CN116963754A - A composition containing Hovenia dulcis Thunb extract for preventing or treating coronavirus infection - Google Patents
A composition containing Hovenia dulcis Thunb extract for preventing or treating coronavirus infection Download PDFInfo
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- CN116963754A CN116963754A CN202180073522.2A CN202180073522A CN116963754A CN 116963754 A CN116963754 A CN 116963754A CN 202180073522 A CN202180073522 A CN 202180073522A CN 116963754 A CN116963754 A CN 116963754A
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Abstract
The present application relates to an antiviral use against coronavirus comprising hovenia dulcis thunb extract or an isolate thereof, and more particularly, to an antiviral pharmaceutical composition against coronavirus comprising hovenia dulcis thunb extract or an isolate thereof, a pharmaceutical composition for preventing or treating infectious diseases of coronavirus, and a method for preventing or treating infectious diseases of coronavirus using the same, a health functional food composition for preventing or improving infectious diseases of coronavirus comprising hovenia dulcis thunb extract or an isolate thereof, and a feed composition for preventing or improving infectious diseases of coronavirus comprising hovenia dulcis thunb extract or an isolate thereof. Since the hovenia dulcis thunb extract of the present application exhibits an effect of inhibiting infection of coronaviruses such as MERS-coronavirus, SARS-coronavirus and SARS-coronavirus-2, it is useful for developing antiviral agents for preventing or treating the above-mentioned viral diseases.
Description
Technical Field
The present application relates to an antiviral use against coronavirus comprising hovenia dulcis thunb extract or an isolate thereof.
Background
Coronaviruses (coronaviruses) were first found in chickens in 1937 and then in humans in 1965 by animals such as dogs, pigs and birds. When the sun is on a full day, the sun's light bulb is covered by the moon, and the phenomenon of white luminescence appears around is similar to coronavirus, so the name is obtained.
Coronaviruses are known to cause mainly pneumonia and enteritis in humans and animals, and occasionally to cause nervous system infections and hepatitis. Coronaviruses belong to the family Coronaviridae (Coronaviridae), have a spherical outer membrane, and are positive senseRNA viruses of about 100-120nm in size (Master, 2006). Coronaviruses share five structural proteins: the outermost spike protein (S), hemagglutinin-esterase (HE) protein, transmembrane (M) protein, small membrane (E) protein and nucleocapsid (N) protein (Lai and Homes,2001.Fields Virology). Among them, spike proteins, which act as ligands binding to cellular receptors and induce fusion of host cells with viruses, are considered to be the most mutated proteins.
Coronaviruses have so far been considered as pathogens which rarely infect humans, mainly animals such as dogs, pigs, cattle, etc. Even if it infects humans, it is only one of many viruses causing respiratory symptoms, causing intestinal diseases such as common cold or diarrhea, which are not very dangerous for children. However, as pathogens causing hundreds of deaths and thousands of patients worldwide, middle East Respiratory Syndrome (MERS) are a new (variant) coronavirus, there is growing interest.
Covd-19 is a disease that causes a progressive pandemic and is an infectious disease caused by the SARS-coronavirus-2. By 5 months and 7 days 2020, 187 countries reported more than 375 thousands of cases, 26.3 thousands of deaths, and 124 thousands of deaths. Common symptoms are fever (fever), cough (co ugh), fatigue (fatigue), dyspnea (shortness of breath), and loss of smell and taste. In most cases, symptoms are mild, but some develop into viral pneumonia (viral lung umonia), multiple-organ failure (multi-organ failure), and cytokine storm (cytokine storm). The time from symptoms to onset is typically about 5 days, but may be between 2and 14 days. Viruses are transmitted from person to person mainly by intimate contact, sometimes by cough, sneeze and droplets produced when speaking. It is most infectious in the first 3 days after symptoms appear and can spread before symptoms appear even at the end of the disease. The standard method of diagnosing it is the real-time reverse transcription polymerase chain reaction (real-time reverse tr anscription polymerase chain reaction; rRT-PCR) using nasopharyngeal swabs (nasopharyngeal swab).
MERS was first found in sauter arabia in 2012 to show severe respiratory symptoms such as high fever, cough, dyspnea, etc., and is a disease that may cause death with complications in severe cases. Although the exact source and route of infection has not been ascertained, it has been reported that infection is most likely by contact with camels in the middle east and may be transmitted by intimate human-to-human contact. Patients are mainly distributed in the middle east but 100 or more infected persons appear in korea since 5 months in 2015.
As described above, MERS and SARS are known to be caused by mutant coronaviruses (MERS-coronavirus, SARS-coronavirus and SARS-coronavirus-2) belonging to the genus Beta coronavirus (Beta coronavirus). Thus MERS-coronavirus, SARS-coronavirus and SARS-coronavirus-2 have similar characteristics in terms of clinical symptoms, pathogenesis and infection. In phylogenetic tree (phyloge netictree), SARS-coronavirus and SARS-coronavirus-2 belong to the B-line comprising bat SARS-like coronavirus and other bat-derived coronaviruses, while MERS-coronavirus belongs to the C-line comprising bat-derived coronaviruses (Trends Microbiol 24:490-502).
MERS-coronavirus, SARS-coronavirus and SARS-coronavirus-2 are all believed to originate from bats (anti-viral Res 101:45-56) of the major carrier of various coronaviruses, the exact infection pathways of which have not been fully elucidated. On the other hand, cross-species transmission of viruses to the castors (palm ci vet) and dromedaries (dromedari camel) increases the likelihood of zoonotic infection (Nat Re v Microbiol 14:523-534), and nosocomial infection is considered to be the main cause of human-transmitted MERS coronavirus and SARS-coronavirus infection (BMC Med 13:1-12).
On the other hand, although several drugs for treating SARS-coronavirus-2 are currently being developed, natural drugs have not been developed mainly based on compound or existing drug development.
In particular, since antiviral drugs developed so far have serious side effects, great care is required in applying them. In fact, such therapeutic agents are not effective and side effects also occur. Therefore, there is an increasing need to develop novel coronavirus drugs having excellent infection-inhibiting effect and low toxicity to prevent and treat coronaviruses.
Against this background, the present inventors have diligently studied on the development of novel coronavirus therapeutic drugs, and have found that hovenia dulcis thunb extract having a ensured stability is effective against the proliferation of SARS-coronavirus-2, SARS-coronavirus and MERS-coronavirus. It was confirmed that the inhibitor has an excellent inhibitory effect, and the present application was completed.
Disclosure of Invention
The present inventors have for the first time identified antiviral effects against coronaviruses of hovenia dulcis thunb containing an extract of hovenia dulcis thunb or an isolate thereof, developed pharmaceutical compositions for antiviral against coronaviruses comprising the extract of hovenia dulcis thunb or an isolate thereof, pharmaceutical compositions for preventing or treating infectious diseases of coronaviruses, methods for preventing or treating infectious diseases of coronaviruses using the above pharmaceutical compositions, health functional food compositions for preventing or improving infectious diseases of coronaviruses comprising the extract of hovenia dulcis thunb or an isolate thereof, and feed compositions for preventing or improving infectious diseases of coronaviruses comprising the extract of hovenia dulcis thunb or an isolate thereof, completed the present application.
An object of the present application is to provide a pharmaceutical composition for antiviral against coronavirus comprising hovenia dulcis thunb extract or an isolate thereof.
Another object of the present application is to provide a pharmaceutical composition for preventing or treating coronavirus infectious diseases comprising hovenia dulcis thunb extract or an isolate thereof.
It is another object of the present application to provide a method for preventing or treating coronavirus infectious diseases using the above pharmaceutical composition.
Another object of the present application is to provide a health functional food composition for preventing or improving coronavirus infectious diseases comprising hovenia dulcis thunb extract or an isolate thereof.
Another object of the present application is to provide a feed composition for preventing or improving coronavirus infectious diseases comprising hovenia dulcis thunb extract or an isolate thereof.
Another object of the present application is to provide a use of a composition for coronavirus for manufacturing an antiviral pharmaceutical composition comprising hovenia dulcis thunb extract or an isolate thereof.
It is another object of the present application to provide a use of the composition for manufacturing a pharmaceutical composition for preventing or treating coronavirus infectious diseases, comprising hovenia dulcis thunb extract or an isolate thereof.
Another object of the present application is to provide a use of the composition for manufacturing a health functional food composition for preventing or improving coronavirus infectious diseases, comprising hovenia dulcis thunb extract or an isolate thereof.
Another object of the present application is to provide a use of the composition for manufacturing a feed composition for preventing or improving coronavirus infectious diseases, comprising hovenia dulcis thunb extract or an isolate thereof.
ADVANTAGEOUS EFFECTS OF INVENTION
Since the hovenia dulcis thunb extract of the present application exhibits an effect of inhibiting coronavirus infection such as SARS-coronavirus-2, SARS-coronavirus and MERS-coronavirus, it is useful for developing an antiviral agent for preventing or treating the above-mentioned viral diseases.
Drawings
Fig. 1 is a graph showing the SARS-coronavirus-2 inhibitory efficacy of the concentrations of hovenia dulcis extract and control group adefovir according to the present application.
Best mode for carrying out the application
The present application will be described in more detail below.
In one aspect, each of the descriptions and embodiments of the present disclosure may also apply to each of the different descriptions and embodiments. That is, all combinations of the elements disclosed in the present application are within the scope of the present application. Furthermore, the scope of the present application is not limited by the following detailed description.
Furthermore, one of ordinary skill in the art can recognize or ascertain using no more than routine experimentation, many equivalents to the specific aspects of the application described herein. Further, such equivalents are intended to be encompassed by the present application.
To achieve the above objects, an embodiment of the present application provides a pharmaceutical composition for antiviral against coronavirus comprising hovenia dulcis thunb extract or an isolate thereof.
To achieve the above objects, another embodiment of the present application provides a pharmaceutical composition for preventing or treating coronavirus infectious diseases comprising hovenia dulcis thunb extract or an isolate thereof as an active ingredient.
In particular, since the pharmaceutical composition of the present application exhibits an inhibitory effect on coronaviruses, the present application can be effectively used for preventing or treating infectious diseases caused by coronaviruses.
The term "hovenia dulcis thunb" of the present application means fruits or seeds of hovenia dulcis thunb with fruit stalks of the Rhamnaceae family, and is called honey because of sweet taste, meaning honey grown on trees. In China, also called a nursery pear, means a pear tree growing in a fairy yard, which is white and hard like stone, also called Bai Danmu.
Is used for fever, thirst, hiccups, vomiting and the like caused by fever, and is well known for promoting urination, treating liver injury caused by alcoholism, promoting blood circulation and relaxing muscles. Further, korean patent No. 0588759 discloses a food composition containing hovenia dulcis thunb for improving cognition and a health functional food using the same, korean patent No. 1314749 discloses a method for manufacturing a composition for tea bags containing hovenia dulcis thunb and hovenia dulcis thunb, and korean registered patent No. 1306878 discloses a composition for preventing and treating bone diseases, which contains hovenia dulcis thunb extract as an active ingredient. However, up to now, there has been no report on antiviral activity against coronaviruses using hovenia dulcis thunb extract.
As mentioned above, the term "extract" according to the present application has the meaning commonly used in the art as crude extract, but also includes in a broad sense the isolate obtained by further separating the crude extract. That is, the hovenia dulcis thunb extract of the present application includes not only an extract obtained using the above-mentioned extract solvent, but also an isolate obtained by additionally applying a purification process thereto. For example, the extract may be passed through an ultrafiltration membrane having a molecular weight cut-off, separated by various chromatographic separations designed for separation according to size, charge, hydrophobicity or affinity, and the separation of the extract solvent by various additional purification methods, such as by secondary or tertiary additional extract separations, is also included in the extract of the present application.
In the hovenia dulcis thunb extract of the present application, a method of extracting hovenia dulcis thunb is not particularly limited, and the extract may be extracted according to a conventional method in the art. Non-limiting examples of the above extraction methods include: hot water extraction, ultrasonic extraction, filtration, reflux extraction, etc., which may be carried out alone or in combination of two or more.
In the present application, the kind of the solvent used for the extract is not particularly limited, and any solvent known in the art may be used. Non-limiting examples of the extract solvent include water, alcohol or a mixed solvent thereof, etc., which may be used alone or in combination of one or more, and specifically, water, methanol, ethanol or butanol may be used. When an alcohol is used as the solvent, an alcohol having 1 to 4 carbon atoms may be specifically used.
For example, the hovenia dulcis thunb extract may be extracted by a hot water extraction method comprising the steps of: step 1), adding distilled water in an amount which is 5-30 times based on the weight of the hovenia dulcis thunb; step 2) hot water extract at 100-130 ℃ for 2-5 hours; step 3) filtering the hot water extract; but is not limited thereto.
The term "coronavirus infectious disease" in the present application means a disease caused by infection of a coronavirus invaded in the body of an organism as a host, and specifically, the coronavirus may be one or more selected from the group consisting of SA RS-coronavirus-2 (coronavirus-19), SARS-coronavirus and MERS-coronavirus, and more specifically, SARS-coronavirus-2.
The term "SARS-coronavirus-2 (SARS-coronavirus-2)" according to the present application is a strain of coronavirus disease-19 (coronavirus disease 2019; COVID-19) which causes respiratory disease, as is known from the national institutes of health (National Institutes of Health; NI H), and is the successor (successor) of SARS-coronavirus (SARS-coronavirus). SARS-coronavirus-2 is a benign single stranded RNA virus (positive-sense single-stran ded RNA virus). It is contagious in humans and the world health organization (World Health Organization; WHO) has announced an ongoing covd-19 pandemic as an international public health emergency (Public Health Emergency of International Concern; PHEIC).
SARS-coronavirus-2 is considered taxonomically a strain (st rain) of SARS-coronavirus, has zoonotic origin (zoonotins), and has close genetic similarity to bat coronavirus. The SARS-coronavirus-2 is transmitted mainly by intimate human-to-human contact and/or by droplets produced during coughing or sneezing, and binds mainly to the receptor angiotensin converting enzyme 2 (receptor angiotensin converting enzyme 2; ACE 2) into human cells.
The term "SARS-coronavirus (SARS-coronavirus)" according to the present application is a ssRNA virus belonging to the genus beta coronavirus having an envelope. The entire genome consists of 29,727 nucleotides, which is the largest genome among the RNA viruses known so far. The genome of SARS-coronavirus is known to have 11 open reading frames (open reading frame, ORF), encoding 23 proteins. The major structural proteins found in SARS-coronavirus are nucleocapsid (N), spike (S), membrane (M) and small envelope (E) proteins.
Sequencing of these proteins revealed very low sequence homology, approximately 40% to 50%, for SARS-coronavirus compared to other coronaviruses. Phylogenetic classification based on antigenicity of coronaviruses has found that SARS coronavirus has a higher affinity with group II among groups I, II, III.
The term "MERS-coronavirus (MERS-coronavirus)" according to the present application is a newly discovered ssRNA virus belonging to the genus betacoronavirus in 9/24 2012, having a 5 '-replicase-structural protein (5' -replicase-membrane-nucleic acid) -poly (a) -3'[5' -ORF1a/b-S-E-M-N-poly (a) ] structure. MERS-coronavirus genomes are phylogenetically divided into a-clade and B-clade, early MERS cases being a-clade (EMC/2012 and Jordan-N3/2012), and newly reported cases are genetically different clades B (Emerging Infectious Diseases, vol.20, no.6, june 2014).
In the present application, a pharmaceutical composition for preventing or treating coronavirus infectious diseases, comprising the hovenia dulcis thunb extract or an isolate thereof, is characterized by inhibiting one or more viruses selected from the group consisting of SARS-coronavirus-2, SARS-coronavirus and MERS-coronavirus. Specifically, in one embodiment of the present application, the above-mentioned hovenia dulcis thunb extract or an isolate thereof was confirmed to have the ability to inhibit SARS-coronavirus-2 infection, and compared with adefovir as a positive control group (fig. 1).
The term "infectious disease" in the present application refers to a disease caused by infection.
The term "infection" refers to the condition in which pathogenic microorganisms invade the host organism and grow.
The term "prevention" according to the present application refers to all the actions of inhibiting or delaying the onset of an infectious disease caused by coronavirus by administering a pharmaceutical composition according to the present application.
The term "treatment" according to the present application refers to the administration of a pharmaceutical composition to improve or beneficially alter all the behaviour of a symptom in an individual suspected or known to be suffering from a coronavirus infectious disease.
The pharmaceutical compositions of the application may also include a pharmaceutically acceptable carrier, excipient or diluent, and such carriers may include non-natural carriers (non-naturally occuring carrie r).
More specifically, as carriers, excipients, and diluents which may be contained in the above pharmaceutical compositions, there may be exemplified: lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginates, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, polycaprolactone (polycaprolacton e), polylactic Acid (Poly Lactic Acid), poly-L-Lactic Acid, mineral oil.
The pharmaceutical composition can be prepared into oral dosage forms such as powder, granules, tablets, capsules, suspension, emulsion, syrup, aerosol and the like according to a conventional method, and can be used in the forms of external preparations, suppositories and sterile injection, wherein the carrier forms can comprise: various irregular carriers, microspheres, nanofibers, and the like.
In the preparation, the composition may be formulated using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant, which are commonly used.
Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which can be prepared by mixing the above extract and its isolate with at least one excipient such as starch, calcium carbonate (calcium carbonate), sucrose (sucrose) or lactose (lactose), gelatin and the like. In addition, lubricants such as magnesium styrene and talc may be used in addition to simple excipients.
Liquid preparations for oral administration include suspensions, solutions for oral administration, emulsions, syrups, and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives, and the like may be included in addition to water and liquid paraffin, which are commonly used as simple diluents.
Formulations for non-oral administration may include sterile aqueous solutions, nonaqueous solvents, suspensions, emulsions, lyophilized formulations, adjuvants and the like. As the nonaqueous solvent and suspending agent, propylene glycol (propylene glyco l), polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, etc. can be used.
The content of the hovenia dulcis thunb extract in the pharmaceutical composition of the present application is not particularly limited, and may include a pharmaceutically effective amount of the hovenia dulcis thunb extract.
The term "pharmaceutically effective amount" according to the application refers to an amount sufficient to treat a disease in an effective amount/risk ratio suitable for medical treatment, and is typically an amount of 0.001 to 1000mg/kg, preferably 0.05 to 200mg/kg, more preferably 0.1 to 100mg/kg administered 1 to several times per day. However, for the purposes of the present application, an effective amount for a particular treatment of a particular patient is preferably applicable in different ways depending on the type and extent of the reaction to be achieved, the particular composition including whether other agents are used as appropriate, the age, weight, general health, sex and diet of the patient, the time of administration, the route of administration and secretion of the composition, the time of treatment, a variety of factors including the drugs used with or concurrently with the particular composition, and similar factors well known in the medical arts.
The pharmaceutical compositions of the present application may be used as a single therapeutic agent or in combination with other therapeutic agents, or may be administered sequentially or simultaneously with conventional therapeutic agents. And may be administered in a single or multiple doses. In view of all the above factors, it is important to administer an amount capable of achieving the maximum effect in a minimum amount without causing side effects, and can be easily decided by a person skilled in the art.
The term "administering" of the present application means introducing the pharmaceutical composition of the present application into a patient by any suitable method, and the route of administration of the composition of the present application may be by various routes, whether oral or non-oral, as long as the target tissue is reached.
The method of administration of the pharmaceutical composition according to the present application is not particularly limited and may be performed according to methods commonly used in the art. As a non-limiting example of a method of administration, the composition may be administered by oral or non-oral administration. The pharmaceutical composition according to the present application can be formulated into various dosage forms according to the intended administration mode.
The pharmaceutical composition of the present application may be administered, for example, to mammals including humans in an amount of 1 to 20 mg/kg per day, more preferably 1 to 10 mg/kg. The frequency of administration of the composition of the present application is not particularly limited, and the composition may be administered once a day or several times in several times.
To achieve the above object, another embodiment of the present application provides a method for preventing or treating coronavirus infectious diseases, comprising the step of administering a pharmaceutical composition to an individual other than a person having symptoms of coronavirus infectious diseases or at risk of developing the same.
At this time, the descriptions of "pharmaceutical composition", "coronavirus", "infection", "prevention" and "treatment" are as described above.
The term "individual" according to the present application may refer to all animals including humans having symptoms of coronavirus infection or at risk of developing a disease. The animal may be not only a human but also mammals in need of treatment for similar symptoms such as cow, horse, sheep, pig, goat, camel, antelope, dog and cat, but is not limited thereto.
The above-described methods of prevention or treatment of the present application may specifically include the step of administering a pharmaceutically effective amount of the composition to an individual having symptoms of or at risk of developing a coronavirus infection.
The term "administering" according to the application means introducing the pharmaceutical composition of the application into an individual having symptoms of or at risk of developing a coronavirus infection by any suitable method, and the route of administration of the composition of the application may be by various routes, whether oral or non-oral, as long as the target tissue is reached.
To achieve the above object, another embodiment of the present application provides a health functional food composition for preventing or improving coronavirus infectious diseases comprising hovenia dulcis thunb extract or an isolate thereof.
At this time, descriptions of "hovenia dulcis thunb extract", "an isolate thereof", "coronavirus", "infection" and "prevention" are as described above.
Since the hovenia dulcis thunb extract according to the present application exhibits excellent inhibitory effect on coronavirus, it can be contained in a food composition to prevent or improve infectious diseases caused by coronavirus, and since the above food composition can be consumed daily, it can be expected to have high effect on prevention or improvement of coronavirus infection.
The term "improvement" according to the present application refers to all actions that at least reduce the degree of a parameter, e.g. a symptom, associated with the condition being treated by administration of the pharmaceutical composition according to the present application.
The term "health functional food" of the present application means food manufactured and processed using raw materials or ingredients beneficial to the human body according to health functional food law No. 6727, and "function" means health beneficial effects such as nutritional regulation or physiological effects on the structure and function of the human body. On the other hand, a health food means a food having a positive health-maintaining or promoting effect as compared with a general food, a health-aid food means a food for the purpose of assisting health, and terms of a health-function food, a health-aid food, and a health-aid food may be mixed according to circumstances.
The hovenia dulcis thunb extract of the present application may be directly added, or may be used together with other foods or food ingredients, and may be suitably used according to a conventional method.
The food of the present application may be prepared by a method commonly used in the art, and may be prepared by adding raw materials and ingredients commonly used in the art to the above preparation process. In particular, the above-mentioned food composition may further include a physiologically acceptable carrier, the kind of which is not particularly limited, and any carrier commonly used in the art may be used. The food composition may further comprise food additives such as preservatives, bactericides, antioxidants, colorants, coloring agents, bleaching agents, flavoring agents, sweeteners, perfumes, bulking agents, reinforcing agents, emulsifiers, thickening agents, coating agents, gum bases, foam inhibitors, solvents, and improvers. The above additives can be used in proper amount according to food.
The formulation of the food may be produced without limitation, as long as it is considered as a food. The food composition of the present application can be formulated into various dosage forms, and unlike general medicines, has the advantage of no side effects that may occur when medicines are taken for a long period of time because of the use of foods as raw materials, and is excellent in portability, and therefore the food of the present application can be used for supplement ingestion for enhancing the effect of preventing or improving infectious diseases caused by coronaviruses.
If the hovenia dulcis thunb extract of the present application can exhibit an effect of preventing or improving infectious diseases caused by coronaviruses, it may be contained in various weight% in the food composition. Specifically, it may comprise 0.00001 to 100 wt% or 0.01 to 80 wt% with respect to the total weight of the food composition, but is not limited thereto. In the case of long-term intake for health and hygiene purposes, the content below the above range may be contained, and since there is no problem in terms of safety, the active ingredient in an amount above the above range may be used.
In order to achieve the above object, another embodiment of the present application provides a feed composition for preventing or improving coronavirus infectious diseases comprising hovenia dulcis thunb extract or an isolate thereof as an active ingredient.
At this time, descriptions of "hovenia dulcis thunb extract", "an isolate thereof", "coronavirus", "infectious disease", "prevention" and "improvement" are as described above.
Since hovenia dulcis thunb extract according to the present application exhibits excellent inhibitory effect on coronavirus, it is included in a feed composition for the purpose of preventing or improving infectious diseases of coronavirus, and animals can ingest the above feed composition on a daily basis, and thus it is expected to have high effect on preventing or improving infectious diseases caused by coronavirus.
The term "feed" according to the present application shall mean any natural or artificial prescribed meal, etc. or component of a meal as used for animal consumption, ingestion and digestion, or as suitable for the purpose.
The type of the above-mentioned feed is not particularly limited, and feeds commonly used in the art can be used. Non-limiting examples of such feeds include: such as cereals, dried fruits, food processing byproducts, algae, celluloses, pharmaceutical byproducts, oils and fats, starches, meal or cereal byproducts; such as protein, inorganic substances, organic substances, mineral substances, organic substances, single cell protein, animal floating substances or animal feeds such as physical substances. These may be used alone or in combination of 2 or more.
It is another object of the present application to provide the use of a composition containing hovenia dulcis thunb extract or an isolate thereof for preparing a pharmaceutical composition for resisting coronavirus.
At this time, descriptions of the "hovenia dulcis thunb extract", "an isolate thereof" and "coronavirus" are as described above.
Another object of the present application is to provide a use of a composition containing hovenia dulcis thunb extract or an isolate thereof in the preparation of a pharmaceutical composition for preventing or treating coronavirus infectious diseases.
At this time, descriptions of "hovenia dulcis thunb extract", "an isolate thereof", "coronavirus", "infectious disease", "prevention" and "treatment" are as described above.
Another object of the present application is to provide a use of a composition containing hovenia dulcis thunb extract or an isolate thereof in preparing a health functional food composition for preventing or improving coronavirus infectious diseases.
At this time, descriptions of "hovenia dulcis thunb extract", "an isolate thereof", "coronavirus", "infectious disease", "prevention" and "improvement" are as described above.
Another object of the present application is to provide a use of a composition containing hovenia dulcis thunb extract or an isolate thereof in preparing a feed composition for preventing or improving coronavirus infectious diseases.
At this time, descriptions of "hovenia dulcis thunb extract", "an isolate thereof", "coronavirus", "infectious disease", "prevention" and "improvement" are as described above.
Detailed Description
Hereinafter, the present application will be described in more detail by the following examples. However, the following examples are merely illustrative of the present application, and the scope of the present application is not limited thereto.
Example 1: preparation of Hovenia dulcis Thunb extract
To prepare the hovenia dulcis extract, after adding 1L of water to 50g, hot water extraction was performed at 115℃for 180 minutes using a heating plate (medical he ating plate; gyeongseo Extractor Cosmos-600, inchon, korea), filtered using a standard sample (standard testing sie ves;150 μm; retsch, haan, germany) and freeze-dried, and the sample was stored at-20℃until the experiment for the present application. For the experiment, after being dissolved in sterilized distilled water at a concentration of 100mg/ml, it was filtered through a 0.2 μm syringe filter (syringfilter) and stored at 4℃and diluted to a desired concentration using 2% DMEM medium and used at the time of the experiment.
Example 2: confirmation of inhibition of SARS-coronavirus-2 infection
Example 2-1: preparation of cell lines and viruses
To determine whether or not there was an inhibitory effect on the novel SARS-coronavirus-2, vero cells (Vero cells) were used, which were American Type Culture Co llection (ATCC, CCL-81; manassas, va.) and cultured in Dulbecco's modified Eagle's medium (DMEM; welgene, gyeongsan, korea) containing 10% heat-inactivated fetal bovine serum and 1X-antimicrobial-Antimycic (Gibco/Thermo Fisher Scientific, waltham, mass.) at 37℃under 5% carbon dioxide.
In addition, the novel SARS-coronavirus-2 is provided and used by the Korean center for disease prevention control. Virus titers were measured using a plaque assay (plaque assay).
Example 2-2: confirmation of Hovenia dulcis Thunb extract for inhibiting SARS-coronavirus-2 infection
Vero cell lines (ATCC, CCL-81) were grown at 2X10 4 Density of individual cells/well after being placed in 96-well plate and cultured for one day, SARS-coronavirus-2 was infected to 0.05MOI in a state having concentrations of hovenia dulcis thunb extract 100, 33, 11, 3.7 and 1.2 (μg/ml). 48 hours after infection, cells were fixed with 1:3 acetone: methanol (v/v) at room temperature for 10 minutes and then were primary-resistant to mice with coronavirus S (GeneT ex, irvine, calif.) protein. The virus-infected cells were stained with Alex Fluor 488-conjugated goat anti-mouse IgG (Invitrogen, carlsbd, CA)) as a secondary antibody, and the infected cells were observed to be green since Alex Fluor 488 used as the secondary antibody fluoresced green. Nuclei were stained blue by DAPI staining. The effect of inhibiting SARS-coronavirus-2 infection was confirmed using the drug Remdesivir (Remdesivir) as a control drug (standard drug). Cell images were acquired using an operatta (PerkinElmer, operatta) device and infection rates were calculated using Harmony software. The infection rate at the time of drug treatment was calculated as 100% for the case of virus infection only and 0% for the case of no infection. The effective drug concentration (EC 50) to inhibit viral infection by 50% was calculated using Prism software (Grap hPad, prism). For cytotoxicity, cells were treated with the same concentration and time of drug alone without viral infection and cell viability was measured by the MTS method. For cytotoxicity, in the absence of virus, only the drug was treated at the same concentration for the same time in the cells, and cell viability was measured by the MTS method. At this time, the concentration (CC 50) decreasing by 50% in cell viability was calculated as the cytotoxicity concentration. The selectivity index (Selectivity Index, SI) is a display that is calculated by dividing the EC50 value by the CC50 value as an indicator of how well a compound is toxic to it.
The specific results are shown in FIG. 1.
The right vertical axis (Cell availability, black) represents cytotoxicity (%) of the sample, and the left vertical axis (Antiviral activity, red) represents the relative amount (%) of S protein of the sample inhibiting SARS coronavirus-2. In addition, specific experimental concentrations were 100, 33, 11, 3.7 and 1.2 (μg/ml).
As a result, as shown in fig. 1, cytotoxicity (CC 50) of the hovenia dulcis thunb extract of the present application was measured up to a maximum experimental concentration of 100 μg/ml, an effective drug concentration (EC 50) was 25.0 μg/ml, and s.i. (selectivity index, CC50/EC 50) was determined to be >4. In addition, positive control group adefovir had a CC50>100 μm, EC50 value of 6.6 μm, SI measured as >15.
Thus, it was confirmed that the hovenia dulcis thunb extract of the present application has an effective inhibitory effect on SARS-coronavirus-2 infection.
From the above description, it will be appreciated by those skilled in the art that the present application can be embodied in other specific forms without changing its technical spirit or essential characteristics. The above-described embodiments are to be considered in all respects as illustrative and not restrictive. The scope of the application should be construed as including all changes and modifications to the meaning and scope of the following claims and derivatives thereof, as compared to the detailed description set forth above.
Claims (8)
1. An antiviral pharmaceutical composition for coronavirus comprising Hovenia dulcis Thunb extract or its isolate.
2. The pharmaceutical composition according to claim 1, wherein the coronavirus is at least one selected from the group consisting of SARS-coronavirus-2 (coronavirus-19), SARS-coronavirus and MERS-coronavirus.
3. The pharmaceutical composition according to claim 1, wherein the hovenia dulcis thunb extract is obtained by extracting hovenia dulcis thunb with water, C1-4 alcohol or a mixed solvent thereof.
4. A pharmaceutical composition according to claim 3, wherein the extraction is hot water extraction, ultrasonic extraction, ambient temperature extraction, cold dip extraction, reflux cooled extraction or steam extraction.
5. A pharmaceutical composition for preventing or treating coronavirus infectious diseases comprises Hovenia dulcis Thunb extract or its isolate.
6. A method for the prevention or treatment of a coronavirus infectious disease comprising the step of administering the pharmaceutical composition of any one of claims 1 to 5 to a subject other than a human having symptoms of or at risk of developing a coronavirus infection.
7. A health food composition for preventing or improving coronavirus infectious diseases comprises Hovenia dulcis Thunb extract or its isolate.
8. A feed composition for preventing or improving coronavirus infectious diseases comprises Hovenia dulcis Thunb extract or its isolate.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
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| KR10-2020-0126188 | 2020-09-28 | ||
| KR10-2021-0067202 | 2021-05-25 | ||
| KR1020210067202A KR102570596B1 (en) | 2020-09-28 | 2021-05-25 | Composition for preventing or treating corona virus comprising Hoveniae Semen Cum Fructus extracts |
| PCT/KR2021/013195 WO2022065971A2 (en) | 2020-09-28 | 2021-09-28 | Composition for prevention or treatment of coronavirus infection, comprising hovenia dulcis thunb extract |
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| CN202180073522.2A Pending CN116963754A (en) | 2020-09-28 | 2021-09-28 | A composition containing Hovenia dulcis Thunb extract for preventing or treating coronavirus infection |
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