CN108324710B - Composition for preventing or treating diseases caused by rotavirus infection containing genipin as active ingredient - Google Patents
Composition for preventing or treating diseases caused by rotavirus infection containing genipin as active ingredient Download PDFInfo
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- CN108324710B CN108324710B CN201810053173.8A CN201810053173A CN108324710B CN 108324710 B CN108324710 B CN 108324710B CN 201810053173 A CN201810053173 A CN 201810053173A CN 108324710 B CN108324710 B CN 108324710B
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- Prior art keywords
- genipin
- rotavirus
- cells
- infection
- preventing
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- AZKVWQKMDGGDSV-UHFFFAOYSA-N genipin Natural products COC(=O)C1=COC(O)C2C(CO)=CCC12 AZKVWQKMDGGDSV-UHFFFAOYSA-N 0.000 title claims abstract description 100
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
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Abstract
The invention relates to a new application of genipin (genipin) compounds, in particular to a composition containing genipin or pharmaceutically acceptable salts thereof as an effective component and used for preventing, treating or improving diseases caused by rotavirus infection. The genipin compound of the invention has excellent effects of preventing and treating rotavirus infection.
Description
Technical Field
The invention relates to a new application of genipin (genipin) compounds, in particular to a composition containing genipin or pharmaceutically acceptable salts thereof as an effective component and used for preventing, treating or improving diseases caused by rotavirus infection.
Background
Rotaviruses (rotaviruses) belong to the Reoviridae (Reoviridae) and are known to be the most important cause of acute infantile enteritis. The double capsids of the viral particles look like a carriage wheel, which is named from wheel of latin (rota, wheel, english) and is therefore called rotavirus. In 1943, leiter (Light) and hades (Hodes) reported the severe diarrhea in infants and isolated the diarrhea-causing filtered pathogens from feces, but their morphological characteristics were revealed by electron microscopy in 1973. Reovirus-like viruses (reoviruses) have been isolated from mammals and birds, and these viruses have been identified as Rotaviruses and classified in 1978 as Rotaviruses (Genus Rotaviruses) of the Reoviridae Family (Family Reoviridae).
The rotavirus genome (genome) consists of 11 segments of double-stranded RNA (double-stranded RNA), and the rotavirus particle is spherical with a diameter of 70nm, with two shells (shells) of outer (outer) and inner (inner) capsid. The inner capsid (inner capsid) is formed from VP6 protein, including a core (core) portion containing 11 double RNA segments and structural proteins VP1, VP2, VP3, and the outer capsid (outer capsid) is composed of VP7 and VP 4. Of VP4 and VP7, VP4 is a virus hemagglutinin (virus hemagglutinin) which protrudes from the surface of the virus like a spike (spike) as an attachment protein of a host cell and accounts for 2.5% of the entire virus. VP7 is a 37kDa glycoprotein (glycoprotein) that forms a smooth outer capsid shell (smoothouter capsid shell) and accounts for 30% of the virus as a whole. Since the VP4 protein is split by the host protease into VP5 and VP8, the serotype is called type P (P type) and the VP7 protein is glycosylated (glycosylation), so the serotype is called type G (G type) (Ciarlet, M.and Ester, M.K.rotaviruses: basic biology, epidemiology and methods in environmental microbiology. pp.2753-2773, 2002). VP4 and VP7 proteins are involved in host defense by inducing neutralizing antibodies. The serotypes are classified into a-G total of 7 according to the serotype for the intermediate layer capsid protein VP 6. Among them, rotavirus a is the most common virus in humans and animals, and it is a very important infectious agent causing enteritis in 1.3 million people worldwide each year, resulting in death of 87 million 3 thousands of people.
Generally, for the treatment of such viral diseases, methods of inhibiting adsorption to epithelial cells, inhibiting invasion into cells, inhibiting gene transcription and replication, inhibiting protein synthesis, and inhibiting release from cells, which are considered as targets of antiviral, respectively, are considered, but there are few clear targets of rotavirus so far.
Recent treatment of rotavirus is non-specific for Human Rotavirus (HRV) infection. Therefore, vaccination plays an important role in protecting children from HRV infection and death. HRV vaccines, including Rotarix TM And RotaTeq, started to be used in 1990 and 2000, respectively. However, these methods, which employ inactivated HRV or injected diluted HRV, require skill and have side effects that alter collective immunity and disease susceptibility, which can induce vaccine-induced disease.
To overcome the disadvantages of vaccines, research on natural materials that can inhibit rotavirus is ongoing.
Disclosure of Invention
In this regard, the present inventors confirmed in the study of anti-rotavirus preparations that genipin (genipin) inhibits the replication of rotavirus, thereby exhibiting anti-rotavirus infection activity, and thus completed the present invention.
Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases caused by rotavirus infection, which contains genipin (genipin) or a pharmaceutically acceptable salt thereof as an active ingredient.
In order to achieve the above objects, the present invention provides a pharmaceutical composition for preventing or treating diseases caused by rotavirus infection, which contains genipin (genipin) or a pharmaceutically acceptable salt thereof as an active ingredient.
The present invention will be described in detail below.
Genipin (genipin) of the present invention has the structure of the following chemical formula 1, and may be purified from natural sources, commercially available, or may be prepared by chemical synthesis methods known in the art.
< chemical formula 1>
The inventors have for the first time ascertained the use of genipin against rotavirus, which is well shown in the examples in the present description.
In one embodiment of the invention, genipin inhibits the production of Nitric Oxide (NO) and inhibits IL-6, IL-10, IL-1 β, PGE 2 And the secretion of cytokines (cytokines) that promote inflammatory reactions, and the secretion of cytokines (cytokines) that inhibit the intracellular replication of viruses, such as TNF- α, are maintained (example 2).
In another embodiment of the present invention, MA104 cells were infected with rotavirus, treated with genipin alone or in parallel with the virus before and after the infection, and the effect thereof was measured (see example 3). As a result, it was confirmed that genipin not only inhibited the replication of rotavirus and had a therapeutic effect on rotavirus infection (refer to example 3-1), but also the preventive effect (refer to examples 3-2 and 3-3) was excellent. Specifically, as shown in examples 3-2 and 3-3, it was confirmed that a better disease-inhibiting effect can be exhibited by using genipin in parallel in the prevention and treatment of rotavirus infection.
Accordingly, the present invention provides a pharmaceutical composition for preventing or treating diseases caused by rotavirus infection, which contains genipin (genipin) or a pharmaceutically acceptable salt thereof as an active ingredient.
The term "prevention" in the present invention means that all actions of inhibiting or delaying the onset of rotavirus infection by administering the composition.
The term "treatment" in the present invention means to alleviate or improve all the behaviors of symptoms caused by rotavirus infection by administering the composition.
The rotavirus is not particularly limited to its source animal, and may be Human (Human) rotavirus, porcine (Pocine) rotavirus, Bovine (Bovine) rotavirus or Goat (coat) rotavirus, and is preferably Human rotavirus.
The kind of the disease caused by the rotavirus infection is not particularly limited as long as it is known in the art as a disease caused by rotavirus, and the type thereof is preferably selected from the group consisting of gastroenteritis, enteritis, diarrhea, cold, pharyngolaryngitis, bronchitis and pneumonia.
The pharmaceutical composition of the present invention is characterized by containing genipin or a pharmaceutically acceptable salt thereof. The "pharmaceutically acceptable salt" refers to an acid addition salt which is physiologically acceptable and does not cause allergic reaction or the like when administered to a human body, and is preferably a pharmaceutically acceptable free acid (free acid). The free acid may be an organic acid or an inorganic acid. Organic acids include, but are not limited to, citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trioroacetic acid, benzoic acid, gluconic acid, meta-sulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, glutamic acid, and aspartic acid. Additionally, inorganic acids include, but are not limited to, hydrochloric acid, bromic acid, sulfuric acid, and phosphoric acid.
The pharmaceutical composition according to the present invention may contain genipin or a pharmaceutically acceptable salt thereof alone or further contain one or more pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutically acceptable carrier may further include a carrier for oral administration or a carrier for non-oral administration, etc. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. In addition, the carrier for parenteral administration may contain water, suitable oils, salt solutions, aqueous dextrose solutions, and glycols, and may additionally contain stabilizers and preservatives. Suitable stabilizers are antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl or propyl paraben and chlorobutanol. Other pharmaceutically acceptable carriers can be found in the following references (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, Pa., 1995).
The pharmaceutical compositions of the present invention can be administered to mammals, including humans, by any method. For example, it can be administered orally or non-orally. Non-oral methods of administration include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, epidural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or intrarectal administration.
As described above, the pharmaceutical composition can be formulated for oral or non-oral administration according to the route of administration. In the case of oral administration preparations, the composition of the present invention can be formulated into powders, granules, tablets, pills, sugar tablets, capsules, liquids, gels, syrups, slurries, suspensions and the like by methods known in the art. For example, oral preparations can be obtained by mixing the active ingredient with a solid excipient, followed by pulverization, addition of suitable auxiliaries, and processing the mixture into a granulated mixture to obtain tablets or sugar tablets. Suitable excipients include sugars such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, starches such as corn starch, wheat starch, rice starch and potato starch, celluloses such as cellulose, methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, fillers such as gelatin, polyvinylpyrrolidone and the like. In addition, crosslinked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may also be added as a disintegrating agent. In addition, the pharmaceutical composition of the present invention may further comprise an anticoagulant, a lubricant, a wetting agent, a fragrance, an emulsifier, and a preservative.
In the case of non-oral administration, it can be formulated by methods known in the art such as injections, creams, emulsions, external ointments, oils, moisturizers, gels, aerosols and nasal inhalants. These formulations are described in the literature of all prescriptions (Remington's Pharmaceutical Science, 15th Edition, 1975.Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour), which are well known in the Pharmaceutical chemistry art.
The total effective amount of genipin or a pharmaceutically acceptable salt thereof according to the present invention may be administered to a patient in a single dose or in a fractionated treatment protocol (fractionated treatment protocol) in which multiple doses are administered over a long period of time. The pharmaceutical composition of the present invention may contain different amounts of active ingredients depending on the kind of disease. The total amount of genipin or a pharmaceutically acceptable salt thereof used in the present invention is preferably about 0.01 to 1000mg, more preferably 0.1 to 100mg per 1 kg of body weight of a patient per day. However, the amount is determined in consideration of various factors such as the administration route and the treatment frequency of the pharmaceutical composition, the age, body weight, health condition, sex, severity of disease, diet and excretion rate of the patient. In view of the above, a person having ordinary knowledge in the art can determine the effective administration amount of genipin or a pharmaceutically acceptable salt thereof according to the specific use thereof as a prophylactic or therapeutic agent for diseases caused by rotavirus infection. The pharmaceutical composition of the present invention is not limited to the dosage form, administration route and administration method thereof, as long as the pharmaceutical composition has the effects of the present invention.
In addition, the genipin or a pharmaceutically acceptable salt thereof of the present invention may be mixed with known antiviral (including not only rotavirus but also other viral inhibitors) effective substances or active ingredients to prepare a composition form.
The invention has the following effects:
the invention relates to an anti-rotavirus effect of genipin, namely, the genipin has very obvious effect on preventing and treating rotavirus infection.
Drawings
Figure 1 is a schematic diagram of the measurement of genipin toxicity to RAW264.7 cells;
figure 2 is a schematic diagram of measuring the toxicity of genipin to MA104 cells;
FIG. 3 is a graph showing the ability of genipin to inhibit NO production in RAW264.7 cells induced by LPS for inflammation;
FIG. 4 is a graph showing the ability of genipin to inhibit IL-6 production in RAW264.7 cells induced by LPS for inflammation;
FIG. 5 is a graph showing the ability of genipin to inhibit IL-10 production in RAW264.7 cells induced by LPS for inflammation;
FIG. 6 is a graphical representation of the ability of genipin to inhibit IL-1 β production in RAW264.7 cells induced by LPS to induce inflammation;
FIG. 7 is PGE inhibition of genipin in RAW264.7 cells induced by LPS 2 A schematic of the generated capabilities;
FIG. 8 is a graphical representation of the ability of genipin to maintain TNF- α secretion levels in RAW264.7 cells induced by LPS for inflammation;
FIG. 9 is a graphical representation of the therapeutic effect of treatment with genipin after infection of MA104 cells with rotavirus Wa strain;
FIG. 10A is a schematic representation of the confirmation of prevention of rotavirus infection and inhibition of virus reproduction (improvement and treatment) by pretreatment of MAl04 cells with a combination of rotavirus Wa strain and genipin, followed by infection with Wa strain and subsequent reprocessing with genipin at different concentrations;
figure 10B is a schematic representation of the effect of genipin pretreatment (effect of genipin in preventing rotavirus infection) in the experimental group confirmed by pretreatment of MA104 cells with a combination of rotavirus Wa strain and genipin, followed by infection with Wa strain, followed by no retreatment with genipin;
FIG. 11A is a schematic representation of the confirmation of the prevention of rotavirus infection and the inhibition of virus propagation (improvement and treatment) by infection with Wa strain after 24 hours of pretreatment of MA104 cells with genipin, followed by retreatment with genipin at different concentrations;
fig. 11B is a graph showing the effect of genipin pretreatment (effect of genipin in preventing rotavirus infection) in the experimental group confirmed by infection with Wa strain after 24 hours of pretreatment of MA104 cells with genipin, followed by no retreatment with genipin.
Detailed Description
The present invention will be described in detail below.
However, the embodiments are only illustrative of the present invention, and the content of the present invention is not limited to the embodiments.
<Example 1>Toxicity evaluation of genipin
Mouse macrophage RAW264.7 cells were passaged 3-4 times per week in DMEM (Dulbecco's Modified Eagle's Medium) containing 20. mu.g/ml gentamicin Reagent Solution (Gibco BRL, Gentamicine Reagent Solution) and 10% FBS (Gibco BRL) at 37 ℃ and 5% CO 2 And (5) culturing under an environment. MA104 cells were obtained from korean cell (strain) banks. Cultured in minimal essential medium alpha (MEM-alpha; Gibco BRL) containing 5% FBS and 20. mu.g/ml gentamicin reagent solution. The virus is human rotavirus group A strain G1P1A (hereinafter referred to as 'Wa strain', ATCC)
VR-2018 TM )。
RAW264.7 cells were plated at 2X 10 3 Individual cells/well concentration were seeded in 96-well plates and cultured for 24 hours. Genipin (Sigma-aldrich) was dissolved in new DMEM medium without FBS to a final concentration of 10, 50, 100, 150, 160, 180, 200. mu.M/ml, and the cells were treated and cultured for 24 hours. To measure the survival rate of the cell line, MTT [3- (4, 5-dimethylthiazol-2) -2 was used,5-Diphenyltetrazolium bromide salt]([3-(4，5-dimethylthiazol-2-yl)-2，5-diphenyltetrazolium bromide]) As a reagent, and was measured by a microplate reader (microplate reader: model Infinite F200, Tecan, Mannedorf, Switzerland), absorbance was measured at 590 nm. Cytotoxicity of MA104 cells was also measured in the same manner.
As a result, as shown in fig. 1 and 2, the cell viability of RAW264.7 cells and MA104 cells treated with genipin tended to decrease significantly from the concentration of 160 μ M/ml, but the viability was 95% or more at a concentration of 100 μ M/ml, and the cell viability was the same as that of the untreated group, and no cytotoxicity was observed.
<Example 2>Analysis of influence of genipin on NO and cytokines
<2-1> detection of NO
Cultured RAW264.7 cells at 3X 10 5 The concentration of individual cells/well was seeded in 24-well plates and cultured for 24 hours. To induce inflammation, LPS was added to new DMEM medium without FBS to a concentration of 0.1 μ g/ml, and cells were treated with genipin at final concentrations of 0, 10, 50, 100 and 150 μ M/ml, respectively, and cultured for 24 hours. After 24 hours, Griess reagent was added to the cell supernatant according to 1: 1 was mixed to measure NO production, and after 10 minutes of reaction, absorbance was measured at 540nm using a microplate reader. In addition, the ability of genipin to express inducible nitric oxide synthase (iNOS: indole nitrile oxide synthase) was measured by the following method. 3X 10 treatment with LPS in the same manner as described above 5 RAW264.7 cells per cell/well and treated with genipin at final concentrations and cultured for 24 hours, respectively. After 24 hours, the cells were harvested by centrifugation, added 900 μ l of TRIZOL reagent (MRC, Cincinnati, Ohio) and homogenized. To this was added 100. mu.l of chloroform, and the mixture was left at room temperature for 5 minutes. The mixture was centrifuged at 13,000 rpm for 10 minutes, the supernatant was collected, an equal amount of isopropanol (isopropanol) was added thereto, and the mixture was left at room temperature for 5 minutes and centrifuged. Washed once with 70% DEPC-ethanol, centrifuged, dried at room temperature, and added with 30. mu.l of distilled water containing 70% DEPC. To make reversalFor the detection of the transcription-polymerase chain reaction (Reverse transcription-PCR assay), 1.4. mu.l of DMSO was added to 5. mu.l of RNA and denatured at 97 ℃ for 5 minutes. A mixture (total of 10. mu.l) containing 1. mu.l of 10 Xbuffer (buffer), 0.4. mu.l of 1 XdNTPs, 0.2. mu.l each of iNOS-specific forward and Reverse primers, 0.1. mu.l of enzyme AMV (enzyme AMV) (Promega, Medison, USA), and RNase-free water was subjected to Reverse transcription polymerase chain reaction assay (Reverse transcription-PCR ay) analysis (60 minutes at 42 ℃ and 5 minutes at 95 ℃) to generate cDNA, and the results were confirmed by electrophoresis.
As a result of the experiment, as shown in fig. 3, the experimental group treated with genipin showed concentration-dependent inhibitory ability of NO production and inhibitory ability of iNOS expression, compared to the control group treated with LPS only. In particular, the 100 μ M/ml genipin-treated group showed 10% NO levels, showing similar NO levels as the LPS untreated group.
<2-2> cytokine assay
Cultured RAW264.7 cells at 3X 10 5 The concentration of individual cells/well was seeded in 24-well plates and cultured for 24 hours. To induce inflammation, LPS was added to new DMEM medium without FBS to a concentration of 0.1 μ g/ml, and cells were treated with genipin at final concentrations of 0, 10, 50, 100, and 150 μ M/ml, respectively, and cultured for 24 hours. After 24 hours, in order to measure the degree of production of IL-6, IL-10, IL-1. beta., TNF-. alpha.and PGE-2 from the cell supernatant, a Parameter determination kit (Parameter) was used TM Immunolaykit) and Quantikine
Immunoassay kit (Quantikine)
Immunoassaykit)(R&D Systems, Minneapolis, MN, USA), the experiments were performed according to the manual. The protein mass of each cytokine was measured for absorbance at 450nm using a microplate reader.
As a result, the bioactive factors IL-6 (FIG. 4) and IL-10 (FIG. 5) which promote the inflammatory reaction in the cells were examinedIL-1 beta (FIG. 6), PGE 2 (FIG. 7), concentration-dependent cytokine secretion inhibitory ability was observed in the experiment group treated with genipin, compared to the control group treated with LPS only. In particular, the cytokine secretion was reduced by 75%, 83%, 77%, 75% at concentrations of 100 and 150. mu.M/ml, respectively, which showed similar levels to those of the LPS-untreated group, and 150. mu.M/ml, respectively. The results of TNF-. alpha.secretion are confirmed in FIG. 8, and it can be seen that high values were maintained at all concentrations of 10, 50, 100 and 150. mu.M/ml. These results indicate that genipin of the present invention inhibits IL-6, IL-10, IL-1. beta. and PGE 2 And the like, promote the secretion of cytokines of inflammatory reaction, and simultaneously maintain the secretion of cytokines of TNF-alpha and the like for inhibiting virus intracellular replication, thereby showing that the genipin has the effect on the rotavirus and can be widely used for preventing the rotavirus or used as a pharmaceutical composition.
<Example 3>Detection of rotavirus replication inhibition ability of genipin
The inhibitory effect of genipin on viral replication in MA104 cells infected with rotavirus was confirmed as follows. MA104 cells were infected with Rotavirus Wa Strain at MOI0.01 and the experiment was performed in 3 ways as follows. Quantification of rotavirus in each experiment was confirmed by real-time RT-PCR. Specifically, Viral RNA was extracted using a Viral RNA extraction Kit (QIA amp Viral RNA Mini Kit) (Qiagen, Valencia, CA, USA). First, 140. mu.l of the supernatant was added to 560. mu.l of AVL solution containing 5.6. mu.g of carrier RNA (carrier RNA) (Qiagen, Valencia, Calif., USA) and mixed for 15 seconds. After 10 minutes of incubation, 560. mu.l of ethanol was added and mixed for 15 seconds. The mixture was transferred to a 2ml tube and centrifuged at 8000rpm for 1 minute. After 2 washes, they were added to 50. mu.l of RNase-free water and stored at-80 ℃ for reverse transcription polymerase chain reaction (RT- (reverse transcription) -PCR).
Reverse transcription-PCR assay (Reverse transcription-PCR assay) was performed using the rotavirus VP6 gene as a template. First, 1.4. mu.l of DMSO was added to 5. mu.l of viral RNA (viral RNA) and then denatured at 97 ℃ for 5 minutes. A mixture (total of 10. mu.l) containing 1. mu.l of 10 Xbuffer (buffer), 0.4. mu.l of 1 XdNTPs 10, 0.2. mu.l each of the forward primer (SEQ ID No. 1: 5'-AATGGAGTAGCGCCACAATC-3') and the Reverse primer (SEQ ID No. 2: 5'-TAAGCCACATGGTTCCCATT-3'), 0.1. mu.l of the enzyme AMV (enzyme AMV) (Promega, medison, USA), and RNase free water (RNase free water) was subjected to Reverse transcription-polymerase chain reaction assay (Reverse transcription-PCR assay) (60 minutes at 42 ℃ and 5 minutes at 95 ℃) to produce cDNA. For real-time PCR assay (real-time PCR assay), a 10. mu.l PCR mix consisting of 2. mu.l cDNA, 5. mu.l reaction mix (master mix) (Applied Biosystems, USA), 0.2. mu.l each of forward and reverse primers (10. mu.M, same sequence as above) and 1.5. mu.l probe (SEQ ID No. 3: 6FAM-GCACCGGATTTGTTTTTCAT-MGBNFQ) (2pM) and RNase free water (RNase free water) was used. Reverse transcription was performed (2 min at 50 ℃ C., 10 min at 95 ℃ C.) using an ABI7500 real-time thermocycler (ABI 7500real-time thermocycler) (Biosystems, Foster City, Calif., USA). Denaturation was carried out at 94 ℃ for 15 seconds and annealing was carried out for 40 cycles (60 ℃ for 1 minute).
3-1 treatment with genipin after infection with rotavirus
MA104 cells at 3X 10 5 The concentration of individual cells/well was seeded in 24-well plates and incubated at 37 ℃ for 24 hours. MA104 cells were infected with Rotavirus Wa Strain at MOI0.01 for 1 hour. After that, the unattached virus was washed 2 times. Cells infected with rotavirus Wa Strain were treated with genipin at concentrations of 0, 10, 50, 100, 130 and 150 μ M/ml, respectively (24 hours).
As a result, as shown in FIG. 9, the number of virus copies decreased depending on the concentration of genipin, and 62% of the reduction effect was exhibited at the maximum concentration of 150. mu.M/ml.
3-2, pretreating with rotavirus and genipin mixture, infecting with rotavirus, and treating with genipin
MA104 cells at 3X 10 5 The concentration of individual cells/well was seeded in 24-well plates and incubated at 37 ℃ for 24 hours. The rotaviruses were mixed with genipin at concentrations of 0, 10, 50, 100, 130 and 150. mu.M/ml in medium and incubated at 37 ℃ for 4 hours, respectively. After washing MA104 cells, useThe prepared virus and genipin mixture was pretreated and cultured for 1 hour. After 1 hour, MA104 cells were infected with Rotavirus Wa Strain at MOI0.01 for 1 hour. After that, the unattached virus was washed 2 times. Rotavirus replication was measured on rotavirus Wa Strain-infected cells prepared by the method, with or without treatment (24 hours) in groups with 0, 10, 50, 100, 130 and 150 μ M/ml concentrations of genipin, respectively.
FIG. 10A is a schematic representation of the confirmation of prevention of rotavirus infection and the effect of inhibition of virus replication (improvement and treatment) by pretreatment of MA104 cells with rotavirus Wa strain and genipin, followed by infection with Wa strain and subsequent reprocessing with genipin at different concentrations. The virus number decreased with increasing genipin concentration, and showed an 88% reduction especially at a concentration of 150. mu.M/ml. Fig. 10B is a graph showing the results of the experimental group which was not retreated with genipin, and the number of viruses decreased as the concentration of genipin increased, showing a 57% decrease effect at a concentration of 150 μ M/ml, compared to the untreated group. As shown in fig. 10B, even after infection with rotavirus, virus infection was still inhibited without reprocessing with genipin, which shows an excellent rotavirus infection prevention effect of genipin.
3-3, infection with rotavirus after pretreatment with genipin, reprocessing with genipin
MA104 cells at 3X 10 5 The concentration of individual cells/well was seeded in 24-well plates and incubated at 37 ℃ for 24 hours. Genipin was added to the medium and mixed with MA104 cells to concentrations of 0, 10, 50, 100, 130 and 150. mu.M/ml, respectively, and cultured for 24 hours. Thereafter, the virus was infected and retreated with genipin using the same method as in the example 3-2 shown.
FIG. 11A is the results of infection with Wa strain after 24 hours of pretreatment of MA104 cells with genipin, followed by reprocessing with genipin at different concentrations. The virus amount decreased with increasing genipin concentration, and the virus amount was greatly decreased at all concentrations compared to the untreated group, and in particular, the decrease effect was about 88% at 130. mu.M/ml and 150. mu.M/ml. FIG. 11B is a graph showing the results of the retreatment without genipin, and the number of viruses decreased as the concentration of genipin increased, showing a 76% decrease effect at a concentration of 150. mu.M/ml, compared with the untreated group. In particular, as shown in fig. 11B, even after infection with rotavirus, virus infection was suppressed without reprocessing with genipin, which shows an excellent rotavirus infection prevention effect of genipin.
Through the experiment of example 3, genipin inhibited rotavirus replication, and was excellent not only in the therapeutic effect on rotavirus infection (see example 3-1) but also in the preventive effect (see examples 3-2 and 3-3). In particular, as shown in examples 3-2 and 3-3, it was confirmed that genipin was used concurrently in the prevention and treatment of rotavirus infection, and a better disease-inhibiting effect was exhibited.
As a result, genipin of the present invention has a preventive effect and an inhibitory effect on rotavirus, and can exhibit a better effect in concurrent prevention and treatment.
Possibility of industrial application
As described above, the present invention relates to a novel use of genipin (genipin) compounds, and more particularly, to a composition for preventing, treating or ameliorating diseases caused by rotavirus infection, which contains genipin or a pharmaceutically acceptable salt thereof as an active ingredient.
The genipin compound has excellent anti-rotavirus effect, can be used for preventing, treating and improving diseases (such as enteritis, diarrhea, cold, sphagitis, bronchitis, pneumonia and the like) caused by rotavirus infection, and has high industrial utilization possibility.
Sequence listing
<110> university school labor cooperation group of central university
<120> composition for preventing or treating diseases caused by rotavirus infection containing genipin as an active ingredient
<130> DAG35590
<160> 3
<170> SIPOSequenceListing 1.0
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<211> 20
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
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<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 2
<210> 3
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<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 3
Claims (4)
1. Use of genipin or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention, treatment or amelioration of a disease caused by rotavirus infection.
2. The use of claim 1, wherein the rotavirus is a human rotavirus, a porcine rotavirus, a bovine rotavirus, or a goat rotavirus.
3. The use according to claim 1, wherein the disease caused by the rotavirus infection is any one selected from the group of a combination of gastroenteritis and diarrhoea.
4. The use according to claim 1 wherein the disease caused by rotavirus infection is enteritis.
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