracts were treated with the BCBL-1 cell line.
- Figure 13 shows the expression levels of EA-D and ZTA when nine types of natural product extracts were treated with Raji cell line.
- Figure 14 shows the expression levels of EA-D and ZTA when nine types of natural product extracts were treated with Akata(+) cell line.
- Figure 15 is a schematic diagram showing the process of evaluating antiviral efficacy against norovirus.
- Figure 16 is a photograph and a graph showing the results of evaluating the antiviral efficacy of extracts of Euphorbia and Euphorbicus flowers against norovirus.
- Figure 17 is a photograph and a graph showing the results of evaluating the antiviral efficacy of five types of noroviruses from the extracts and fractions of Somnambula flower.
- Figure 18 is a schematic diagram showing the process of evaluating antiviral efficacy against alphaherpesvirus.
- Figure 19 is a photograph and graph showing the results of evaluating the antiviral efficacy of extracts of Lithuanian lily and Lithuanian lily against HSV-1 alphaherpesvirus.
- Figure 20 is a photograph and graph showing the change in plaque size in the evaluation of the antiviral efficacy of extracts of Lilium vulgaris and Lilium vulgaris against HSV-1 alphaherpesvirus.
- Figure 21 is a photograph and graph showing the results of evaluating the antiviral efficacy of Jeonho extract against HSV-1 alphaherpesvirus.
- Figure 22 is a photograph and graph showing the results of evaluating the antiviral efficacy of 5 types of HSV-1 alphaherpesvirus extracts and fractions of Sulfuria chinensis.
- Figure 23 is a photograph and a graph showing the results of evaluating the antiviral efficacy of extracts of Lithuanian vulgaris, Liquoria vulgaris, and Chrysanthemum vulgaris against VZV alphaherpesvirus.
- Figure 24 is a photograph and graph showing the change in plaque size in the evaluation of the antiviral efficacy of extracts of Prickly pear and Prickly pear extract against VZV alphaherpesvirus.
- Figure 25 is a photograph and graph showing the results of evaluating the antiviral efficacy of 5 types of extracts and fractions of Sulfuria chinensis against VZV alphaherpesvirus.
- Figure 26 is a photograph and a graph showing the results of evaluating the antiviral efficacy of two types of Prickly pear fractions against VZV alphaherpesvirus.
- Figure 27 is a photograph and graph showing the change in plaque size in the evaluation of the antiviral efficacy of the hexane fraction of Solanum vulgaris against VZV alphaherpesvirus.
- prevention refers to any action that suppresses or delays a disease, etc. by administration of the composition according to the present invention
- treatment refers to symptoms of a suspected disease or diseased individual by administration of the composition. This means any action that improves or changes to benefit.
- improvement refers to any action that results in at least a reduction in the severity of a parameter, such as a symptom, associated with the condition being treated by administration of a composition comprising an extract of the present invention.
- the hemlock tree of the present invention is Tsuga sieboldii Carriere , which belongs to the genus of Hemlock family of the Pinaceae family, is mainly distributed in Ulleungdo and Japan, and is known to be used as an ingredient in the treatment of allergic diseases.
- the cotton bellflower of the present invention is Potentilla discolor Bunge , which belongs to the Rosaceae genus and is widely distributed in Korea, Taiwan, Russia, Japan, China, etc., and is known to be used for diabetes, immune diseases, etc.
- the flower of the present invention is Potentilla nivea L. , which belongs to the Rosaceae genus and is distributed in the northern part of the Korean Peninsula, Russia, Japan, China, Europe, North America, etc.
- the Jeju marigold of the present invention is Hydrocotyle yabei Makino , which belongs to the genus Apiaceae and is distributed in Jeju Island and Japan.
- the general name of the present invention is Anthriscus sylvestris , which belongs to the genus Apiaceae and is distributed in Europe, Asia, Africa, etc.
- non-virus used in the present invention refers to a virus belonging to the Caliciviridae and Norovirus genus, which has positive single-stranded RNA as its genome.
- alphaherpesvirus used in the present invention refers to a virus belonging to the herpesviridae or alphaherpesvirinae subfamily.
- Epstein-Barr virus (EBV) and Kaposi's sarcoma herpesvirus (KSHV) belong to the gammaherpesviruses.
- Epstein Barr virus used in the present invention refers to the Epstein-Barr virus belonging to the Gammaherpesvirinae and Lymphocryptovirus genus, and is also referred to as "EBV”.
- Kaposi's sarcoma herpesvirus used in the present invention refers to Kaposi's sarcoma-associated herpesvirus belonging to the Gammaherpesvirinae and Rhadinovirus genus, and is also referred to as "KSHV".
- variable cella-zoster virus used in the present invention refers to Varicella-zoster virus belonging to the Alphaherpesvirinae and Varicellovirus genus, and is referred to as "VZV” or "Human herpesvirus 3" It can also happen.
- herpes simplex virus used in the present invention refers to Herpes simplex virus-1 belonging to the Alphaherpesvirinae and Simplexvirus genus, and is also referred to as “HSV-1.”
- the present inventors discovered for the first time that one or more extracts selected from the group consisting of hemlock, hemlock, euphorbia, and Jeju marigold have an antiviral effect against gammaherpesvirus. Specifically, it was found that one or more extracts selected from the group consisting of hemlock, hemlock, euphorbia, and Jeju capsicum inhibit the activity of KSHV and EBV.
- the extracts of hemlock, hemlock, euphorbia, jeju capifolia, and jeonho may be extracts of stems, fruits, roots, or leaves, but are not limited thereto.
- extract used in the present invention refers to what is commonly used in the art as a crude extract, but in a broad sense also includes fractions obtained by additional fractionation of the extract. That is, the extract includes not only those obtained using the above-mentioned solvents, but also those obtained by additionally applying a purification process. For example, fractions obtained by passing the extract through an ultrafiltration membrane with a certain molecular weight cut-off value, separation by various chromatographs (designed for separation according to size, charge, hydrophobicity, or affinity), etc. Fractions obtained through purification methods are also included in the extract of the present invention.
- the extract used in the present invention may be extracted through hot water extraction, cold needle extraction, reflux cooling extraction, ultrasonic extraction, or conventional extraction methods known in the art.
- the extract used in the present invention can be obtained using a conventional extraction solvent known in the art.
- a polar solvent or a non-polar solvent can be used.
- Polar solvents include water, C1 to C6 alcohols (e.g., methanol, ethanol, propanol, butanol, n-propanol, iso-propanol, and n-butanol, etc.), acetic acid, or mixtures of the above polar solvents.
- Nonpolar solvents include acetone, acetonitrile, ethyl acetate, methyl acetate, butyl acetate, fluoroalkane, hexane, ether, chloroform, dichloromethane, or mixtures of the above nonpolar solvents.
- the food composition of the present invention may be a health functional food, dairy product, fermented product, or food additive.
- the above health functional foods refer to foods manufactured and processed using raw materials or ingredients with functional properties useful to the human body. “Functional” refers to foods that are useful for health purposes such as regulating nutrients for the structure and function of the human body or physiological effects. It means taking it for the purpose of obtaining effects.
- the animal feed composition of the present invention can be ingested by all non-human animals, such as non-human primates, sheep, dogs, cows, horses, etc.
- Extracts of three types of natural products including Psyllium vulgaris herbaceous plant, Psyllium spp. leaf, stem, and flower, were purchased from the Korea Plant Extract Bank (Korea Research Institute of Bioscience and Biotechnology, Ochang Branch), and the extracts were prepared by dissolving 100% DMSO as a solvent.
- the BC-3-G cell line in which dsGFP (Green Fluorescent Protein) was introduced as a reporter gene into BC-3 cells latently infected with KSHV, a gammaherpesvirus, was used.
- the BC-3-G cell line has the characteristic of expressing GFP due to active infection (lytic replication) of the virus.
- a total of 86 mixture samples derived from natural products were prepared for screening, and each mixture sample consisted of three types of natural product extracts.
- a total of 258 natural product samples were distributed from the Korea Plant Extract Bank (Korea Research Institute of Bioscience and Biotechnology, Ochang Branch) and prepared at a concentration of 50 mg/ml using 100% DMSO as a solvent. Each natural product sample was divided into 3 alphabets by country name (or product name). The 86 natural product-derived mixture samples were prepared by mixing 40 ⁇ l each in a 1:1:1 ratio, and the types of natural product samples are shown in Table 1 below.
- the KSHV latently infected cells were treated with 20 ng/ml of TPA (12-O-Tetradecanoylphorbol-13-acetate), which induces reactivation of the virus, and 50 ⁇ g/ml of the mixture sample derived from the 86 natural products, and after 24 hours, the natural product Flow cytometry analysis was performed to confirm the KSHV inhibitory effect of the derived mixture sample, and the degree of KSHV reactivation was measured by analyzing the number of GFP-expressing cells among living cells.
- TPA 12-O-Tetradecanoylphorbol-13-acetate
- DMSO Dimethyl Sulfoxide
- Figure 1 shows the level of GFP expression when processing the natural product-derived mixture sample based on the negative control group treated with the BC-3-G cell line
- Figure 2 shows the degree of KSHV inhibition of 86 natural product-derived mixture samples for easy analysis.
- the level of GFP expression in the negative control group was set to 0 and was schematized.
- TPA and 10 25, and 50 respectively were added to KSHV latently infected cell lines BC-3, BC-3-G, and BCBL-1.
- a mixture sample at a concentration of ⁇ g/ml was processed, and the expression levels of lytic proteins RTA and K8 were confirmed through Western blot analysis.
- the Raji cell line was treated with TPA to induce virus reactivation, and the Akata(+) cell line was treated with IgG, and the Raji cell line and the Akata(+) cell line were treated with 50 ⁇ g/ml of each of the six natural product-derived mixtures,
- Example 2 in order to confirm whether the selected natural product-derived mixture sample was effective in suppressing EBV reactivation in a concentration-dependent manner, IgG and IgG at concentrations of 10, 25, and 50 ⁇ g/ml were applied to the Akata (+) cell line. Mixture samples No. 52, 64, and 70 were processed, and the expression levels of lytic proteins EA-D and ZTA were confirmed by Western blot analysis.
- mixture samples Nos. 52, 64, and 70 had a concentration-dependent antiviral effect against EBV.
- mixture samples 52, 64, and 70 among the mixtures derived from natural products were effective not only for KSHV but also for EBV. Based on the results, in the examples below, the mixtures contained in the three types of mixtures derived from natural products were tested. An experiment on antiviral efficacy was conducted on a total of 9 types of natural product extracts.
- KSHV antiviral efficacy was confirmed in hemlock (A), hemlock (B), euphorbia (F), and jeonho (G), especially in hemlock (B) and Prickly pear (F) showed strong antiviral efficacy in both BC-3-G and BCBL-1 cell lines.
- the Raji cell line an EBV latently infected cell line
- 20ng/ml TPA and 3mM NaB sodium butyrate
- the Akata(+) cell line was treated with 10 ⁇ g/ml of IgG
- 50 ⁇ g/ml of 9 natural product extracts were treated each on Raji cell line and Akate(+) cell line, and after 24 hours, Western blot analysis revealed the lytic protein of EBV. ), the expression levels of EA-D and ZTA were confirmed.
- Prickly pear (B), Prickly pear (F), and Jeju capsicum (H) showed antiviral efficacy against Raji cell lines
- Prickly pear (B) and Prickly pear (B) ( F), Jeonho (G), and Jeju Capricorn (H) showed antiviral efficacy against Akata (+) cell line.
- Eunuchia, Eunbi and Jeonho have antiviral effects against both KSHV and EBV
- Hemlock is specific for Kaposi's sarcoma herpes virus (KSHV)
- Jeju capifolia is specific for Kaposi's sarcoma herpes virus (KSHV). It was confirmed that it has a specific antiviral effect against Epstein-Barr virus (EBV).
- the Raw264.7 cell line a murine macrophage cell line
- MNV-1 was added at an MOI (Multiplicity of infection) of 0.01.
- the extracts of the natural products Somnorrhea (B) and Euphorbia (F) were treated with 50 ug/ml.
- the supernatant was collected, serially diluted 10 times, and the diluted solution was infected with BV-2, a mouse microglial cell line, and cultured for 3 days to measure virus titer by plaque assay.
- the antiviral efficacy of the five fractions of the Prickly pear extract (B) was evaluated in the same manner.
- the whole plant extracts of Prickly pear (B) and Prickly pear (F), and the hexane and chloroform fractions of Prickly pear (B) have excellent antiviral efficacy and contain powerful antiviral substances that inhibit MNV-1 proliferation.
- a plaque reduction assay was performed to evaluate the antiviral efficacy against HSV-1 and VZV, which are alphaherpesviruses that infect the nervous system.
- Vero cells or 12-well plates were seeded one day before infection, and on the day of the experiment, each well was infected with >100 PFU of virus for 1 hour, and then overlay media mixed with the extract or fraction was added to each well. After filling and culturing HSV-1 for 3 days, the number of plaques formed was counted.
- VZV was infected in MeWo cells for 2 hours, the extract or fraction was treated, and the number of plaques was counted after culturing for 4-6 days.
- the relative rate of viral plaque formation (%) in extract or fraction treated samples was analyzed based on the number of plaques in vehicle treated samples.
- Vero cells a cell line derived from the African Green Monkey kidney, were infected with >100 PFU of HSV-1 per well for 1 hour, then treated with overlay media treated with 10, 25, and 50 ⁇ g/ml extract, and cultured for 3 days. The results are shown in Figure 19.
- Gancyclovir a nucleoside analog used as a positive control
- GCV Gancyclovir
- B Prickly pear
- F Prickly pear
- the number of plaques formed and the size of the plaques are also indicators of antiviral efficacy.
- the size of plaques decreased in a concentration-dependent manner at 10 and 25 ⁇ g/ml, as shown in Figure 20.
- MeWo cells a cell line derived from human malignant melanoma, were infected with >100 PFU of VZV for 2 hours, and media treated with 10, 25, and 50 ⁇ g/ml extract were cultured for 4-6 days.
- Plaque reduction assay was performed on five types of fractions of Prickly pear (B) that showed concentration-dependent inhibitory efficacy against VZV infection at the concentrations shown in Table 3 above, and the results are shown in Figures 25 to 27. As shown in Figure 25, it was confirmed that among the five fractions (hexane, chloroform, ethyl acetate, butanol, and water fractions) of the extract of Prickly pear (B), the butanol, ethyl acetate, and water fractions did not show antiviral efficacy. .
- the extracts of Lilium vulgaris and Lilium vulgaris have antiviral effects that effectively inhibit infection by varicella-zoster virus (VZV), one of the alphaherpesviruses that infect the nervous system.
- VZV varicella-zoster virus
- the hexane fraction of Lilium vulgaris has a concentration-dependent antiviral effect. Able to know.
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Abstract
The present invention relates to a natural substance extract exhibiting antiviral activity against gammaherpesvirus, alphaherpesvirus, or norovirus. Specifically, the present invention relates to: a composition for treating or preventing a disease caused by gammaherpesvirus infection, comprising an extract of Tsuga sieboldii, Potentilla discolor Bunge, Potentilla nivea L., or Hydrocotyle yabei Makino; a composition for treating or preventing a disease caused by alphaherpesvirus infection, comprising an extract of Potentilla discolor Bunge, Potentilla nivea L., or Anthriscus sylvestris; and a composition for treating or preventing a disease caused by norovirus infection, comprising a Potentilla discolor Bunge or Potentilla nivea L. extract. The composition of the present invention inhibits the activity of viruses, and thus can be effectively used as a therapeutic agent for viral infectious diseases.
Description
본 발명은 감마허피스바이러스, 알파허피스바이러스 또는 노로바이러스에 대하여 항바이러스 활성을 나타내는 천연물 추출물에 관한 것이다. 구체적으로, 솔송나무, 솜양지꽃, 은양지꽃, 또는 제주피막이 추출물을 포함하는 감마허피스바이러스 감염에 의한 질환을 치료 또는 예방하는 조성물; 솜양지꽃, 은양지꽃, 또는 전호 추출물을 포함하는 알파허피스바이러스 감염에 의한 질환을 치료 또는 예방하는 조성물; 및 솜양지꽃 또는 은양지꽃 추출물을 포함하는 노로바이러스 감염에 의한 질환을 치료 또는 예방하는 조성물에 관한 것이다.The present invention relates to a natural product extract that exhibits antiviral activity against gammaherpesvirus, alphaherpesvirus, or norovirus. Specifically, a composition for treating or preventing diseases caused by gammaherpes virus infection comprising extracts of hemlock, hemlock, chinensis, or Jeju capsicum; A composition for treating or preventing diseases caused by alphaherpesvirus infection, comprising extracts of Euphorbia chinensis, Euphorbia chinensis, or Jeonho; And it relates to a composition for treating or preventing diseases caused by norovirus infection, comprising extracts of Euphorbia chinensis or Euphorbia chinensis.
바이러스란 자가 복제가 불가능한 미생물을 의미하며, 현재 지구상에 수천 종의 바이러스가 존재한다. 이들 중 일부 바이러스들은 인간을 감염시키며, 이러한 바이러스성 감염은 현재 지구 온난화 및 세계화 등으로 세계적인 증가 추세에 있다.Viruses are microorganisms that cannot replicate on their own, and thousands of types of viruses currently exist on Earth. Some of these viruses infect humans, and these viral infections are currently on the rise worldwide due to global warming and globalization.
허피스바이러스과(Herpesviridae)는 120 내지 230 kbp 크기의 이중 가닥 DNA를 바이러스 유전체로 갖는 비교적 크고 복잡한 구조로 이루어진 외피가 있는 바이러스이다. 상기 바이러스 계열은 자손 바이러스가 복제되는 용균성 감염(lytic infection)과 더불어 숙주의 면역 시스템을 회피하여 잠복감염(latent infection)을 형성함으로써 평생 숙주에 감염할 수 있도록 진화하였고, 생물학적 특성 차이에 따라 알파허피스바이러스아과(Alpha herpesvirinae), 베타허피스바이러스아과(Beta herpesvirinae), 및 감마허피스바이러스아과(Gamma herpesvirinae) 세 가지로 분류된다. Herpesviridae is an enveloped virus with a relatively large and complex structure whose viral genome is double-stranded DNA of 120 to 230 kbp in size. The above virus family has evolved to be able to infect the host throughout its life by evading the host's immune system and forming a latent infection in addition to lytic infection, in which progeny viruses replicate, and alpha according to differences in biological characteristics. It is classified into three groups: Alpha herpesvirinae , Beta herpesvirinae , and Gamma herpesvirinae .
인체 감염 허피스바이러스 대부분은 국내 70-90% 이상의 높은 감염률을 나타내며, 한 번 감염되면 인체에서 잠복감염을 형성하고, 숙주에서 잠복감염과 재활성을 반복하여 평생동안 감염성 유지하는 만성바이러스로서, 면역기능 저하에 따른 재활성이나 선천감염을 통해 다양한 질병을 유발하고 환자의 면역상태에 따라 치명적인 감염 예후를 나타내는 대표적인 기회감염 병원체(opportunistic infection pathogens)이다. 장기이식(organ transplant) 및 조혈모세포 이식(Hematopoietic Stem Cell Transplant)의 증가, 인체면역결핍바이러스 (HIV-1) 감염 등, 면역 저하에 따른 재활성 허피스바이러스 감염 제어가 중요한 이슈가 되고 있으며, 허피스바이러스의 지속감염으로 인한 노년층 인구의 면역 저하는 최고속으로 고령화 사회에 진입하고 있는 국가들에서 중요한 보건 사회경제적 부담으로 작용하고 있다. Most human-infecting herpes viruses have a high infection rate of over 70-90% in Korea. Once infected, they form a latent infection in the human body and are chronic viruses that remain infectious throughout life by repeating latent infection and reactivation in the host, affecting immune function. They are representative opportunistic infection pathogens that cause various diseases through reactivation or congenital infection due to degradation and have a fatal infection prognosis depending on the patient's immune status. Control of reactivated herpes virus infections due to decreased immunity, such as the increase in organ transplants and hematopoietic stem cell transplants and human immunodeficiency virus (HIV-1) infections, is becoming an important issue. The decline in immunity of the elderly population due to persistent infections is acting as an important health and socioeconomic burden in countries that are entering aging societies at the fastest rate.
현재까지 8가지 유형의 인체 감염 허피스바이러스가 발견되었는데, Herpes simplex virus I(HSV-I), Herpes simplex virus II(HSV-II), Varicella zoster virus (VZV), Human cytomegalovirus (HCMV), Human herpesvirus 6, Human herpesvirus 7, Epstein-barr virus (EBV), 및 Kaposi's sarcoma-associated herpesvirus (KSHV)가 이에 해당하고, 이중 엡스타인 바 바이러스(EBV)와 카포시 육종 허피스바이러스(KSHV)는 감마허피스바이러스에 속한다.To date, eight types of human herpesviruses have been discovered: Herpes simplex virus I (HSV-I), Herpes simplex virus II (HSV-II), Varicella zoster virus (VZV), Human cytomegalovirus (HCMV), and Human herpesvirus 6. , Human herpesvirus 7, Epstein-barr virus (EBV), and Kaposi's sarcoma-associated herpesvirus (KSHV), of which Epstein-Barr virus (EBV) and Kaposi's sarcoma herpesvirus (KSHV) belong to gammaherpesviruses.
감마허피스바이러스는 알파 및 베타 허피스바이러스와 달리 세포 친화성이 뚜렷하여 림프구에서의 잠복을 통해 숙주에 지속적인 감염을 유발하는 특징을 가지고, 감염된 숙주에서 양성 또는 악성 종양을 유발하는데, 전세계 인구의 90% 이상이 감염되어 있는 EBV는 만성 감염시 버킷림프종(Burkitt's lymphoma), 위암종(Gastric carcinoma), 코인두암종(Nasopharyngeal carcinoma), 이식 후 B 세포 림프종(post-transplant B cell lymphomas) 및 호지킨림프종(Hodgkin's disease) 등의 종양 형성에 기여하고, KSHV는 카포시 육종(Kaposi's sarcoma), 원발성 삼출성 림프종(Primary effusion lymphoma) 및 다발성 캐슬만병(Multicentric castleman's disease)의 원인이 된다.Unlike alpha and beta herpesviruses, gammaherpesvirus has distinct cell tropism and has the characteristic of causing persistent infection in the host through latency in lymphocytes. It causes benign or malignant tumors in infected hosts, affecting 90% of the world's population. In chronic infection, EBV causes Burkitt's lymphoma, gastric carcinoma, nasopharyngeal carcinoma, post-transplant B cell lymphomas, and Hodgkin's lymphoma ( KSHV contributes to the formation of tumors such as Hodgkin's disease, and KSHV is the cause of Kaposi's sarcoma, primary effusion lymphoma, and multicentric castleman's disease.
인체 감염 허피스바이러스 1형인 단순포진바이러스(Herpes simplex virus-1; HSV-1)는 신경계에서 잠복감염을 형성하는 알파허피스바이러스로 숙주에서 평생 감염을 지속하면서 면역 저하 등에 의해 재활성되어 증식함으로써 피부와 입, 입술, 눈 또는 성기 주변 등에서 나타나는 포진으로 인한 단순포진, 구순포진, 구내염, 단순포진각막염과 더불어 수막염, 뇌염을 유발할 수 있으며, 신생아에서는 치명적인 뇌염(encephalitis)을 유발할 수 있다. Herpes simplex virus-1 (HSV-1), a type 1 human infectious herpes virus, is an alphaherpesvirus that forms a latent infection in the nervous system. It continues to infect the host for life and is reactivated and proliferates due to decreased immunity, etc., infecting the skin and skin. Herpes that appears around the mouth, lips, eyes, or genitals can cause herpes simplex, cold sores, stomatitis, and herpes simplex keratitis, as well as meningitis and encephalitis. In newborns, it can cause fatal encephalitis.
인체 감염 허피스바이러스 3형인 수두-대상포진바이러스(Varicella-Zoster virus; VZV)는 초기감염에서 전염성이 매우 높은 수두(Varicella)를 일으키는 원인성 감염체로 잘 알려져 있으며, VZV는 초기 감염 이후, 감각신경계 (dorsal root ganglia, DRG)에서 잠복감염을 형성하다가 면역 저하 등에 의한 재활성으로 극심한 통증을 유발하는 대상포진을 일으킨다. VZV의 재활성은 흉부, 시신경절, 안면신경 부위 등에 발생하는 대상포진을 유발하며, 또한 피부 포진이 없이도 피부 이상 감각이나 방사통이 발생하는 무발진 대상포진(Zoster Sine Herpete)이 발생할 수 있다. 일부 환자에서는 대상포진이 치료된 후에도 통증이 지속되는 '대상포진 후 신경통 (postherpetic neuralgia, PHN)'을 유발할 수 있다. 재활성화 된 VZV에 의한 대상포진 후 발병하는 합병증 중 가장 흔한 합병증인 '대상포진 후 신경통(PHN)'은 환자마다 다양한 정도의 통증을 느끼며, 보통 발진 후 적어도 4 개월 이상 통증이 지속되는 경우 대상포진 후 신경통으로 분류하는데, 이러한 만성적인 통증은 환자에게 육체적인 고통은 물론 심리적으로 불안, 우울, 불면증을 야기하여 환자의 삶의 질에 상당히 큰 악영향을 끼치기 때문에 VZV의 재활성 및 감염의 신속 제어가 매우 중요하다. Varicella-Zoster virus (VZV), a type 3 human infectious herpesvirus, is well known as the causative agent that causes highly contagious chickenpox (Varicella) in the initial infection. After the initial infection, VZV affects the sensory nervous system ( A latent infection forms in the dorsal root ganglia (DRG) and reactivation due to decreased immunity causes shingles, which causes extreme pain. Reactivation of VZV causes shingles that occurs in the chest, optic ganglion, and facial nerve areas, and can also cause herpes zoster (zoster sine herpete), which causes abnormal skin sensation or radiating pain even without skin herpes. In some patients, it can cause ‘postherpetic neuralgia (PHN),’ where pain persists even after shingles is treated. 'Postherpetic neuralgia (PHN)', the most common complication after shingles caused by reactivated VZV, causes varying degrees of pain for each patient, and usually occurs when pain persists for at least 4 months or more after the rash. It is classified as posterior neuralgia. This chronic pain causes not only physical pain but also psychological anxiety, depression, and insomnia in patients, which has a significant negative impact on the patient's quality of life. Therefore, rapid control of VZV reactivation and infection is very important. It is important.
기존에 사용되는 항허피스바이러스제들의 경우 잠복감염까지 제어할 수 있는 근원적인 치료법은 전무하고, 대부분 바이러스 DNA 중합효소(DNA pol)을 타겟으로 개발된 뉴클레오시드 유사체이다. 이들 약물은 고령의 노인뿐 아니라 장기이식 및 조혈모세포이식, HIV 감염으로 인한 면역결핍환자의 경우 약물의 독성이 심하게 나타나고, 더 중요하게는 이들 환자에게서 약물내성의 돌연변이 출현이 증가하고 있어 신규 감염 제어물질의 발굴이 시급하다.In the case of existing antiherpesvirus drugs, there is no fundamental treatment that can control latent infection, and most of them are nucleoside analogs developed to target viral DNA polymerase (DNA pol). These drugs are highly toxic not only to the elderly but also to patients with organ transplants, hematopoietic stem cell transplants, and immunodeficiency due to HIV infection, and more importantly, the emergence of drug-resistant mutations is increasing in these patients, thereby controlling new infections. Excavation of the material is urgent.
인체 노로바이러스는 양성단일가닥 RNA를 게놈으로 가지는 칼리시바이러스과(Caliciviridae)에 속하는 노로바이러스로, 전세계적으로 겨울철 장염의 주된 원인이 되는 비세균성 위장염(gastroenteritis) 원인 중 가장 높은 비율을 차지한다. 인체노로바이러스는 감염된 환자의 분변 또는 에어로졸화 된 구토물을 통해 환경에 유입되며, 바이러스로 오염된 음식이나 식수를 섭취함으로써 감염된다. 인체 노로바이러스의 방출은 설사와 같은 증상이 멈춘 이후에도 최대 8주까지 관찰된다는 보고가 있다. 또한 100개 미만의 바이러스 입자로도 감염이 가능하기 때문에 전염성이 매우 높으며, 적은 양의 바이러스 오염이 광범위한 집단 장염을 초래하는 등 국민 보건 증진을 위해 제어해야 하는 중요한 병원체에 해당한다. 특히 요양원 등 다수의 면역저하자들이 집단생활을 하는 시설에서는 전파가 용이하고 증상도 중증으로 악화될 수 있으므로 노로바이러스에 대한 예방 및 치료 관리가 시급하다.Human norovirus is a norovirus belonging to the Caliciviridae family that has positive single-stranded RNA as its genome, and accounts for the highest percentage of non-bacterial gastroenteritis, the main cause of enteritis in winter worldwide. Human norovirus enters the environment through the feces or aerosolized vomit of infected patients, and is contracted by consuming food or drinking water contaminated with the virus. There are reports that shedding of human norovirus can be observed for up to eight weeks even after symptoms such as diarrhea have stopped. In addition, since infection is possible with less than 100 virus particles, it is highly contagious, and a small amount of virus contamination can cause widespread mass enteritis, making it an important pathogen that must be controlled to improve public health. In particular, prevention and treatment for norovirus is urgent because it is easy to spread in facilities where many immunocompromised people live together, such as nursing homes, and symptoms can worsen to severe cases.
인체 노로바이러스 연구가 어려운 가장 큰 문제는 인체 노로바이러스(human noroviruses)를 감염하여 바이러스를 생산할 수 있는 배양 시스템이 매우 비효율적이라는 점이다. 그 결과 감염성이 있는 인체 노로바이러스의 바이러스 유전자의 역할 및 생활사에 대한 연구는 매우 제한적일 수밖에 없다. 또한 바이러스 감염제어를 확인할 수 있는 바이러스 배양시스템의 부재는 항바이러스제 개발의 가장 중요한 제한단계로 작용하고 있다. 이러한 문제를 극복하기 위한 대체 바이러스(surrogate virus) 시스템으로서 마우스노로바이러스 (murine noroviruses, MNVs)가 활용되고 있다. 특히 마우스노로바이러스(MNV-1)는 마우스를 숙주로 감염시키는 노로바이러스로 발견된 이후, 노로바이러스 중에서는 유일하게 세포배양이 용이하며 인체 노로바이러스와 동일한 감염경로를 갖는다. 마우스노로바이러스의 발견 이전에는 칼리시바이러스과에 속하는 고양이 칼리시바이러스(Feline calicivirus 9, FCV-9)가 한때 인체 노로바이러스의 대체바이러스로 받아들여졌으나, 마우스노로바이러스 발견 이후에는 전파경로와 병원성 특징이 상이하여 사용되지 않고 있다. 인체 노로바이러스와 마우스노로바이러스는 위장관 감염을 통해 분변으로 전파되는 반면, 고양이 칼리시바이러스는 호흡기감염을 통해 전파되는 바이러스로 상이한 성질을 다수 가지고 있어 마우스노로바이러스가 보다 적절한 대체 바이러스 시스템으로 받아들여지고 있다.The biggest problem in studying human noroviruses is that the culture system that can produce viruses by infecting human noroviruses is very inefficient. As a result, research on the role and life cycle of viral genes of infectious human noroviruses is inevitably very limited. Additionally, the absence of a virus culture system that can confirm viral infection control serves as the most important limiting step in the development of antiviral drugs. Murine noroviruses (MNVs) are being used as a surrogate virus system to overcome these problems. In particular, since mouse norovirus (MNV-1) was discovered as a norovirus that infects mice as a host, it is the only norovirus that is easy to cell culture and has the same infection route as human norovirus. Before the discovery of mouse norovirus, feline calicivirus 9 (FCV-9), which belongs to the caliciviridae family, was once accepted as an alternative virus to human norovirus, but after the discovery of mouse norovirus, the transmission route and pathogenic characteristics changed. It is not used because it is different. While human norovirus and mouse norovirus are transmitted through feces through gastrointestinal infection, feline calicivirus is a virus transmitted through respiratory infection and has many different properties, so mouse norovirus is accepted as a more appropriate alternative virus system. .
현재 전세계적으로 인체 노로바이러스에 대한 특이적 백신 또는 항바이러스제가 허가받은 경우는 전무한 상황이나, 고령화로 인해 요양원 등 집단생활시설이 늘어나는 등 노로바이러스 감염 치료에 대한 미충족 의료수요는 점점 증가하고 있다. Currently, there are no specific vaccines or antiviral drugs approved for human norovirus worldwide, but the unmet medical demand for treatment of norovirus infections is increasing, as the number of group living facilities such as nursing homes increases due to the aging population.
본 발명자들은 천연물이 바이러스 활성에 미치는 영향을 연구하여, 노로바이러스, 알파허피스바이러스 및 감마허피스바이러스의 감염을 효과적으로 억제할 수 있는 천연물 추출물들을 개발하여 본 발명을 완성하였다.The present inventors studied the effect of natural products on virus activity and completed the present invention by developing natural product extracts that can effectively inhibit infection by norovirus, alphaherpesvirus, and gammaherpesvirus.
본 발명은 감마허피스바이러스의 감염에 의한 질환을 치료 또는 예방할 수 있는, 솔송나무, 솜양지꽃, 은양지꽃, 또는 제주피막이 추출물을 유효성분으로 하는 항바이러스 활성을 갖는 조성물을 제공하는 것을 목적으로 한다.The purpose of the present invention is to provide a composition with antiviral activity containing extracts of hemlock, hemlock, euphorbia, or Jeju mantle as an active ingredient, which can treat or prevent diseases caused by gammaherpesvirus infection.
또한, 본 발명은 노로바이러스 감염에 의한 질환을 예방 또는 치료할 수 있는, 솜양지꽃 또는 은양지꽃 추출물을 유효성분으로 하는 항바이러스 활성을 갖는 조성물을 제공하는 것을 목적으로 한다.In addition, the purpose of the present invention is to provide a composition with antiviral activity containing extracts of Euphorbia or Euphorbia as an active ingredient, which can prevent or treat diseases caused by norovirus infection.
또한, 본 발명은 알파허피스바이러스 감염에 의한 질환을 예방 또는 치료할 수 있는, 솜양지꽃, 은양지꽃 또는 전호 추출물을 유효성분으로 하는 항바이러스 활성을 갖는 조성물을 제공하는 것을 목적으로 한다.Additionally, the purpose of the present invention is to provide a composition with antiviral activity containing as an active ingredient extracts of Euphorbia chinensis, Euphorbia chinensis, or Jeonho chinensis, which can prevent or treat diseases caused by alphaherpesvirus infection.
상기 과제를 해결하기 위하여, 본 발명은 솔송나무, 솜양지꽃, 은양지꽃, 또는 제주피막이 추출물을 포함하는 조성물을 제공한다.In order to solve the above problems, the present invention provides a composition containing extracts of hemlock, hemlock, euphorbia, or Jeju mantle.
상기 조성물은 약학 조성물, 식품 조성물 또는 동물용 사료 조성물일 수 있다.The composition may be a pharmaceutical composition, food composition, or animal feed composition.
일 실시태양에서, 상기 조성물은 감마허피스바이러스 감염 질환의 예방, 치료, 또는 개선용일 수 있다.In one embodiment, the composition may be used to prevent, treat, or improve gammaherpes virus infectious disease.
일 실시태양에서, 상기 조성물은 카포시 육종 허피스 바이러스 감염 질환의 예방, 치료, 또는 개선용일 수 있다.In one embodiment, the composition may be for preventing, treating, or improving Kaposi's sarcoma herpes virus infectious disease.
일 실시태양에서, 상기 조성물은 카포시 육종 허피스 바이러스의 용균 단백질의 발현을 감소시킬 수 있다.In one embodiment, the composition is capable of reducing the expression of the lytic protein of Kaposi's sarcoma herpes virus.
일 실시태양에서, 상기 감염 질환은 카포시 육종, 원발성 삼출성 림프종, 및 다발성 캐슬만병으로 이루어진 그룹에서 선택되는 하나 이상의 질환일 수 있다.In one embodiment, the infectious disease may be one or more diseases selected from the group consisting of Kaposi's sarcoma, primary exudative lymphoma, and multicentric Castleman's disease.
일 실시태양에서, 상기 조성물은 엡스타인 바 바이러스 감염 질환의 예방, 치료, 또는 개선용일 수 있다.In one embodiment, the composition may be for preventing, treating, or ameliorating Epstein-Barr virus infectious disease.
일 실시태양에서, 상기 조성물은 엡스타인 바 바이러스의 용균 단백질의 발현을 감소시킬 수 있다.In one embodiment, the composition is capable of reducing expression of the lytic protein of Epstein Barr virus.
일 실시태양에서, 상기 감염 질환은 버킷림프종, 위암종, 코인두암종, 호지킨림프종, 및 이식 후 B 세포 림프종으로 이루어진 그룹에서 선택되는 하나 이상의 질환일 수 있다.In one embodiment, the infectious disease may be one or more diseases selected from the group consisting of Burkitt's lymphoma, gastric carcinoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, and post-transplant B cell lymphoma.
본 발명은 솜양지꽃 및 은양지꽃 추출물로 이루어진 군에서 선택된 하나 이상의 추출물을 유효성분으로 포함하는 노로바이러스 감염 질환의 예방 또는 치료용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for the prevention or treatment of norovirus infectious diseases, comprising as an active ingredient one or more extracts selected from the group consisting of Prickly pear and Prickly pear extracts.
일 실시태양에서, 상기 약학 조성물은 솜양지꽃 및 은양지꽃 추출물로 이루어진 군에서 선택되는 하나 이상의 추출물을 포함하거나, 솜양지꽃 및 은양지꽃 추출물로 이루어진 군으로부터 선택된 혼합물로부터 추출된 추출물을 포함할 수 있다.In one embodiment, the pharmaceutical composition may include one or more extracts selected from the group consisting of Lilium vulgaris and Lilium vulgaris extracts, or may include an extract extracted from a mixture selected from the group consisting of Lilium vulgaris and Lilium vulgaris extracts.
일 실시태양에서, 상기 노로바이러스는 인체 노로바이러스일 수 있다.In one embodiment, the norovirus may be a human norovirus.
일 실시태양에서, 상기 노로바이러스 감염 질환은 비세균성 위장염일 수 있다.In one embodiment, the norovirus infectious disease may be non-bacterial gastroenteritis.
일 실시태양에서, 상기 은양지꽃 추출물은 헥산, 클로로포름, 부탄올, 에틸 아세테이트 및 물로 이루어진 군에서 하나 이상 선택된 용매로 분획될 수 있다.In one embodiment, the Euphorbia chinensis extract may be fractionated with one or more solvents selected from the group consisting of hexane, chloroform, butanol, ethyl acetate, and water.
일 실시태양에서, 상기 은양지꽃 추출물은 헥산 분획물 또는 클로로포름 분획물일 수 있다.In one embodiment, the Euphorbia chinensis extract may be a hexane fraction or a chloroform fraction.
본 발명은 솜양지꽃 및 은양지꽃 추출물로 이루어진 군에서 선택된 하나 이상의 추출물을 유효성분으로 포함하는 노로바이러스 감염 질환의 예방 또는 개선용 식품 조성물을 제공한다.The present invention provides a food composition for preventing or improving norovirus infectious diseases, comprising as an active ingredient one or more extracts selected from the group consisting of Prickly pear and Prickly pear extracts.
일 실시태양에서, 상기 노로바이러스 감염 질환은 비세균성 위장염일 수 있다.In one embodiment, the norovirus infectious disease may be non-bacterial gastroenteritis.
본 발명은 솜양지꽃 및 은양지꽃 추출물로 이루어진 군에서 선택된 하나 이상의 추출물을 유효성분으로 포함하는 노로바이러스 감염 질환의 예방 또는 개선용 동물용 사료 조성물을 제공한다.The present invention provides a feed composition for animals for preventing or ameliorating norovirus infectious diseases, comprising as an active ingredient one or more extracts selected from the group consisting of Prickly pear and Prickly pear extracts.
일 실시태양에서, 상기 노로바이러스 감염 질환은 비세균성 위장염일 수 있다.In one embodiment, the norovirus infectious disease may be non-bacterial gastroenteritis.
본 발명은 솜양지꽃, 은양지꽃 및 전호 추출물로 이루어진 군에서 선택된 하나 이상의 추출물을 유효성분으로 포함하는 알파허피스바이러스 감염 질환의 예방 또는 치료용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for the prevention or treatment of alphaherpesvirus infectious diseases, comprising as an active ingredient one or more extracts selected from the group consisting of Euphorbia chinensis, Euphorbia chinensis and Jeonho extract.
일 실시태양에서, 상기 약학 조성물은 솜양지꽃, 은양지꽃 및 전호 추출물로 이루어진 군에서 선택되는 하나 이상의 추출물을 포함하거나, 솜양지꽃, 은양지꽃 및 전호 추출물로 이루어진 군으로부터 선택된 혼합물로부터 추출된 추출물을 포함할 수 있다.In one embodiment, the pharmaceutical composition comprises one or more extracts selected from the group consisting of extracts of Corolla, Corolla, and Corolla extracts, or comprises an extract extracted from a mixture selected from the group consisting of extracts of Corolla, Corolla, and Corolla extracts. can do.
일 실시태양에서, 상기 알파허피스바이러스는 단순포진바이러스 또는 수두-대상포진바이러스일 수 있다.In one embodiment, the alphaherpesvirus may be herpes simplex virus or varicella-zoster virus.
일 실시태양에서, 상기 단순포진바이러스 감염 질환은 단순포진, 구순포진, 구내염, 수막염 및 뇌염(encephalitis)으로 이루어진 그룹에서 선택되는 하나 이상의 질환일 수 있다.In one embodiment, the herpes simplex virus infectious disease may be one or more diseases selected from the group consisting of herpes simplex, cold sores, stomatitis, meningitis, and encephalitis.
일 실시태양에서, 상기 수두-대상포진바이러스 감염 질환은 수두-대상포진바이러스 대상포진 및 무발진 대상포진(Zoster Sine Herpete)로 이루어진 그룹에서 선택되는 하나 이상의 질환일 수 있다.In one embodiment, the varicella-zoster virus infectious disease may be one or more diseases selected from the group consisting of varicella-zoster virus shingles and Zoster Sine Herpete.
일 실시태양에서, 상기 은양지꽃 추출물은 헥산, 클로로포름, 부탄올, 에틸 아세테이트 및 물로 이루어진 군에서 하나 이상 선택된 용매로 분획될 수 있다.In one embodiment, the Euphorbia chinensis extract may be fractionated with one or more solvents selected from the group consisting of hexane, chloroform, butanol, ethyl acetate, and water.
일 실시태양에서, 상기 은양지꽃 추출물은 헥산 분획물 또는 클로로포름 분획물일 수 있으며, 바람직하게는 헥산 분획물일 수 있다.In one embodiment, the Euphorbia chinensis extract may be a hexane fraction or a chloroform fraction, and preferably may be a hexane fraction.
본 발명은 솜양지꽃, 은양지꽃 및 전호 추출물로 이루어진 군에서 선택된 하나 이상의 추출물을 유효성분으로 포함하는 알파허피스바이러스 감염 질환의 예방 또는 개선용 식품 조성물을 제공한다.The present invention provides a food composition for preventing or ameliorating alphaherpesvirus infectious disease, comprising as an active ingredient one or more extracts selected from the group consisting of Euphorbia flower, Euphorbia chinensis and Jeonho extract.
일 실시태양에서, 상기 알파허피스바이러스는 단순포진바이러스 또는 수두-대상포진바이러스일 수 있다.In one embodiment, the alphaherpesvirus may be herpes simplex virus or varicella-zoster virus.
본 발명은 솜양지꽃, 은양지꽃 및 전호 추출물로 이루어진 군에서 선택된 하나 이상의 추출물을 유효성분으로 포함하는 알파허피스바이러스 감염 질환의 예방 또는 개선용 동물용 사료 조성물을 제공한다.The present invention provides a feed composition for animals for preventing or ameliorating alphaherpesvirus infection disease, which contains as an active ingredient one or more extracts selected from the group consisting of Euphorbia chinensis, Euphorbia chinensis and Jeonho extract.
일 실시태양에서, 상기 알파허피스바이러스는 단순포진바이러스 또는 수두-대상포진바이러스일 수 있다.In one embodiment, the alphaherpesvirus may be herpes simplex virus or varicella-zoster virus.
본 발명에 따른 솔송나무, 솜양지꽃, 은양지꽃, 또는 제주피막이 추출물을 포함하는 조성물은 KSHV 및 EBV에 대한 항바이러스 효과를 가진다. 따라서, 본 발명의 조성물은 감마허피스바이러스의 감염에 의한 질환을 치료 또는 예방할 수 있다.A composition containing extracts of Hemlock, Hemlock, Euphorbia, or Jeju mantle according to the present invention has an antiviral effect against KSHV and EBV. Therefore, the composition of the present invention can treat or prevent diseases caused by gammaherpesvirus infection.
본 발명의 솜양지꽃 및 은양지꽃 추출물은 노로바이러스의 증식 억제를 유도하는 우수한 효과를 갖는다. 따라서, 본 발명의 솜양지꽃 및 은양지꽃 추출물은 노로바이러스의 감염 질환의 예방 또는 치료에 사용될 수 있다.The Prickly pear and Prickly pear extracts of the present invention have an excellent effect of inducing inhibition of the proliferation of norovirus. Accordingly, the extracts of Prickly pear and Prickly pear of the present invention can be used for the prevention or treatment of norovirus infectious diseases.
또한, 본 발명의 솜양지꽃, 은양지꽃 및 전호 추출물은 알파허피스바이러스의 증식 억제를 유도하는 우수한 효과를 갖는다. 따라서, 본 발명의 조성물은 알파허피스바이러스의 감염 질환의 예방 또는 치료에 사용될 수 있다.In addition, the extracts of the present invention, such as euphorbia vulgaris, euphorbia vulgaris, and jeonho, have an excellent effect of inducing inhibition of the proliferation of alphaherpesvirus. Therefore, the composition of the present invention can be used for the prevention or treatment of alphaherpesvirus infectious diseases.
도 1은 천연물 유래 혼합물 86종을 BC-3-G 세포주에 처리하였을 때 GFP 발현 정도를 나타낸다.Figure 1 shows the level of GFP expression when 86 natural product-derived mixtures were treated with the BC-3-G cell line.
도 2는 천연물 유래 혼합물 86종을 BC-3-G 세포주에 처리하였을 때 GFP 발현 정도를 음성대조군을 0으로 지정하여 나타낸다.Figure 2 shows the level of GFP expression when 86 natural product-derived mixtures were treated with the BC-3-G cell line, with the negative control group designated as 0.
도 3은 천연물 유래 혼합물 6종을 BC-3-G 세포주에 처리하였을 때 유세포 분석에서 GFP positive cell을 나타낸다.Figure 3 shows GFP positive cells in flow cytometry when BC-3-G cell line was treated with six types of natural product-derived mixtures.
도 4는 천연물 유래 혼합물 6종을 BC-3-G 세포주에 처리하였을 때 RTA 및 K8의 발현 수준을 나타낸다.Figure 4 shows the expression levels of RTA and K8 when BC-3-G cell line was treated with six types of natural product-derived mixtures.
도 5는 천연물 유래 혼합물 3종을 농도를 달리하여 BC-3 세포주에 처리하였을 때 RTA 및 K8의 발현 수준을 나타낸다. Figure 5 shows the expression levels of RTA and K8 when BC-3 cell line was treated with three mixtures derived from natural products at different concentrations.
도 6은 천연물 유래 혼합물 3종을 농도를 달리하여 BC-3-G 세포주에 처리하였을 때 RTA 및 K8의 발현 수준을 나타낸다.Figure 6 shows the expression levels of RTA and K8 when BC-3-G cell line was treated with three mixtures derived from natural products at different concentrations.
도 7은 천연물 유래 혼합물 3종을 농도를 달리하여 BCBL-1 세포주에 처리하였을 때 RTA 및 K8의 발현 수준을 나타낸다.Figure 7 shows the expression levels of RTA and K8 when BCBL-1 cell line was treated with three mixtures derived from natural products at different concentrations.
도 8은 천연물 유래 혼합물 6종을 Raji 세포주에 처리하였을 때 ZTA의 발현 수준을 나타낸다.Figure 8 shows the expression level of ZTA when Raji cell line was treated with six types of natural product-derived mixtures.
도 9는 천연물 유래 혼합물 3종을 Akata(+) 세포주에 처리하였을 때 EA-D 및 ZTA의 발현 수준을 나타낸다.Figure 9 shows the expression levels of EA-D and ZTA when Akata (+) cell line was treated with three types of natural product-derived mixtures.
도 10은 천연물 유래 혼합물 3종을 농도를 달리하여 Akata(+) 세포주에 처리하였을 때 EA-D 및 ZTA의 발현 수준을 나타낸다.Figure 10 shows the expression levels of EA-D and ZTA when the Akata (+) cell line was treated with three mixtures derived from natural products at different concentrations.
도 11은 천연물 추출물 9종을 BC-3-G 세포주에 처리하였을 때 RTA 및 K8의 발현 수준을 나타낸다.Figure 11 shows the expression levels of RTA and K8 when nine types of natural product extracts were treated with BC-3-G cell line.
도 12는 천연물 추출물 9종을 BCBL-1 세포주에 처리하였을 때 RTA 및 K8의 발현 수준을 나타낸다.Figure 12 shows the expression levels of RTA and K8 when nine types of natural product extracts were treated with the BCBL-1 cell line.
도 13은 천연물 추출물 9종을 Raji 세포주에 처리하였을 때 EA-D 및 ZTA의 발현 수준을 나타낸다.Figure 13 shows the expression levels of EA-D and ZTA when nine types of natural product extracts were treated with Raji cell line.
도 14는 천연물 추출물 9종을 Akata(+) 세포주에 처리하였을 때 EA-D 및 ZTA의 발현 수준을 나타낸다.Figure 14 shows the expression levels of EA-D and ZTA when nine types of natural product extracts were treated with Akata(+) cell line.
도 15는 노로바이러스에 대한 항바이러스 효능 평가 과정을 나타낸 모식도이다.Figure 15 is a schematic diagram showing the process of evaluating antiviral efficacy against norovirus.
도 16은 솜양지꽃 및 은양지꽃 추출물의 노로바이러스에 대한 항바이러스 효능 평가 결과를 나타낸 사진 및 그래프이다.Figure 16 is a photograph and a graph showing the results of evaluating the antiviral efficacy of extracts of Euphorbia and Euphorbicus flowers against norovirus.
도 17은 솜양지꽃 추출물 및 분획물 5종의 노로바이러스에 대한 항바이러스 효능 평가 결과를 나타낸 사진 및 그래프이다.Figure 17 is a photograph and a graph showing the results of evaluating the antiviral efficacy of five types of noroviruses from the extracts and fractions of Somnambula flower.
도 18은 알파허피스바이러스에 대한 항바이러스 효능 평가 과정을 나타낸 모식도이다.Figure 18 is a schematic diagram showing the process of evaluating antiviral efficacy against alphaherpesvirus.
도 19는 솜양지꽃 및 은양지꽃 추출물의 HSV-1 알파허피스바이러스에 대한 항바이러스 효능 평가 결과를 나타낸 사진 및 그래프이다.Figure 19 is a photograph and graph showing the results of evaluating the antiviral efficacy of extracts of Lithuanian lily and Lithuanian lily against HSV-1 alphaherpesvirus.
도 20은 솜양지꽃 및 은양지꽃 추출물의 HSV-1 알파허피스바이러스에 대한 항바이러스 효능 평가에서 플라크 크기 변화를 나타낸 사진 및 그래프이다.Figure 20 is a photograph and graph showing the change in plaque size in the evaluation of the antiviral efficacy of extracts of Lilium vulgaris and Lilium vulgaris against HSV-1 alphaherpesvirus.
도 21은 전호 추출물의 HSV-1 알파허피스바이러스에 대한 항바이러스 효능 평가 결과를 나타낸 사진 및 그래프이다.Figure 21 is a photograph and graph showing the results of evaluating the antiviral efficacy of Jeonho extract against HSV-1 alphaherpesvirus.
도 22는 솜양지꽃 추출물 및 분획물 5종의 HSV-1 알파허피스바이러스에 대한 항바이러스 효능 평가 결과를 나타낸 사진 및 그래프이다.Figure 22 is a photograph and graph showing the results of evaluating the antiviral efficacy of 5 types of HSV-1 alphaherpesvirus extracts and fractions of Sulfuria chinensis.
도 23은 솜양지꽃, 은양지꽃 및 전호 추출물의 VZV 알파허피스바이러스에 대한 항바이러스 효능 평가 결과를 나타낸 사진 및 그래프이다.Figure 23 is a photograph and a graph showing the results of evaluating the antiviral efficacy of extracts of Lithuanian vulgaris, Liquoria vulgaris, and Chrysanthemum vulgaris against VZV alphaherpesvirus.
도 24는 솜양지꽃 및 은양지꽃 추출물의 VZV 알파허피스바이러스에 대한 항바이러스 효능 평가에서 플라크 크기 변화를 나타낸 사진 및 그래프이다.Figure 24 is a photograph and graph showing the change in plaque size in the evaluation of the antiviral efficacy of extracts of Prickly pear and Prickly pear extract against VZV alphaherpesvirus.
도 25는 솜양지꽃 추출물 및 분획물 5종의 VZV 알파허피스바이러스에 대한 항바이러스 효능 평가 결과를 나타낸 사진 및 그래프이다.Figure 25 is a photograph and graph showing the results of evaluating the antiviral efficacy of 5 types of extracts and fractions of Sulfuria chinensis against VZV alphaherpesvirus.
도 26은 솜양지꽃 분획물 2종의 VZV 알파허피스바이러스에 대한 항바이러스 효능 평가 결과를 나타낸 사진 및 그래프이다.Figure 26 is a photograph and a graph showing the results of evaluating the antiviral efficacy of two types of Prickly pear fractions against VZV alphaherpesvirus.
도 27은 솜양지꽃 헥산 분획물의 VZV 알파허피스바이러스에 대한 항바이러스 효능 평가에서 플라크 크기 변화를 나타낸 사진 및 그래프이다.Figure 27 is a photograph and graph showing the change in plaque size in the evaluation of the antiviral efficacy of the hexane fraction of Solanum vulgaris against VZV alphaherpesvirus.
이하, 첨부한 도면을 참조하여 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 본원의 실시태양 및 실시예를 상세히 설명한다. 그러나 본원은 여러 가지 형태로 구현될 수 있으며 여기에서 설명하는 실시태양 및 실시예에 한정되지 않는다.Hereinafter, with reference to the attached drawings, embodiments and examples of the present invention will be described in detail so that those skilled in the art can easily implement the present invention. However, the present application may be implemented in various forms and is not limited to the embodiments and examples described herein.
본원 명세서 전체에서, 어떤 부분이 어떤 구성 요소를 “포함” 한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성 요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.Throughout the specification of the present application, when a part “includes” a certain component, this means that it may further include other components rather than excluding other components unless specifically stated to the contrary.
본 발명에 사용된 용어 “예방”은 본 발명에 따른 조성물의 투여에 의해 질환 등을 억제 또는 지연시키는 모든 행위를 의미하고, “치료”는 상기 조성물의 투여에 의해 질환의 의심 및 발병 개체의 증상이 호전되거나 이롭게 변경되는 모든 행위를 의미한다. 본 발명에 사용된 용어 “개선”은 본 발명의 추출물을 포함하는 조성물의 투여로 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.As used in the present invention, the term “prevention” refers to any action that suppresses or delays a disease, etc. by administration of the composition according to the present invention, and “treatment” refers to symptoms of a suspected disease or diseased individual by administration of the composition. This means any action that improves or changes to benefit. As used herein, the term “improvement” refers to any action that results in at least a reduction in the severity of a parameter, such as a symptom, associated with the condition being treated by administration of a composition comprising an extract of the present invention.
본 발명의 솔송나무는 Tsuga sieboldii Carriere으로 소나무과 솔송나무속에 속하며, 주로 울릉도와 일본에 분포하고, 알레르기 질환 치료제의 성분으로 사용될 수 있음이 알려져 있다.The hemlock tree of the present invention is Tsuga sieboldii Carriere , which belongs to the genus of Hemlock family of the Pinaceae family, is mainly distributed in Ulleungdo and Japan, and is known to be used as an ingredient in the treatment of allergic diseases.
본 발명의 솜양지꽃은 Potentilla discolor Bunge으로 장미과 양지꽃속에 속하며, 한국, 대만, 러시아, 일본, 중국 등지에서 넓은 분포를 나타내고, 당뇨병, 면역 질환 등에 사용될 수 있음이 알려져 있다.The cotton bellflower of the present invention is Potentilla discolor Bunge , which belongs to the Rosaceae genus and is widely distributed in Korea, Taiwan, Russia, Japan, China, etc., and is known to be used for diabetes, immune diseases, etc.
본 발명의 은양지꽃은 Potentilla nivea L.으로 장미과 양지꽃속에 속하며, 한반도 북부지방 및 러시아, 일본, 중국, 유럽, 북미 등에 분포한다.The flower of the present invention is Potentilla nivea L. , which belongs to the Rosaceae genus and is distributed in the northern part of the Korean Peninsula, Russia, Japan, China, Europe, North America, etc.
본 발명의 제주피막이는 Hydrocotyle yabei Makino으로 미나리과 피막이속에 속하며, 제주도 및 일본 등에 분포한다.The Jeju marigold of the present invention is Hydrocotyle yabei Makino , which belongs to the genus Apiaceae and is distributed in Jeju Island and Japan.
본 발명의 전호는 Anthriscus sylvestris으로 미나리과 전호속에 속하며, 유럽, 아시아, 아프리카 등에 분포한다.The general name of the present invention is Anthriscus sylvestris , which belongs to the genus Apiaceae and is distributed in Europe, Asia, Africa, etc.
본 발명에 사용된 용어 "노로바이러스"는 양성단일가닥 RNA를 게놈으로 가지는 칼리시바이러스과(Caliciviridae), 노로바이러스속(Norovirus)에 속하는 바이러스를 의미한다.The term "norovirus" used in the present invention refers to a virus belonging to the Caliciviridae and Norovirus genus, which has positive single-stranded RNA as its genome.
본 발명에 사용된 용어 "알파허피스바이러스"는 허피스바이러스과(Herpesviridae) 또는 알파허피스바이러스아과(Alphaherpesvirinae)에 속하는 바이러스를 의미한다.The term “alphaherpesvirus” used in the present invention refers to a virus belonging to the herpesviridae or alphaherpesvirinae subfamily.
이중 엡스타인 바 바이러스(EBV)와 카포시 육종 허피스바이러스(KSHV)는 감마허피스바이러스에 속한다.Among them, Epstein-Barr virus (EBV) and Kaposi's sarcoma herpesvirus (KSHV) belong to the gammaherpesviruses.
본 발명에 사용된 용어 "엡스타인 바 바이러스"는 감마허피스바이러스아과(Gammaherpesvirinae), 림포크립토바이러스속(Lymphocryptovirus)에 속하는 Epstein-Barr virus를 의미하며, "EBV"로 지칭되기도 한다.The term "Epstein Barr virus" used in the present invention refers to the Epstein-Barr virus belonging to the Gammaherpesvirinae and Lymphocryptovirus genus, and is also referred to as "EBV".
본 발명에 사용된 용어 "카포시 육종 허피스바이러스"는 감마허피스바이러스아과(Gammaherpesvirinae), 라디노바이러스속(Rhadinovirus)에 속하는 Kaposi's sarcoma-associated herpesvirus를 의미하며, "KSHV"로 지칭되기도 한다.The term "Kaposi's sarcoma herpesvirus" used in the present invention refers to Kaposi's sarcoma-associated herpesvirus belonging to the Gammaherpesvirinae and Rhadinovirus genus, and is also referred to as "KSHV".
본 발명에 사용된 용어 "수두-대상포진바이러스"는 알파허피스바이러스아과(Alphaherpesvirinae), 바이셀라바이러스속(Varicellovirus)에 속하는 Varicella-zoster virus를 의미하며, "VZV" 또는 "Human herpesvirus 3"으로 지칭되기도 한다.The term "varicella-zoster virus" used in the present invention refers to Varicella-zoster virus belonging to the Alphaherpesvirinae and Varicellovirus genus, and is referred to as "VZV" or "Human herpesvirus 3" It can also happen.
본 발명에 사용된 용어 "단순포진바이러스"는 알파허피스바이러스아과(Alphaherpesvirinae), 단순바이러스속(Simplexvirus)에 속하는 Herpes simplex virus-1를 의미하며, "HSV-1"으로 지칭되기도 한다.The term “herpes simplex virus” used in the present invention refers to Herpes simplex virus-1 belonging to the Alphaherpesvirinae and Simplexvirus genus, and is also referred to as “HSV-1.”
본 발명자들은 솔송나무, 솜양지꽃, 은양지꽃, 및 제주피막이로 이루어진 군에서 하나 이상 선택된 추출물이 감마허피스바이러스에 대한 항바이러스 효과를 가진다는 점을 최초로 발견하였다. 구체적으로, 솔송나무, 솜양지꽃, 은양지꽃, 및 제주피막이로 이루어진 군에서 하나 이상 선택된 추출물이 KSHV 및 EBV의 활성을 억제한다는 점을 발견하였다.The present inventors discovered for the first time that one or more extracts selected from the group consisting of hemlock, hemlock, euphorbia, and Jeju marigold have an antiviral effect against gammaherpesvirus. Specifically, it was found that one or more extracts selected from the group consisting of hemlock, hemlock, euphorbia, and Jeju capsicum inhibit the activity of KSHV and EBV.
상기 솔송나무, 솜양지꽃, 은양지꽃, 제주피막이, 및 전호 추출물은 줄기, 열매, 뿌리, 또는 잎의 추출물일 수 있으나, 이에 제한되지 않는다.The extracts of hemlock, hemlock, euphorbia, jeju capifolia, and jeonho may be extracts of stems, fruits, roots, or leaves, but are not limited thereto.
본 발명에 사용된 용어 "추출물"은 당업계에서 조추출물(crude extract)로 통용되는 것을 의미하지만, 광의적으로 추출물을 추가적으로 분획(fractionation)한 분획물도 포함한다. 즉 추출물은 상술한 용매를 이용하여 얻은 것뿐만 아니라, 여기에 정제 과정을 추가적으로 적용하여 얻은 것을 포함한다. 예컨대, 상기 추출물을 일정한 분자량 컷-오프 값을 갖는 한외여과막을 통과시켜 얻은 분획, 다양한 크로마토그래프(크기, 전하, 소수성 또는 친화성에 따른 분리를 위해 제작된 것)에 의한 분리 등, 추가적으로 실시된 다양한 정제 방법을 통해 얻어진 분획도 본 발명의 추출물에 포함된다.The term “extract” used in the present invention refers to what is commonly used in the art as a crude extract, but in a broad sense also includes fractions obtained by additional fractionation of the extract. That is, the extract includes not only those obtained using the above-mentioned solvents, but also those obtained by additionally applying a purification process. For example, fractions obtained by passing the extract through an ultrafiltration membrane with a certain molecular weight cut-off value, separation by various chromatographs (designed for separation according to size, charge, hydrophobicity, or affinity), etc. Fractions obtained through purification methods are also included in the extract of the present invention.
본 발명에 사용되는 추출물은 열수 추출, 냉침 추출, 환류 냉각 추출, 초음파 추출 또는 당업계에 알려진 통상적인 추출방법을 통해 추출한 것일 수 있다.The extract used in the present invention may be extracted through hot water extraction, cold needle extraction, reflux cooling extraction, ultrasonic extraction, or conventional extraction methods known in the art.
본 발명에 사용되는 추출물은 당업계에서 공지된 통상적인 추출용매를 사용하여 얻을 수 있다. 추출용매로는 극성 용매 또는 비극성 용매를 이용할 수 있다. 극성 용매로는 물, C1 내지 C6의 알코올(예: 메탄올, 에탄올, 프로판올, 부탄올, 노말-프로판올, 이소-프로판올 및 노말-부탄올 등), 아세트산, 또는 상기 극성 용매들의 혼합물을 포함한다. 비극성 용매로는 아세톤, 아세토나이트릴, 에틸아세테이트, 메틸아세테이트, 부틸아세테이트, 플루오로알칸, 헥산, 에테르, 클로로포름, 디클로로메탄 또는 상기 비극성 용매들의 혼합물을 포함한다.The extract used in the present invention can be obtained using a conventional extraction solvent known in the art. As the extraction solvent, a polar solvent or a non-polar solvent can be used. Polar solvents include water, C1 to C6 alcohols (e.g., methanol, ethanol, propanol, butanol, n-propanol, iso-propanol, and n-butanol, etc.), acetic acid, or mixtures of the above polar solvents. Nonpolar solvents include acetone, acetonitrile, ethyl acetate, methyl acetate, butyl acetate, fluoroalkane, hexane, ether, chloroform, dichloromethane, or mixtures of the above nonpolar solvents.
본 발명의 식품 조성물은 건강기능식품, 유제품, 발효제품 또는 식품 첨가물일 수 있다.The food composition of the present invention may be a health functional food, dairy product, fermented product, or food additive.
상기 건강기능식품은 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, “기능성”은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.The above health functional foods refer to foods manufactured and processed using raw materials or ingredients with functional properties useful to the human body. “Functional” refers to foods that are useful for health purposes such as regulating nutrients for the structure and function of the human body or physiological effects. It means taking it for the purpose of obtaining effects.
본 발명의 동물용 사료 조성물은, 모든 비-인간 동물, 예를들어 비-인간 영장류, 양, 개, 소, 말 등에게 섭취시킬 수 있다.The animal feed composition of the present invention can be ingested by all non-human animals, such as non-human primates, sheep, dogs, cows, horses, etc.
이하 실시예를 통하여 본 발명을 더욱 상세하게 설명하고자 하나, 하기의 실시예는 단지 설명의 목적을 위한 것이며 본원 발명의 범위를 한정하고자 하는 것은 아니다.The present invention will be described in more detail through examples below. However, the examples below are for illustrative purposes only and are not intended to limit the scope of the present invention.
[제조예 1][Production Example 1]
솜양지꽃, 은양지꽃 및 전호 추출물의 제조Manufacture of Extracts of Euphorbia flower, Euphorbia chinensis and Jeonho extract
솜양지꽃 전초, 은양지꽃 전초, 전호 잎, 줄기 및 꽃의 3종 천연물 추출물을 한국식물추출물은행 (한국생명공학연구원 오창분원)으로부터 분양받아 100% DMSO를 용매로 용해시켜 추출물을 제조하였다.Extracts of three types of natural products, including Psyllium vulgaris herbaceous plant, Psyllium spp. leaf, stem, and flower, were purchased from the Korea Plant Extract Bank (Korea Research Institute of Bioscience and Biotechnology, Ochang Branch), and the extracts were prepared by dissolving 100% DMSO as a solvent.
[제조예 2][Production Example 2]
솜양지꽃 전초 분획물의 제조Preparation of the whole plant fraction of the flower
솜양지꽃 전초에 10배수의 99.5% 메틸알콜을 넣은 후, 450분간 sonication 한 뒤 72시간 침지추출하였다. 상기 추출물을 여과한 다음 50℃에서 감압농축하여 솜양지꽃 전초 추출물을 제조하였다. 이후 상기 방법으로 제조된 전초 추출물을 10배수의 증류수에 녹였다. 해당 용액에 동일한 부피의 핵산을 넣어 액체-액체 추출법으로 3회 추출한 뒤 50℃에서 감압농축하여 솜양지꽃 전초 헥산(Hexane) 분획물을 제조하였다. 여액에 동일한 부피의 클로로포름(Chloroform)을 넣어 액체-액체 추출법으로 3회 추출한 뒤 50℃에서 감압농축하여 솜양지꽃 전초 클로로포름 분획물을 제조하였다. 여액에 동일한 부피의 에틸아세테이트(Ethyl Acetate)를 넣어 액체-액체 추출법으로 3회 추출한 뒤 50℃에서 감압농축하여 솜양지꽃 전초 에틸아세테이트 분획물을 제조하였다. 여액에 동일한 부피의 수포화 부탄올(Butanol)을 넣어 액체-액체 추출법으로 3회 추출한 뒤 50℃에서 감압농축하여 솜양지꽃 전초 부탄올 분획물을 제조하였다. 여액을 50℃에서 감압농축하여 솜양지꽃 전초 물 분획물을 제조하였다.After adding 10 times 99.5% methyl alcohol to the whole plant, it was sonified for 450 minutes and then immersed and extracted for 72 hours. The extract was filtered and then concentrated under reduced pressure at 50°C to prepare an extract of the whole plant extract. Afterwards, the whole plant extract prepared by the above method was dissolved in 10 times the amount of distilled water. An equal volume of nucleic acid was added to the solution, extracted three times by liquid-liquid extraction, and then concentrated under reduced pressure at 50°C to prepare a hexane fraction of the herbaceous plant. An equal volume of chloroform was added to the filtrate, extracted three times using liquid-liquid extraction, and then concentrated under reduced pressure at 50°C to prepare a chloroform fraction from the herbaceous plant. An equal volume of ethyl acetate was added to the filtrate, and the extract was extracted three times using liquid-liquid extraction, and then concentrated under reduced pressure at 50°C to prepare an ethyl acetate fraction. An equal volume of saturated butanol was added to the filtrate, extracted three times using liquid-liquid extraction, and then concentrated under reduced pressure at 50°C to prepare a butanol fraction from the plant. The filtrate was concentrated under reduced pressure at 50°C to prepare a water fraction of Soybean herbaceous plant.
[실시예 1] [Example 1]
감마허피스바이러스 억제 효능을 나타내는 천연물 추출물 선정을 위한 스크리닝Screening to select natural extracts showing gammaherpesvirus inhibitory effect
감마허피스바이러스 억제 효능을 나타내는 천연물 추출물을 선정하기 위해 감마허피스바이러스 가운데 KSHV가 잠복감염된 BC-3 세포에 dsGFP(Green Fluorescent Protein)를 reporter gene로 도입한 BC-3-G 세포주를 이용하였다. 상기 BC-3-G 세포주는 바이러스의 활성 감염(lytic replication)에 의해 GFP를 발현하는 특징을 가진다.To select a natural product extract showing gammaherpesvirus inhibition efficacy, the BC-3-G cell line, in which dsGFP (Green Fluorescent Protein) was introduced as a reporter gene into BC-3 cells latently infected with KSHV, a gammaherpesvirus, was used. The BC-3-G cell line has the characteristic of expressing GFP due to active infection (lytic replication) of the virus.
총 86개의 천연물 유래 혼합물 시료가 스크리닝을 위해 준비되었고, 각 혼합물 시료는 3종의 천연물 추출물로 구성하였다.A total of 86 mixture samples derived from natural products were prepared for screening, and each mixture sample consisted of three types of natural product extracts.
총 258개의 천연물 시료를 한국식물추출물은행 (한국생명공학연구원 오창분원)으로부터 분양받아 100% DMSO를 용매로 하여 50 mg/ml 농도로 제조하였고, 각 천연물 시료 국명 (또는 품명)의 가나다 순으로 3개씩 1:1:1 비율로 40 μl씩 혼합하여 상기 86개의 천연물 유래 혼합물 시료를 준비하였으며, 하기 표 1에 천연물 시료의 종류를 표시하였다.A total of 258 natural product samples were distributed from the Korea Plant Extract Bank (Korea Research Institute of Bioscience and Biotechnology, Ochang Branch) and prepared at a concentration of 50 mg/ml using 100% DMSO as a solvent. Each natural product sample was divided into 3 alphabets by country name (or product name). The 86 natural product-derived mixture samples were prepared by mixing 40 μl each in a 1:1:1 ratio, and the types of natural product samples are shown in Table 1 below.
번호number | 국명/품명Country name/product name |
1One | 가는오이풀, 가시딸기, 가시복분자딸기Thin cucumber grass, thorn strawberry, thorn raspberry |
22 | 가시여뀌, 가침박달, 각시둥굴레Prickly pear, prickly pear, prickly pear |
33 | 각시원추리, 갈기조팝나무, 감자난초Day lily, mane lily, potato orchid |
44 | 감절대, 개구릿대, 개대황Gamjeoldae, frog stalk, rhubarb rhubarb |
55 | 개맥문동, 개박달나무, 개발나물Gaemacmundong, Gaebaek tree, and development greens |
66 | 개벚나무, 개살구나무, 개서어나무Dog cherry tree, dog apricot tree, dog hornbeam tree |
77 | 개소시랑개비, 개시호, 개암나무Gaesosiranggabi, Gagiho, hazel tree |
88 | 개여뀌, 개잎갈나무, 개키버들Larch tree, Larch tree, Willow tree |
99 | 개회나무, 갯강활, 갯대추나무Gaehoe tree, Gaetgan bow, Gaetgan jujube tree |
1010 | 갯버들, 갯사상자, 거문딸기Pussy willow, Pussy willow, Geomun strawberry |
1111 | 거제딸기, 거지딸기, 검은딸기Geoje strawberry, beggar strawberry, black strawberry |
1212 | 겨울딸기, 고마리, 곰딸기Winter strawberries, gomari, bear strawberries |
1313 | 공조팝나무, 구골나무, 구릿대Coniferous pop tree, googol tree, copper pole |
1414 | 구상나무, 국수나무, 궁궁이Korean fir tree, noodle tree, Gunggungi |
1515 | 귀룽나무, 금감, 금강애기나리Euphorbia tree, golden persimmon, Geumgang lily |
1616 | 금난초, 금목서, 금새우난Geum orchid, Geum mokseo, Geum saeun orchid |
1717 | 긴사상자, 긴잎조팝나무, 까마귀베개Long-leafed spirea, long-leafed spirea, crow's pillow |
1818 | 까치박달, 꼬리조팝나무, 꽃사과나무Magpie birch, spirea, flowering apple tree |
1919 | 꽃여뀌, 꽃장포, 꿩의다리아재비Flower lily, peduncle, pheasant's leg flower |
2020 | 끈끈이여뀌, 나도국수나무, 나도양지꽃Sticky fish, Nado noodle tree, Nado brisket flower |
2121 | 내버들, 넓은잎산사, 눈갯버들Nae willow, broadleaf willow, snowy willow |
2222 | 능수버들, 다정큼나무, 단풍터리풀Weeping willow, weeping willow, maple leaf weed |
2323 | 닭의난초, 당근, 당조팝나무Chicken orchid, carrot, poplar tree |
2424 | 당키버들, 덩굴모밀, 독일가문비Danki willow, vine buckwheat, German spruce |
2525 | 돌가시나무, 돌배나무, 돌소리쟁이Stone thorn tree, Stone pear tree, Stone thorn tree |
2626 | 돌양지꽃, 두루미꽃, 두메부추Dried plum blossoms, crane blossoms, plum chives |
2727 | 둥근잎다정큼, 들메나무, 땃딸기Round leaves, wild buckthorn, wild strawberries |
2828 | 떡버들, 떡윤노리나무, 떡조팝나무Prickly pear tree, Prickly pear tree, Prickly pear tree |
2929 | 리기다소나무, 마가목, 만년청Rigida pine, mountain ash, perennial blue |
3030 | 맥도딸기, 맥문아재비, 메밀Macdo strawberry, croaker, buckwheat |
3131 | 며느리배꼽, 명아자여뀌, 목서Daughter-in-law's belly button, Myeong-a-ja-yekwi, Mok-seo |
3232 | 묏미나리, 묵밭소리쟁이, 물개암나무Water parsley, mukbat screech, seal hazelnut tree |
3333 | 물박달나무, 물양지꽃, 물오리나무Water birch, water birch, teal alder |
3434 | 물푸레나무, 미국산사, 미꾸리낚시Ash tree, American mountain lion, loach fishing |
3535 | 미루나무, 민미꾸리낚시, 밀나물Cottonwood tree, loach fishing, wheat sprouts |
3636 | 바디나물, 박달나무, 박달목서Body namul, birch tree, birch tree |
3737 | 박새, 백선, 백송Chickadee, white line, white pine |
3838 | 백운기름나물, 백운배나무, 버드나무Baekun oil plant, Baekun pear tree, willow tree |
3939 | 벚나무, 병아리꽃나무, 복사나무Cherry tree, chickweed tree, peach tree |
4040 | 분버들, 분비나무, 붉은사철란willow, willow tree, red perennial orchid |
4141 | 붉은참반디, 붉은호장근, 비짜루Red firefly, Red knotweed, Vizzaru |
4242 | 사방오리, 사스래나무, 산돌배Sabang duck, cypress tree, sandol pear |
4343 | 산딸기, 산복사나무, 산부추Wild strawberries, wild bok choy, wild chives |
4444 | 산여뀌, 산오이풀, 산외Mountain yeokyui, mountain cucumber grass, mountain outside |
4545 | 산조팝나무, 산파, 산황나무Sanjo pop tree, Sanpa, Sanhwang tree |
4646 | 삿갓나물, 상동잎쥐똥나무, 상산Prickly pear, Sangdong leaf privet, Sangsan |
4747 | 생열귀나무, 서어나무, 서울귀룽나무Lively quince tree, hornbeam, Seoul quince tree |
4848 | 선밀나물, 선피막이, 섬개벚나무Seonmilnamul, Seonmilnamul, Japanese cherry tree |
4949 | 섬개회나무, 섬나무딸기, 섬딸기Island ash tree, island raspberry, island strawberry |
5050 | 섬말나리, 섬바디, 섬버들Summal lily, Sum body, Sum willow |
5151 | 섬벚나무, 섬쥐똥나무, 소사나무Island cherry tree, island cherry tree, pine tree |
5252 | 솔송나무, 솜양지꽃, 쇠물푸레나무Hemlock, hemlock, and ash tree |
5353 | 수리딸기, 수박, 수수꽃다리Suri strawberry, watermelon, sorghum flower stalk |
5454 | 쉬나무, 쉬땅나무, 스트로브잣나무sycamore tree, sycamore tree, strobe pine tree |
5555 | 신감채, 아구장나무, 아그배나무Singamchae, Monk fir tree, Agpear tree |
5656 | 애기원추리, 앵도나무, 야광나무Daylily, cherry tree, glow-in-the-dark tree |
5757 | 약난초, 양지꽃, 얼레지Medicinal orchid, prickly pear, ragweed |
5858 | 여로, 여우버들, 연영초Yeo-ro, fox willow, Yeonyeongcho |
5959 | 오이, 올벚나무, 왕버들Cucumber, cherry tree, willow tree |
6060 | 왕쥐똥나무, 왕호장근, 왜방풍Chinese sycamore, Japanese knotweed, Japanese apricot |
6161 | 왜벚나무, 용둥굴레, 용버들Japanese cherry tree, Yongdung bridle, Yongdung willow |
6262 | 윤노리나무, 윤판나물, 윤판나물아재비Yunpan tree, Yunpan greens, Yunpan sprouts |
6363 | 은대난초, 은목서, 은방울꽃Silver orchid, silver tree, lily of the valley |
6464 | 은백양, 은사시나무, 은양지꽃Silver aspen, silver aspen, silver aspen flower |
6565 | 이삭여뀌, 이태리포플러, 인가목조팝나무Isak-yeo-kwi, Italian poplar, artificial wooden pop tree |
6666 | 일본잎갈나무, 일본조팝나무, 일월비비추Japanese larch, Japanese spirea, Ilwolbibichu |
6767 | 자두나무, 자주가는오이풀, 잔잎바디Plum tree, common cucumber plant, fine leaf body |
6868 | 잔털벚나무, 잣나무, 장딸기Cherry blossom tree, pine tree, raspberry |
6969 | 장미, 장수만리화, 전나무Rose, Longevity Flower, Fir Tree |
7070 | 전호, 제주피막이, 조팝나무Jeonho, Jeju marigold, spirea tree |
7171 | 좀비비추, 좀사방오리, 좀조팝나무Zombie beetle, mothball duck, moth pop tree |
7272 | 종비나무, 주름제비란, 죽단화Spruce tree, Swallow orchid, bamboo flower |
7373 | 줄딸기, 쥐꼬리풀, 지리터리풀Strawberry, rattail grass, geoliter grass |
7474 | 진황정, 짝자래나무, 참갈매나무Jinhwangjeong, Prickly pear tree, Quercus columbine |
7575 | 참개암나무, 참나물, 참반디Hazelnut tree, Quercus herb, Cham firefly |
7676 | 참산부추, 참소리쟁이, 참여로Chamsan Chives, Chamsorijaengi, Participation |
7777 | 채진목, 처진개벚나무, 콩배나무Chaejin tree, drooping cherry tree, pear tree |
7878 | 큰애기나리, 큰연영초, 큰원추리Large lily, large columbine, large daylily |
7979 | 큰피막이, 키다리난초, 키버들Large orchid, tall orchid, quiver |
8080 | 터리풀, 털갈매나무, 털개벚나무Turtle grass, Buckthorn tree, Buckthorn tree |
8181 | 털개회나무, 털야광나무, 털여뀌Prickly pear tree, Prickly pear tree, Prickly pear tree |
8282 | 털팥배나무, 테다소나무, 퉁둥굴레Red bean pear tree, Teda pine tree, Tungdung Gulre |
8383 | 파드득나물, 팥배나무, 풀솜대Paddeuknamul, red bean pear tree, grass floss stalk |
8484 | 피라칸다, 하늘말나리, 호랑버들Pyracanda, sky lily, swallowtail |
8585 | 호장근, 홍가시나무, 홍도원추리Japanese knotweed, red thorn tree, red daylily |
8686 | 흰꽃여뀌, 흰바디나물, 흰여뀌White flowering plant, white-bodied herb, white flowering plant |
상기 KSHV 잠복감염 세포에 바이러스의 재활성을 유도하는 TPA(12-O-Tetradecanoylphorbol-13-acetate) 20ng/㎖ 와 상기 86개 천연물 유래 혼합물 시료 50㎍/㎖를 처리하고, 24시간이 지난 후 천연물 유래 혼합물 시료의 KSHV 억제 효능을 확인하기 위한 유세포 분석(Flow cytometry analysis)을 하였고, 이를 통해 살아있는 세포 중 GFP 발현 세포수를 분석하여 KSHV 재활성 정도를 측정하였다.The KSHV latently infected cells were treated with 20 ng/ml of TPA (12-O-Tetradecanoylphorbol-13-acetate), which induces reactivation of the virus, and 50 ㎍/ml of the mixture sample derived from the 86 natural products, and after 24 hours, the natural product Flow cytometry analysis was performed to confirm the KSHV inhibitory effect of the derived mixture sample, and the degree of KSHV reactivation was measured by analyzing the number of GFP-expressing cells among living cells.
이때 TPA와 천연물 유래 혼합물 시료의 용매로 사용한 DMSO(Dimethyl Sulfoxide)를 음성대조군으로 사용하였다.At this time, DMSO (Dimethyl Sulfoxide), which was used as a solvent for the TPA and natural product-derived mixture samples, was used as a negative control.
도 1은 상기 천연물 유래 혼합물 시료 처리 시 GFP 발현 정도를 BC-3-G 세포주에 음성대조군을 처리한 경우를 기준으로 나타낸 것이고, 도 2는 86개 천연물 유래 혼합물 시료의 KSHV 억제정도를 용이하게 분석하기 위해 음성대조군에서의 GFP 발현 정도를 0으로 하여 도식화한 것이다.Figure 1 shows the level of GFP expression when processing the natural product-derived mixture sample based on the negative control group treated with the BC-3-G cell line, and Figure 2 shows the degree of KSHV inhibition of 86 natural product-derived mixture samples for easy analysis. To this end, the level of GFP expression in the negative control group was set to 0 and was schematized.
그 결과, 도 2에 나타낸 바와 같이, 22, 28, 29, 51, 52, 57, 63, 64 및 70번 혼합물 시료의 KSHV 억제정도는 음성대조군보다 40% 이상 높은 것으로 나타났다. 다만, 상기 29, 57 및 63번 3종의 천연물 유래 혼합물에서 세포독성(cytotoxicity)이 확인되어, 이를 제외한 22, 28, 51, 52, 64, 및 70번 총 6종의 혼합물을 KSHV 항바이러스 효능이 있는 천연물 유래 혼합물로 선별하였다.As a result, as shown in Figure 2, the degree of KSHV inhibition of mixture samples 22, 28, 29, 51, 52, 57, 63, 64, and 70 was found to be more than 40% higher than that of the negative control group. However, cytotoxicity was confirmed in the three natural product-derived mixtures Nos. 29, 57, and 63, and a total of six mixtures Nos. 22, 28, 51, 52, 64, and 70, excluding this, were tested for KSHV antiviral efficacy. It was selected as a mixture derived from natural products.
[실시예 2] [Example 2]
선별된 천연물 유래 혼합물의 KSHV 항바이러스 효능 평가Evaluation of KSHV antiviral efficacy of selected natural product-derived mixtures
상기 실시예 1을 통해 선별된 6종의 천연물 유래 혼합물의 KSHV 항바이러스 효능을 평가하기 위해 BC-3-G 세포에 TPA를 처리하고, 상기 6종의 천연물 유래 혼합물 각 50㎍/㎖를 처리하였으며, 양성대조군으로 간시클로비어(Ganciclovir)를 사용하여 유세포 분석 및 웨스턴 블롯(western blot) 분석을 실시하였다.To evaluate the KSHV antiviral efficacy of the six natural product-derived mixtures selected through Example 1, BC-3-G cells were treated with TPA, and each of the six natural product-derived mixtures was treated with 50 μg/ml. , flow cytometry and western blot analysis were performed using ganciclovir as a positive control.
도 3에서 나타낸 바와 같이, 유세포 분석 결과, 52, 64, 및 70번 혼합물 시료를 처리하는 경우 대조군에 비해 GFP 발현 세포수가 적은 것으로 나타났고, 도 4의 웨스턴 블롯 결과에서도 KSHV의 용균 단백질(lytic protein)인 RTA와 K8의 단백질 밴드 굵기가 감소하는 것을 확인하였다.As shown in Figure 3, flow cytometry results showed that the number of GFP-expressing cells was lower when processing mixture samples 52, 64, and 70 compared to the control group, and the Western blot results in Figure 4 also showed that the lytic protein of KSHV ), it was confirmed that the protein band thickness of RTA and K8 decreased.
또한, 상기 3종의 혼합물 시료가 농도 의존적으로 KSHV 재활성을 억제하는지 확인하기 위해, KSHV 잠복감염 세포주인 BC-3, BC-3-G, 및 BCBL-1에 TPA 및 각 10, 25, 50㎍/㎖의 농도의 혼합물 시료를 처리하고 웨스턴 블롯 분석을 통해 용균 단백질(lytic protein)인 RTA와 K8의 발현 수준을 확인하였다.In addition, to confirm whether the above three mixture samples inhibit KSHV reactivation in a concentration-dependent manner, TPA and 10, 25, and 50 respectively were added to KSHV latently infected cell lines BC-3, BC-3-G, and BCBL-1. A mixture sample at a concentration of ㎍/ml was processed, and the expression levels of lytic proteins RTA and K8 were confirmed through Western blot analysis.
그 결과, 도 5 내지 도 7에서 확인할 수 있듯이 3종의 혼합물 시료는 농도 의존적으로 KSHV의 재활성을 억제하였다.As a result, as can be seen in Figures 5 to 7, the three mixture samples inhibited the reactivation of KSHV in a concentration-dependent manner.
이로써, 상기 실시예 1을 통해 선별된 6종의 천연물 유래 혼합물 가운데 52, 64, 및 70번 혼합물 시료에서 KSHV에 대한 항바이러스 효과가 있음을 확인하였다.As a result, it was confirmed that mixture samples 52, 64, and 70 among the six natural product-derived mixtures selected through Example 1 had an antiviral effect against KSHV.
[실시예 3][Example 3]
선별된 천연물 유래 혼합물의 EBV 항바이러스 효능 평가Evaluation of EBV antiviral efficacy of selected natural product-derived mixtures
상기 실시예 1을 통해 선별된 6종의 천연물 유래 혼합물의 감마허피스바이러스 가운데 EBV에 대한 항바이러스 효능을 평가하기 위해, EBV가 잠복감염된 Raji 세포주와 Akata(+) 세포주를 사용하였다.To evaluate the antiviral efficacy against EBV among the gammaherpesviruses of the six natural product-derived mixtures selected through Example 1, Raji cell line and Akata(+) cell line latently infected with EBV were used.
Raji 세포주에 바이러스 재활성 유도를 위한 TPA를, Akata(+) 세포주에는 IgG를 각 처리하고, 상기 6종의 천연물 유래 혼합물 각 50㎍/㎖를 Raji 세포주와 Akata(+) 세포주에 처리한 후, EBV의 용균 단백질(lytic protein)인 ZTA와 EA-D의 발현 수준을 웨스턴 블랏 분석을 통해 확인하였다.The Raji cell line was treated with TPA to induce virus reactivation, and the Akata(+) cell line was treated with IgG, and the Raji cell line and the Akata(+) cell line were treated with 50 μg/ml of each of the six natural product-derived mixtures, The expression levels of ZTA and EA-D, which are lytic proteins of EBV, were confirmed through Western blot analysis.
도 8에서 나타낸 바와 같이, 52, 64, 및 70번 혼합물 시료를 처리한 경우, Raji 세포주에서 ZTA의 발현 수준이 감소하는 것을 확인하였고, 도 9를 통해 상기 52, 64, 및 70번 혼합물 시료를 처리한 경우 Akata(+) 세포주에서 ZTA와 EA-D의 단백질 밴드 굵기가 감소하는 것을 확인하였다.As shown in Figure 8, when the mixture samples 52, 64, and 70 were treated, the expression level of ZTA was confirmed to decrease in the Raji cell line. As shown in Figure 9, the mixture samples 52, 64, and 70 were confirmed to be When treated, it was confirmed that the protein band thickness of ZTA and EA-D decreased in Akata(+) cell line.
또한, 상기 실시예 2에서와 마찬가지로 선별된 천연물 유래 혼합물 시료가 EBV 재활성 억제에 농도 의존적으로 효과가 있는지 확인하기 위해 Akata(+) 세포주에 IgG 및 각 10, 25, 50㎍/㎖의 농도의 52, 64, 및 70번 혼합물 시료를 처리하고 웨스턴 블롯 분석으로 용균 단백질(lytic protein)인 EA-D와 ZTA의 발현 수준을 확인하였다.In addition, as in Example 2, in order to confirm whether the selected natural product-derived mixture sample was effective in suppressing EBV reactivation in a concentration-dependent manner, IgG and IgG at concentrations of 10, 25, and 50 μg/ml were applied to the Akata (+) cell line. Mixture samples No. 52, 64, and 70 were processed, and the expression levels of lytic proteins EA-D and ZTA were confirmed by Western blot analysis.
그 결과, 도 10에 나타낸 바와 같이, 상기 52, 64, 및 70번 혼합물 시료가 EBV에 대해 농도 의존적으로 항바이러스 효과가 있음을 확인하였다.As a result, as shown in FIG. 10, it was confirmed that mixture samples Nos. 52, 64, and 70 had a concentration-dependent antiviral effect against EBV.
상기와 같이 천연물 유래 혼합물 중 52, 64, 및 70번 혼합물 시료가 KSHV 뿐만 아니라 EBV에서도 효과가 있음이 확인되었는 바, 해당 결과를 바탕으로 하기의 실시예에서 상기 3종의 천연물 유래 혼합물에 포함된 총 9종의 천연물 추출물을 대상으로 항바이러스 효능에 관한 실험을 진행하였다.As described above, it was confirmed that mixture samples 52, 64, and 70 among the mixtures derived from natural products were effective not only for KSHV but also for EBV. Based on the results, in the examples below, the mixtures contained in the three types of mixtures derived from natural products were tested. An experiment on antiviral efficacy was conducted on a total of 9 types of natural product extracts.
[실시예 4] [Example 4]
솔송나무, 솜양지꽃, 은양지꽃, 및 제주피막이 추출물의 KSHV 항바이러스 효능 평가Evaluation of KSHV antiviral efficacy of extracts of hemlock, cypress, euphorbia, and Jeju mantle extracts
항바이러스 효능을 나타낸 천연물 유래 혼합물 3종에 포함된 개별 천연물 추출물의 종류는 하기 표 2와 같으며, 각 천연물 추출물의 항바이러스 효능을 평가하기 위한 실험을 진행하였다.The types of individual natural product extracts included in the three natural product-derived mixtures that showed antiviral efficacy are shown in Table 2 below, and an experiment was conducted to evaluate the antiviral efficacy of each natural product extract.
AA | 솔송나무hemlock tree |
BB | 솜양지꽃cotton brisket flower |
CC | 쇠물푸레나무ash tree |
DD | 은백양silver white sheep |
EE | 은사시나무silver aspen tree |
FF | 은양지꽃silver lily flower |
GG | 전호phone |
HH | 제주피막이Jeju cover |
II | 조팝나무spirea tree |
상기 9종의 천연물 추출물이 KSHV 항바이러스 효능을 가지는지 평가하기 위해, 바이러스의 재활성을 유도하는 TPA 20ng/㎖를 KSHV 잠복 감염 세포주인 BC-3-G, BCBL-1에 처리하고, 천연물 추출물 각 50㎍/㎖를 처리하였으며, 24시간이 지난 후 웨스턴 블롯 분석을 통해 KSHV의 용균 단백질(lytic protein)인 RTA와 K8의 발현 수준을 확인하였다.To evaluate whether the nine types of natural product extracts have KSHV antiviral efficacy, 20ng/ml of TPA, which induces virus reactivation, was treated with KSHV latently infected cell lines BC-3-G and BCBL-1, and the natural product extracts were 50 μg/ml of each was treated, and after 24 hours, the expression levels of RTA and K8, the lytic proteins of KSHV, were confirmed through Western blot analysis.
그 결과, 도 11 및 도 12에 나타낸 바와 같이, 솔송나무(A), 솜양지꽃(B), 은양지꽃(F) 및 전호(G)에서 KSHV 항바이러스 효능을 확인하였고, 특히 솜양지꽃(B)과 은양지꽃(F)이 BC-3-G, BCBL-1 두 세포주 모두에서 강한 항바이러스 효능을 나타내었다.As a result, as shown in Figures 11 and 12, KSHV antiviral efficacy was confirmed in hemlock (A), hemlock (B), euphorbia (F), and jeonho (G), especially in hemlock (B) and Prickly pear (F) showed strong antiviral efficacy in both BC-3-G and BCBL-1 cell lines.
[실시예 5] [Example 5]
솔송나무, 솜양지꽃, 은양지꽃, 및 제주피막이 추출물의 EBV 항바이러스 효능 평가Evaluation of EBV antiviral efficacy of extracts of hemlock, cypress, euphorbia, and Jeju mantle.
상기 표 2의 천연물 추출물의 EBV 항바이러스 효능 평가를 위해 EBV 잠복 감염 세포주인 Raji 세포주에 바이러스의 재활성을 유도하는 TPA 20ng/㎖와 NaB(sodium butyrate) 3mM을 함께 처리하고, Akata(+) 세포주에는 IgG 10㎍/㎖를 처리하였으며, 9종의 천연물 추출물을 Raji 세포주와 Akate(+) 세포주에 각 50㎍/㎖ 처리하고, 24시간이 지난 후 웨스턴 블롯 분석을 통해 EBV의 용균 단백질(lytic protein)인 EA-D와 ZTA의 발현 수준을 확인하였다.To evaluate the EBV antiviral efficacy of the natural product extract in Table 2, the Raji cell line, an EBV latently infected cell line, was treated with 20ng/ml TPA and 3mM NaB (sodium butyrate), which induce reactivation of the virus, and the Akata(+) cell line. was treated with 10㎍/㎖ of IgG, and 50㎍/㎖ of 9 natural product extracts were treated each on Raji cell line and Akate(+) cell line, and after 24 hours, Western blot analysis revealed the lytic protein of EBV. ), the expression levels of EA-D and ZTA were confirmed.
그 결과, 도 13 및 도 14에 나타낸 바와 같이, 솜양지꽃(B), 은양지꽃(F) 및 제주피막이(H)가 Raji 세포주에 항바이러스 효능을 나타내었고, 솜양지꽃(B), 은양지꽃(F), 전호(G) 및 제주피막이(H)가 Akata(+) 세포주에 항바이러스 효능을 나타내었다.As a result, as shown in FIGS. 13 and 14, Prickly pear (B), Prickly pear (F), and Jeju capsicum (H) showed antiviral efficacy against Raji cell lines, and Prickly pear (B) and Prickly pear (B) ( F), Jeonho (G), and Jeju Capricorn (H) showed antiviral efficacy against Akata (+) cell line.
따라서, 상기 실시예 4 및 5를 통해 솜양지꽃, 은양지꽃 및 전호는 KSHV와 EBV 모두에서 항바이러스 효과가 있는 것을 확인하였고, 솔송나무는 카포시 육종 허피스 바이러스(KSHV)에 특이적으로, 제주피막이는 엡스타인 바 바이러스(EBV)에 특이적으로 항바이러스 효과가 있는 것을 확인하였다.Accordingly, through Examples 4 and 5, it was confirmed that Eunuchia, Eunbi and Jeonho have antiviral effects against both KSHV and EBV, Hemlock is specific for Kaposi's sarcoma herpes virus (KSHV), and Jeju capifolia is specific for Kaposi's sarcoma herpes virus (KSHV). It was confirmed that it has a specific antiviral effect against Epstein-Barr virus (EBV).
[실시예 6][Example 6]
노로바이러스에 대한 솜양지꽃 및 은양지꽃 전초 추출물 및 솜양지꽃 분획물의 항바이러스 효능 평가Evaluation of the antiviral efficacy of the whole plant extract and fractions of the flowering plant and the flowering plant against norovirus
마우스노로바이러스인 murine norovirus 1(MNV-1, CW3 strain)을 대상으로 솜양지꽃(B) 및 은양지꽃(F) 및 솜양지꽃의 5종의 분획물에 대한 항바이러스 효능 평가를 수행하였다. The antiviral efficacy of five types of fractions from Prickly pear (B), Prickly pear (F), and Prickly pear flowers was evaluated against murine norovirus 1 (MNV-1, CW3 strain), a mouse norovirus.
도 15에 나타난 바와 같이, 마우스대식세포주(murine macrophage)인 Raw264.7 세포주에 감염 하루 전 6 well plate에 3x10^5 cells/well로 분주하였고, 다음 날 MNV-1을 MOI (Multiplicity of infection) 0.01로 감염시킨 후 천연물 솜양지꽃(B) 및 은양지꽃(F) 추출물을 50 ug/ml로 처리하였다. 감염 24시간일 때 상등액을 수거하여 10배 계대희석 시킨 희석액을 마우스 미세아교세포주(Murine microglial cell)인 BV-2에 감염시키고 3일간 배양함으로써 plaque assay로 바이러스 역가를 측정하였다. As shown in Figure 15, the Raw264.7 cell line, a murine macrophage cell line, was seeded at 3x10^5 cells/well in a 6-well plate one day before infection, and the next day, MNV-1 was added at an MOI (Multiplicity of infection) of 0.01. After infection with , the extracts of the natural products Somnorrhea (B) and Euphorbia (F) were treated with 50 ug/ml. At 24 hours after infection, the supernatant was collected, serially diluted 10 times, and the diluted solution was infected with BV-2, a mouse microglial cell line, and cultured for 3 days to measure virus titer by plaque assay.
솜양지꽃 5종의 분획물의 시료 농도 및 처리농도는 하기 표 3과 같다.The sample concentration and treatment concentration of the fractions of the five species of Solanum vulgaris are shown in Table 3 below.
시료sample | 시료 농도(mg/ml)Sample concentration (mg/ml) | 처리 농도(μg/ml)Treatment concentration (μg/ml) |
헥산 분획물hexane fraction | 7.977.97 | 7.977.97 |
클로로포름 분획물Chloroform fraction | 11.8711.87 | 11.8711.87 |
에틸아세테이트 분획물Ethyl acetate fraction | 1.921.92 | 1.921.92 |
부탄올 분획물Butanol fraction | 3.73.7 | 3.73.7 |
물 분획물water fraction | 24.624.6 | 24.624.6 |
솜양지꽃 추출물(B)의 분획물 5종에 대해서도 동일한 방식으로 항바이러스 효능을 평가하였다.The antiviral efficacy of the five fractions of the Prickly pear extract (B) was evaluated in the same manner.
솜양지꽃(B)과 은양지꽃(F) 추출물에 대한 실험결과를 도 16에 나타내었고, 도 2에 나타낸 바와 같이 솜양지꽃(B)과 은양지꽃(F) 처리시 노로바이러스 증식이 현저히 저해되었다. 특히 은양지꽃(F) 추출물 처리시에 100% 저해효능을 나타내어 매우 우수한 항바이러스 효능을 확인하였다.The results of the experiment on extracts of Lilium chinensis (B) and Lilium chinensis (F) are shown in Figure 16, and as shown in Figure 2, norovirus proliferation was significantly inhibited when treated with Lilium chinensis (B) and Lilium chinensis (F). In particular, when treated with the Euphorbia flower (F) extract, a 100% inhibitory effect was observed, confirming excellent antiviral efficacy.
솜양지꽃(B) 추출물의 5종의 분획물에 대한 실험결과를 도 17에 나타내었고, 도 3에 나타낸 바와 같이 솜양지꽃(B)의 헥산 분획물 및 클로로포름 분획물을 처리한 실험군에서 플라크 형성이 현저히 저해되어 우수한 항바이러스 효능을 갖는 것을 확인하였다.The experimental results of the five types of fractions of the extract of Solanum vulgaris (B) are shown in Figure 17, and as shown in Fig. 3, plaque formation was significantly inhibited in the experimental group treated with the hexane fraction and the chloroform fraction of Lilium vulgaris (B). It was confirmed to have excellent antiviral efficacy.
따라서, 솜양지꽃(B) 및 음양지꽃(F) 전초 추출물, 및 솜양지꽃(B)의 헥산 분획물 및 클로로포름 분획물은 우수한 항바이러스 효능을 갖고, MNV-1 증식을 저해하는 강력한 항바이러스 물질을 포함하는 것을 알 수 있다.Therefore, the whole plant extracts of Prickly pear (B) and Prickly pear (F), and the hexane and chloroform fractions of Prickly pear (B) have excellent antiviral efficacy and contain powerful antiviral substances that inhibit MNV-1 proliferation. You can see that
[실시예 7][Example 7]
알파허피스바이러스에 대한 솜양지꽃 전초 추출물, 은양지꽃 전초 추출물, 솜양지꽃 분획물 및 전호 추출물의 항바이러스 효능 평가Evaluation of the antiviral efficacy of Elephant chinensis whole plant extract, Elephant perilla alla extract, Fraction of Elephant herbacea, and Jeonho extract against alphaherpesvirus.
신경계감염 알파허피스바이러스인 HSV-1과 VZV에 대한 항바이러스 효능을 평가하기 위해 plaque reduction assay를 수행하였다. A plaque reduction assay was performed to evaluate the antiviral efficacy against HSV-1 and VZV, which are alphaherpesviruses that infect the nervous system.
도 18에 나타낸 바와 같이, 감염 하루 전에 Vero 세포나 12웰 플레이트에 분주하고, 실험 당일 각 웰 당 >100 PFU의 바이러스를 1시간 동안 감염시킨 후, 추출물 또는 분획물과 혼합한 overlay media를 각 웰에 채우고 HSV-1을 3일간 배양한 후 형성되는 플라크(plaque)의 숫자를 계수하였다. As shown in Figure 18, Vero cells or 12-well plates were seeded one day before infection, and on the day of the experiment, each well was infected with >100 PFU of virus for 1 hour, and then overlay media mixed with the extract or fraction was added to each well. After filling and culturing HSV-1 for 3 days, the number of plaques formed was counted.
VZV를 MeWo 세포에서 2시간 동안 감염시키고, 추출물 또는 분획물을 처리한 후 4-6일간 배양한 후 플라크의 숫자를 계수하였다. Vehicle 처리 샘플에서의 플라크 숫자를 기준으로 추출물 또는 분획물처리 샘플의 상대적인 바이러스 플라크 형성 비율(%)을 분석하였다.VZV was infected in MeWo cells for 2 hours, the extract or fraction was treated, and the number of plaques was counted after culturing for 4-6 days. The relative rate of viral plaque formation (%) in extract or fraction treated samples was analyzed based on the number of plaques in vehicle treated samples.
2-1 HSV-1 항바이러스 효능 평가 결과2-1 HSV-1 antiviral efficacy evaluation results
HSV-1에 대한 항바이러스 효능평가를 위해 gold standard assay에 해당하는 plaque reduction assay를 수행하였다. African Green Monkey kidney 유래 세포주인 Vero 세포에 각 well 당 >100 PFU의 HSV-1을 1시간 동안 감염시킨 후, 추출물을 10, 25, 50 ㎍/㎖ 처리한 overlay media를 처리하여 3일간 배양하여 그 결과를 도 19에 나타내었다. To evaluate antiviral efficacy against HSV-1, a plaque reduction assay corresponding to the gold standard assay was performed. Vero cells, a cell line derived from the African Green Monkey kidney, were infected with >100 PFU of HSV-1 per well for 1 hour, then treated with overlay media treated with 10, 25, and 50 ㎍/ml extract, and cultured for 3 days. The results are shown in Figure 19.
도 19에 나타낸 바와 같이, 양성대조군으로서 사용한 뉴클레오사이드 유사체인 Gancyclovir (GCV)는 40 ㎍/㎖ 농도로 처리하였고, 플라크의 형성이 저해되는 것을 확인하였다. 또한, 솜양지꽃(B)와 은양지꽃(F) 추출물을 10, 25, 50 ㎍/㎖ 농도로 처리했을 때, 고농도에서 매우 높은 항바이러스 효능을 나타내었다. As shown in Figure 19, Gancyclovir (GCV), a nucleoside analog used as a positive control, was treated at a concentration of 40 μg/ml, and it was confirmed that plaque formation was inhibited. In addition, when extracts of Prickly pear (B) and Prickly pear (F) were treated at concentrations of 10, 25, and 50 ㎍/㎖, very high antiviral efficacy was shown at high concentrations.
Plaque reduction assay에서는 플라크 형성 숫자와 더불어 플라크의 사이즈도 항바이러스 효능의 지표가 된다. 솜양지꽃(B)와 은양지꽃(F) 추출물을 처리했을 때, 도 20에 나타낸 바와 같이 플라크의 크기가 10 및 25 ㎍/㎖에서 농도 의존적으로 감소하는 것을 확인하였다.In the plaque reduction assay, the number of plaques formed and the size of the plaques are also indicators of antiviral efficacy. When treated with extracts of Prickly pear (B) and Prickly pear (F), it was confirmed that the size of plaques decreased in a concentration-dependent manner at 10 and 25 μg/ml, as shown in Figure 20.
또한, 전호(G) 추출물에 대한 plaque reduction assay를 수행하여 그 결과를 도 21에 나타내었다. 도 21에 나타낸 바와 같이, 전호(G) 추출물을 10, 25, 50 ㎍/㎖ 농도로 처리했을 때 모든 농도에서 플라크가 형성되지 않아 매우 뛰어난 항바이러스 효능이 나타내었다. 또한, 농도를 더욱 낮추어 2와 5 ㎍/㎖ 농도로 처리했을 때도 플라크의 형성이 완전히 저해되는 것을 확인하였다.Additionally, a plaque reduction assay was performed on the Jeonho (G) extract, and the results are shown in Figure 21. As shown in Figure 21, when the Jeonho (G) extract was treated at concentrations of 10, 25, and 50 ㎍/㎖, no plaques were formed at all concentrations, showing excellent antiviral efficacy. In addition, it was confirmed that the formation of plaques was completely inhibited even when the concentration was further lowered to 2 and 5 ㎍/㎖.
결국, 솜양지꽃(B), 은양지꽃(F) 및 전호(G)의 추출물은 HSV-1에 대한 뛰어난 항바이러스 효능을 갖는 것을 알 수 있다.In the end, it can be seen that the extracts of Prickly pear (B), Prickly pear (F), and Prickly pear (G) have excellent antiviral efficacy against HSV-1.
추가로, 솜양지꽃(B)의 분획물 5종에 대해 항바이러스 효능을 상기 표 3에 나타낸 농도로 plaque reduction assay를 수행하여 그 결과를 도 22에 나타내었다. 도 22에 나타낸 바와 같이, 솜양지꽃(B)의 헥산 분획물과 클로로포름 분획물이 HSV-1에 대한 우수한 항바이러스 효능을 나타내는 것을 확인하였다.Additionally, a plaque reduction assay was performed on the antiviral efficacy of five types of fractions of Prickly pear (B) at the concentrations shown in Table 3 above, and the results are shown in Figure 22. As shown in Figure 22, it was confirmed that the hexane fraction and chloroform fraction of Prickly pear (B) exhibited excellent antiviral efficacy against HSV-1.
2-2 VZV 항바이러스 효능 평가 결과2-2 VZV antiviral efficacy evaluation results
Human malignant melanoma 유래 세포주인 MeWo 세포에 >100 PFU의 VZV을 2시간 동안 감염시킨 후, 추출물을 10, 25, 50 ㎍/㎖ 처리한 media를 4-6일간 배양하였다. MeWo cells, a cell line derived from human malignant melanoma, were infected with >100 PFU of VZV for 2 hours, and media treated with 10, 25, and 50 μg/ml extract were cultured for 4-6 days.
도 23에 나타낸 바와 같이, 솜양지꽃(B)과 은양지꽃(F) 추출물을 처리했을 때 농도 의존적으로 VZV 플라크 수가 감소하였다. As shown in Figure 23, the number of VZV plaques decreased in a concentration-dependent manner when treated with extracts of Prickly pear (B) and Prickly pear (F) extracts.
또한 도 24에 나타낸 바와 같이, 솜양지꽃(B)과 은양지꽃(F) 추출물을 처리했을 때 VZV 플라크의 크기도 농도 의존적으로 감소하는 것을 확인하였다.In addition, as shown in Figure 24, it was confirmed that the size of VZV plaques decreased in a concentration-dependent manner when treated with extracts of Euphorbia flower (B) and Euphorbia chinensis (F).
VZV 감염에 대해 농도의존적 억제 효능을 나타낸 솜양지꽃(B)의 분획물 5종을 대상으로 상기 표 3에 나타낸 농도로 plaque reduction assay를 수행하여 그 결과를 도 25 내지 도 27에 나타내었다. 도 25에 나타낸 바와 같이, 솜양지꽃(B) 추출물에 대한 5종의 분획물(헥산, 클로로포름, 에틸 아세테이트, 부탄올 및 물 분획물) 중 부탄올, 에틸 아세테이트 및 물 분획물은 항바이러스 효능을 나타내지 않는 것을 확인하였다. Plaque reduction assay was performed on five types of fractions of Prickly pear (B) that showed concentration-dependent inhibitory efficacy against VZV infection at the concentrations shown in Table 3 above, and the results are shown in Figures 25 to 27. As shown in Figure 25, it was confirmed that among the five fractions (hexane, chloroform, ethyl acetate, butanol, and water fractions) of the extract of Prickly pear (B), the butanol, ethyl acetate, and water fractions did not show antiviral efficacy. .
또한, 도 26 및 도 27에 나타낸 바와 같이, 헥산 분획물(1.59, 3.99, 7.97 ㎍/㎖)과 클로로포름 분획물(2.37, 5.94, 11.87 ㎍/㎖)에 대하여 농도의존적 항바이러스 효능 시험시, 헥산 분획물은 농도의존적으로 VZV 플라크 형성이 감소하고 플라크의 사이즈가 감소하여 항바이러스 효능을 갖는 것을 확인하였다.In addition, as shown in Figures 26 and 27, when testing the concentration-dependent antiviral efficacy of the hexane fraction (1.59, 3.99, 7.97 μg/ml) and the chloroform fraction (2.37, 5.94, 11.87 μg/ml), the hexane fraction was It was confirmed that VZV plaque formation was reduced in a concentration-dependent manner and the size of plaques was reduced, showing antiviral efficacy.
따라서, 솜양지꽃 및 은양지꽃 추출물은 신경계감염 알파허피스바이러스 중 수두-대상포진바이러스(VZV)의 감염을 효과적으로 억제하는 항바이러스 효능을 가지고, 특히 솜양지꽃의 헥산 분획물은 농도의존적 항바이러스 효능을 갖는 것을 알 수 있다.Therefore, the extracts of Lilium vulgaris and Lilium vulgaris have antiviral effects that effectively inhibit infection by varicella-zoster virus (VZV), one of the alphaherpesviruses that infect the nervous system. In particular, the hexane fraction of Lilium vulgaris has a concentration-dependent antiviral effect. Able to know.
Claims (10)
- 솔송나무, 솜양지꽃, 은양지꽃 및 제주피막이로 이루어진 군에서 선택된 하나 이상의 추출물을 유효성분으로 포함하는, 감마허피스바이러스 감염 질환의 예방 또는 치료용 약학 조성물.A pharmaceutical composition for the prevention or treatment of gammaherpesvirus infectious diseases, comprising as an active ingredient one or more extracts selected from the group consisting of hemlock, hemlock, euphorbia, and Jeju mantle.
- 제1항에 있어서, 상기 감마허피스바이러스는 카포시 육종 허피스 바이러스(Kaposi's sarcoma-associated herpesvirus, KSHV)인 것을 특징으로 하는, 약학 조성물.The pharmaceutical composition according to claim 1, wherein the gammaherpesvirus is Kaposi's sarcoma-associated herpesvirus (KSHV).
- 제2항에 있어서, 상기 조성물은 카포시 육종 허피스 바이러스의 용균 단백질(lytic protein)의 발현을 감소시키는 것을 특징으로 하는, 약학 조성물.The pharmaceutical composition according to claim 2, wherein the composition reduces the expression of the lytic protein of Kaposi's sarcoma herpes virus.
- 제2항에 있어서, 상기 감마허피스바이러스 감염 질환은 카포시 육종, 원발성 삼출성 림프종 및 다발성 캐슬만병으로 이루어진 군에서 하나 이상 선택되는 것을 특징으로 하는, 약학 조성물. The pharmaceutical composition according to claim 2, wherein the gammaherpesvirus infectious disease is one or more selected from the group consisting of Kaposi's sarcoma, primary exudative lymphoma, and multiple Castleman's disease.
- 제1항에 있어서, 상기 감마허피스바이러스는 엡스타인 바 바이러스(Epstein-barr virus, EBV)인 것을 특징으로 하는, 약학 조성물.The pharmaceutical composition according to claim 1, wherein the gammaherpesvirus is Epstein-Barr virus (EBV).
- 제5항에 있어서, 상기 조성물은 엡스타인 바 바이러스의 용균 단백질(lytic protein)의 발현을 감소시키는 것을 특징으로 하는, 약학 조성물.The pharmaceutical composition according to claim 5, wherein the composition reduces the expression of the lytic protein of the Epstein-Barr virus.
- 제5항에 있어서, 상기 감마허피스바이러스 감염 질환은 버킷림프종, 위암종, 코인두암종, 호지킨림프종 및 이식 후 B 세포 림프종으로 이루어진 군에서 하나 이상 선택되는 것을 특징으로 하는, 약학 조성물.The pharmaceutical composition according to claim 5, wherein the gammaherpesvirus infectious disease is one or more selected from the group consisting of Burkitt's lymphoma, gastric carcinoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, and post-transplant B cell lymphoma.
- 솔송나무, 솜양지꽃, 은양지꽃 및 제주피막이로 이루어진 군에서 하나 이상 선택된 추출물을 유효성분으로 포함하는, 감마허피스바이러스 감염 질환의 예방 또는 개선용 식품 조성물.A food composition for preventing or improving gammaherpes virus infectious diseases, comprising as an active ingredient one or more extracts selected from the group consisting of hemlock, cypress, euphorbia, and Jeju eucalyptus.
- 솔송나무, 솜양지꽃, 은양지꽃 및 제주피막이로 이루어진 군에서 하나 이상 선택된 추출물을 유효성분으로 포함하는, 감마허피스바이러스 감염 질환의 예방 또는 개선용 동물용 사료 조성물.A feed composition for animals for preventing or improving gammaherpesvirus infection disease, comprising as an active ingredient one or more extracts selected from the group consisting of hemlock, hemlock, eucalyptus, and Jeju marigold.
- 제1항에 있어서, 솔송나무, 솜양지꽃, 은양지꽃 및 제주피막이로 이루어진 군으로부터 선택되는 하나 이상의 추출물을 포함하거나, 솔송나무, 솜양지꽃, 은양지꽃 및 제주피막이로 이루어진 군으로부터 선택된 혼합물로부터 추출된 추출물을 포함하는 것을 특징으로 하는, 약학 조성물.The method of claim 1, comprising one or more extracts selected from the group consisting of hemlock, hemlock, euphorbia, and Jeju euphorbia, or extracted from a mixture selected from the group consisting of hemlock, euphorbia, euphorbia, and Jeju eucalyptus. A pharmaceutical composition comprising an extract.[청구항 11][Claim 11]솜양지꽃 및 은양지꽃 추출물로 이루어진 군에서 선택된 하나 이상의 추출물을 유효성분으로 포함하는, 노로바이러스 감염 질환의 예방 또는 치료용 약학 조성물A pharmaceutical composition for the prevention or treatment of norovirus infectious diseases, comprising as an active ingredient one or more extracts selected from the group consisting of Euphorbia flower and Euphorbia chinensis extract.[청구항 12][Claim 12]제11항에 있어서, 상기 노로바이러스는 인체 노로바이러스(human norovirus)인 것을 특징으로 하는, 노로바이러스 감염 질환의 예방 또는 치료용 약학 조성물The pharmaceutical composition for preventing or treating norovirus infectious diseases according to claim 11, wherein the norovirus is a human norovirus.[청구항 13][Claim 13]제11항에 있어서, 상기 노로바이러스 감염 질환은 비세균성 위장염인 것을 특징으로 하는, 약학 조성물.The pharmaceutical composition according to claim 11, wherein the norovirus infectious disease is non-bacterial gastroenteritis.[청구항 14][Claim 14]제11항에 있어서, 상기 은양지꽃 추출물은 헥산, 클로로포름, 부탄올, 에틸 아세테이트 및 물로 이루어진 군에서 하나 이상 선택된 용매로 분획되는 것을 특징으로 하는, 약학 조성물.12. The pharmaceutical composition according to claim 11, wherein the Euphorbia chinensis extract is fractionated with one or more solvents selected from the group consisting of hexane, chloroform, butanol, ethyl acetate, and water.[청구항 15][Claim 15]제11항에 있어서, 상기 은양지꽃 추출물은 헥산 분획물 또는 클로로포름분획물인 것을 특징으로 하는, 약학 조성물.The pharmaceutical composition according to claim 11, wherein the Euphorbia flower extract is a hexane fraction or a chloroform fraction.[청구항 16][Claim 16]솜양지꽃 및 은양지꽃 추출물로 이루어진 군에서 선택된 하나 이상의 추출물을 유효성분으로 포함하는, 노로바이러스 감염 질환의 예방 또는 개선용 식품 조성물A food composition for preventing or improving norovirus infectious diseases, comprising as an active ingredient one or more extracts selected from the group consisting of Prickly pear and Prickly pear extracts[청구항 17][Claim 17]솜양지꽃 및 은양지꽃 추출물로 이루어진 군에서 선택된 하나 이상의 추출물을 유효성분으로 포함하는, 노로바이러스 감염 질환의 예방 또는 개선용 동물용 사료 조성물A feed composition for animals for preventing or improving norovirus infection disease, comprising as an active ingredient one or more extracts selected from the group consisting of Prickly pear and Prickly pear extracts[청구항 18][Claim 18]제11항에 있어서, 솜양지꽃 및 은양지꽃 추출물로 이루어진 군에서 선택되는 하나 이상의 추출물을 포함하거나, 솜양지꽃 및 은양지꽃 추출물로 이루어진 군으로부터 선택된 혼합물로부터 추출된 추출물을 포함하는 것을 특징으로 하는, 약학 조성물.The pharmaceutical composition according to claim 11, comprising one or more extracts selected from the group consisting of extracts of Lilium chinensis and Lilium chinensis extract, or comprising an extract extracted from a mixture selected from the group consisting of extracts of Lilium chinensis and Lilium chinensis extract. Composition.[청구항 19][Claim 19]솜양지꽃, 은양지꽃 및 전호 추출물로 이루어진 군에서 선택된 하나 이상의 추출물을 유효성분으로 포함하는, 알파허피스바이러스 감염 질환의 예방 또는 치료용 약학 조성물A pharmaceutical composition for the prevention or treatment of alphaherpesvirus infectious disease, comprising as an active ingredient one or more extracts selected from the group consisting of Achyranthesia flower, Achyranthesia flower, and Jeonho extract.[청구항 20][Claim 20]제19항에 있어서, 상기 알파허피스바이러스는 단순포진바이러스 (Herpes simplex virus-1; HSV-1) 또는 수두-대상포진바이러스 (Varicella-Zoster virus; VZV)인 것을 특징으로 하는, 약학 조성물.The pharmaceutical composition according to claim 19, wherein the alphaherpesvirus is Herpes simplex virus-1 (HSV-1) or Varicella-Zoster virus (VZV).[청구항 21][Claim 21]제20항에 있어서, 상기 단순포진바이러스 감염 질환은 단순포진, 구순포진, 구내염, 수막염 및 뇌염(encephalitis)으로 이루어진 군에서 선택된 하나 이상인 것을 특징으로 하는, 약학 조성물.The pharmaceutical composition according to claim 20, wherein the herpes simplex virus infectious disease is at least one selected from the group consisting of herpes simplex, cold sores, stomatitis, meningitis, and encephalitis.[청구항 22][Claim 22]제20항에 있어서, 상기 수두-대상포진바이러스 감염 질환은 수두-대상포진바이러스 대상포진 및 무발진 대상포진(Zoster Sine Herpete)로 이루어진 군에서 선택된 하나 이상인 것을 특징으로 하는, 약학 조성물.The pharmaceutical composition of claim 20, wherein the varicella-zoster virus infectious disease is at least one selected from the group consisting of varicella-zoster virus herpes zoster and Zoster Sine Herpete.[청구항 23][Claim 23]제19항에 있어서, 상기 은양지꽃 추출물은 헥산, 클로로포름, 부탄올, 에틸 아세테이트 및 물로 이루어진 군에서 하나 이상 선택된 용매로 분획되는 것을 특징으로 하는, 약학 조성물.20. The pharmaceutical composition according to claim 19, wherein the Euphorbia chinensis extract is fractionated with one or more solvents selected from the group consisting of hexane, chloroform, butanol, ethyl acetate, and water.[청구항 24][Claim 24]제19항에 있어서, 상기 은양지꽃 추출물은 헥산 분획물 및 클로로포름 분획물인 것을 특징으로 하는, 약학 조성물.The pharmaceutical composition according to claim 19, wherein the Euphorbia flower extract is a hexane fraction and a chloroform fraction.[청구항 25][Claim 25]제24항에 있어서, 상기 은양지꽃 추출물은 헥산 분획물인 것을 특징으로 하는, 약학 조성물.25. The pharmaceutical composition according to claim 24, wherein the Euphorbia chinensis extract is a hexane fraction.[청구항 26][Claim 26]솜양지꽃, 은양지꽃 및 전호 추출물로 이루어진 군에서 선택된 하나 이상의 추출물을 유효성분으로 포함하는, 알파허피스바이러스 감염 질환의 예방 또는 개선용 식품 조성물A food composition for preventing or improving alphaherpesvirus infection disease, comprising as an active ingredient one or more extracts selected from the group consisting of Euphorbia flower, Euphorbia flower, and Jeonho extract.[청구항 27][Claim 27]솜양지꽃, 은양지꽃 및 전호 추출물로 이루어진 군에서 선택된 하나 이상의 추출물을 유효성분으로 포함하는, 알파허피스바이러스 감염 질환의 예방 또는 개선용 동물용 사료 조성물Animal feed composition for preventing or ameliorating alphaherpesvirus infection disease, comprising as an active ingredient one or more extracts selected from the group consisting of Euphorbia flower, Euphorbia flower, and Jeonho extract.[청구항 28][Claim 28]제19항에 있어서, 솜양지꽃, 은양지꽃 및 전호 추출물로 이루어진 군에서 선택되는 하나 이상의 추출물을 포함하거나, 솜양지꽃, 은양지꽃 및 전호 추출물로 이루어진 군으로부터 하나 이상 선택된 혼합물로부터 추출된 추출물을 포함하는 것을 특징으로 하는, 약학 조성물.20. The method of claim 19, comprising one or more extracts selected from the group consisting of Lilac flower, Euphorbia flower, and Jeonho extract, or comprising an extract extracted from a mixture selected from one or more of the group consisting of extracts of Orchid flower, Euphorbia flower, and Jeonho extract. A pharmaceutical composition, characterized in that.
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