WO2022098133A1 - Souche de streptomyces sp. ayant une efficacité antivirale et composition antivirale la comprenant - Google Patents

Souche de streptomyces sp. ayant une efficacité antivirale et composition antivirale la comprenant Download PDF

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WO2022098133A1
WO2022098133A1 PCT/KR2021/015945 KR2021015945W WO2022098133A1 WO 2022098133 A1 WO2022098133 A1 WO 2022098133A1 KR 2021015945 W KR2021015945 W KR 2021015945W WO 2022098133 A1 WO2022098133 A1 WO 2022098133A1
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strain
composition
extract
culture
streptomyces
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PCT/KR2021/015945
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English (en)
Korean (ko)
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남상집
임병관
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이화여자대학교 산학협력단
중원대학교 산학협력단
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Priority claimed from KR1020200148081A external-priority patent/KR102540830B1/ko
Priority claimed from KR1020200148080A external-priority patent/KR102424404B1/ko
Application filed by 이화여자대학교 산학협력단, 중원대학교 산학협력단 filed Critical 이화여자대학교 산학협력단
Publication of WO2022098133A1 publication Critical patent/WO2022098133A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/14—Nitrogen or oxygen as hetero atom and at least one other diverse hetero ring atom in the same ring
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/465—Streptomyces
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a Streptomyces sp. strain having antiviral efficacy and an antiviral composition comprising the same.
  • Viruses are one of the representative causes of numerous incurable diseases that threaten human health. Entero virus, Chikungunya Virus, SARS virus, MERS virus and Zika Intractable RNA viruses such as Zika virus pose a serious risk to civilization. Most of the epidemics have slightly different symptoms, but the period of the epidemic is roughly fixed, and huge capital is invested worldwide to detect and prevent or treat it.
  • enterovirus is prevalent in young children during spring and summer. In particular, children under the age of three are more easily exposed to the virus as more and more children under the age of three are left in daycare facilities. Enteroviruses are well known as the cause of enteritis, hand, foot and mouth disease, herpangina (stomy herpes), spinal polio, aseptic meningitis in infants, and encephalitis. Enteroviruses are fatal enough to cause death in severe cases, so there is an urgent need to develop a virus treatment that can suppress their proliferation, but there is currently no treatment or preventive agent that can effectively suppress these viruses.
  • One object of the present invention is to provide an antiviral composition
  • an antiviral composition comprising a compound of Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, isomer, or derivative thereof.
  • Another object of the present invention is to provide a method for producing an antiviral composition and a strain capable of producing the composition.
  • Another object of the present invention is a Streptomyces genus strain having antiviral efficacy, a culture of the strain, a lysate of the strain, an extract of the cell, an extract of the culture, and an extract of the lysate. It is to provide an antiviral composition comprising one or more selected from.
  • Another object of the present invention Streptomyces sp. strain or the step of extracting fractional extraction of the culture solution of the strain with an organic solvent; And to provide a method for preparing a compound having Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, isomer, or derivative thereof, comprising the step of separating and purifying the fractionated extract by chromatography.
  • Another object of the present invention Streptomyces sp. strain or the step of extracting fractional extraction of the culture solution of the strain with an organic solvent; And a method for preparing an antiviral composition comprising the step of separating and purifying the fractionated extract by chromatography, comprising the compound of Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, isomer, or derivative thereof is to provide
  • Antiviral agents can inhibit viruses through various mechanisms, among which the following two mechanisms are known that can be used to effectively inhibit viruses.
  • SAH hydrolase is a tetramer-type enzyme that uses NAD+ as a coenzyme. It reversibly hydrolyzes SAH into adenosine (Ado) and homocysteine (Hcy), and proteins, lipids in vivo. , it is a very important enzyme for the methylation of substances in the body, such as histamine and norepinephrine, as well as nucleic acids.
  • SAH hydrolase Inhibition of this SAH hydrolase causes the accumulation of SAH, and the excess SAH sequentially suppresses S-adenosylmethionine (AdoMet)-dependent transmethylase and capping of viral mRNA so that the protein necessary for viral replication is released. By preventing it from being made properly, it results in an antiviral effect. Since most animal DNA viruses as well as RNA viruses require methylation enzymes (viral mRNA guanosine N7-methytransferases, O-2′-methytransferases) for mRNA capping, SAH hydrolase is considered an essential element in the development of broad-spectrum antiviral agents. do. That is, the development of RNA virus therapeutics and SAH hydrolase inhibitors are considered to have a high correlation.
  • AdoMet S-adenosylmethionine
  • RNA viruses are replicated by inserting the substrate Nucleoside-5'-triphosphate (NTP) into the RNA chain by RNA polymerase. Therefore, a substance that inhibits RNA polymerase can also act as an antiviral agent, and it is converted into triphosphate in the body to selectively inhibit viral RNA polymerase or is directly inserted into the viral RNA chain to cause chain termination ), it is believed that effective antiviral agents can be developed.
  • NTP Nucleoside-5'-triphosphate
  • antiviral agents are mostly nucleoside derivatives such as iododeoxyuridine (IDU), acyclovir (ACV), azidothymidine (AZT), or proteins such as interferon (IFN), but these substances are cytotoxic. , hepatotoxicity, hyper-tolerance, and other side effects.
  • IDU iododeoxyuridine
  • ACV acyclovir
  • AVT azidothymidine
  • IFN interferon
  • the present inventors made diligent efforts to discover substances exhibiting effective antiviral efficacy, and as a result, 4-benzoxazole carboxylic acid, 2-(2-hydroxyphenyl)- from Marine Streptomyces among microorganisms isolated from marine sediment , isolated the methyl ester, and found that the compound can effectively inhibit the proliferation of viruses, thereby completing the present invention.
  • the antiviral efficacy of the Streptomyces sp. strain fraction isolated from the marine sediments of Antarctica was verified, and 4-benzoxazolecarboxyl, a compound of Formula 1, isolated from the Streptomyces sp. strain through detailed verification
  • the antiviral effect of acid, 2-(2-hydroxyphenyl)-, methyl ester was confirmed.
  • 4-benzoxazole carboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester was added to the cell culture medium at a concentration of 100-0.0001 ⁇ g/ml to HeLa cells cultured in a 96-well cell culture dish, and the virus was treated.
  • An example of the present invention relates to an antiviral composition
  • an antiviral composition comprising a compound having the following formula (1), a pharmaceutically acceptable salt, hydrate, solvate, isomer, or derivative thereof:
  • 4-benzoxazole carboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester of the present invention includes, without limitation, the substance represented by Formula 1 and derivatives, isomers, etc. that can be recognized in the art as similar thereto Unless otherwise specified below, as an active (active) ingredient included in the composition of the present invention, 4-benzoxazole carboxylic acid of Formula 1, 2-(2-hydroxyphenyl)-, methyl All esters as well as pharmaceutically acceptable salts, hydrates, solvates, isomers (preferably optical isomers) or derivatives thereof are included, and all of these should be construed as being included in the scope of the present invention.
  • the active ingredient of the present invention may exist in the form of a salt, particularly a pharmaceutically acceptable salt.
  • a salt particularly a pharmaceutically acceptable salt.
  • salts commonly used in the art may be used without limitation.
  • pharmaceutically acceptable salt refers to a concentration having an effective action that is relatively non-toxic and harmless to a patient, and the side effects caused by this salt are 4-benzoxazolecarboxylic acid, 2-(2-hydroxyphenyl) -, means any and all organic or inorganic addition salts of said compounds which do not impair the beneficial efficacy of the methyl esters.
  • composition of the present invention pharmaceutically acceptable salts thereof, as well as solvates such as hydrates that can be prepared therefrom, and possible derivatives and isomers, preferably optical isomers, are included without limitation.
  • solvates, derivatives and isomers of 4-benzoxazolecarboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester can be prepared using methods known in the art to form 4-benzoxazolecarboxylic acid, 2-( 2-hydroxyphenyl)-, methyl ester.
  • the antiviral composition according to the present invention is a compound of Formula 1, 4-benzoxazolecarboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester, a pharmaceutically acceptable salt, hydrate, solvate, isomer, or a derivative as an active ingredient
  • the composition may be a pharmaceutical composition, a cosmetic composition, a composition for external application for skin, a health functional food, or a quasi-drug composition, and these may be injections, solutions, tablets, capsules, ointments, ointments, creams, Essence, foam, lotion, nourishing lotion, soft water, softening lotion, pack, emulsion, makeup base, soap, detergent, bath agent, sun cream, sun oil, suspension, emulsion, paste, gel, lotion, powder, soap, surfactant It may have a formulation selected from the group consisting of containing cleansing, oil, foundation, powder foundation, emulsion foundation, wax foundation, patch and spray.
  • the composition may be a pharmaceutical composition having antiviral effic
  • antiviral efficacy may be, for example, prevention, treatment, or improvement of enterovirus infection, but is not limited thereto, and includes any activity that prevents, treats or ameliorates general viral infection.
  • 4-benzoxazolecarboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester contained in the composition of the present invention, a pharmaceutically acceptable salt, hydrate, solvate, isomer (preferably, optical isomer) thereof ) or derivatives may inhibit virus proliferation or growth.
  • the "inhibition of virus proliferation” means inhibiting S-adenosylhomocysteine (hereinafter referred to as SAH) hydrolase in the body or in vitro, such as inhibiting viral RNA polymerase (polymerase) of the virus in vivo or in vitro It may include any mechanism that inhibits proliferation.
  • SAH S-adenosylhomocysteine
  • polymerase viral RNA polymerase
  • the "inhibition of virus growth” refers to inhibiting the attachment of a virus to a host cell, inhibiting the initiation of invasion into the host cell, attacking the invading virus and promoting its degradation, inhibiting the proliferation of the virus, and Similarly, it may include both mechanisms that lower the activity of the virus in the cell and suppress the infectivity.
  • Said 4-benzoxazolecarboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester, a pharmaceutically acceptable salt, hydrate solvate, isomer (preferably optical isomer) or derivative thereof is a virus, in particular an enterovirus. Because it inhibits proliferation and exhibits excellent antiviral efficacy, enterovirus infection and related diseases, such as enteritis, hand, foot and mouth disease, stomatitis, stomatitis herpes, polio, spinal polio, meningitis, infantile aseptic meningitis, encephalitis One or more diseases selected from the group consisting of can be prevented, improved, alleviated or treated.
  • enterovirus infection and related diseases such as enteritis, hand, foot and mouth disease, stomatitis, stomatitis herpes, polio, spinal polio, meningitis, infantile aseptic meningitis, encephalitis
  • enterovirus infection and related diseases such as enteritis, hand,
  • another embodiment of the present invention relates to a composition for preventing or treating enterovirus infection, comprising the compound of Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, isomer, or derivative thereof.
  • the infection may be one or more selected from the group consisting of enteritis, hand, foot and mouth disease, stomatitis, herpetic stomatitis, polio, spinal polio, meningitis, infantile aseptic meningitis, and encephalitis.
  • the composition may be a pharmaceutical composition, a health functional food, a cosmetic composition, or a quasi-drug composition.
  • the 4-benzoxazolecarboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester, pharmaceutically acceptable salt, hydrate solvate, isomer (preferably
  • the effective amount of the optical isomer) or derivative will vary depending on the form in which the pharmaceutical composition having antiviral activity is commercialized, the method in which the compound is applied to the body, and the length of time it stays in the body.
  • the pharmaceutical composition having the antiviral activity when commercialized as a drug for the treatment of anterovirus infection, it may include a pharmaceutically acceptable salt, hydrate solvate, isomer (preferably optical isomer) or derivative thereof. There will be.
  • the antiviral composition according to the present invention includes 4-benzoxazolecarboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester, pharmaceutically acceptable salts, hydrates, solvates, isomers ( Preferably, the optical isomer) or derivative based on the total weight of the pharmaceutical composition having the antiviral activity, 0.0001 to 15% by weight, for example, 0.001 to 10% by weight, for example 0.001 to 5% by weight.
  • the pharmaceutical composition having antiviral activity according to the present invention contains 4-benzoxazolecarboxylic acid, 2-(2-hydroxyphenyl)-, and methyl ester in the form of an extract and/or fraction containing them
  • the Based on the total weight of the pharmaceutical composition having antiviral activity 0.001 to 50% by weight, for example, 0.01 to 30% by weight, or 0.1 to 10% by weight, for example, 1 to 5% by weight may be included.
  • the above ratio varies depending on the dosage form in which the pharmaceutical composition of the present invention is prepared, its specific application site (face, neck, etc.) or its desired application amount, the above ratio limits the scope of the present invention in any aspect. should not be construed as
  • composition having antiviral activity according to the present invention may be a pharmaceutical composition.
  • the pharmaceutical composition having antiviral activity according to the present invention is 4-benzoxazolecarboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester, a pharmaceutically acceptable salt, hydrate, solvate, derivative or isomer thereof.
  • a cosmetically acceptable carrier or additive may be included.
  • fatty substances for example, fatty substances, organic solvents, solubilizers, thickeners, gelling agents, emollients, antioxidants, suspending agents, stabilizers, foaming agents, fragrances, surfactants, emulsifiers, fillers, sequestering agents, chelating agents, preservatives, Vitamins, blocking agents, wetting agents, oils, dyes, pigments, hydrophilic or lipophilic active agents, lipid vesicles, etc., but are not limited thereto, and may include all known substances applicable to the pharmaceutical composition.
  • the pharmaceutical composition having antiviral activity according to the present invention may be formed in one or more formulations selected from the group consisting of injections, ointments, external solutions, patches, capsules, and tablets, but is not limited thereto, and all known formulations can be formed.
  • the composition having antiviral efficacy of the present invention having the above formulation is formed in an ointment, paste, cream or gel state, animal oil, vegetable oil, wax, paraffin, starch, gum tragacanth, cellulose derivative , polyethylene glycol, silicon, bentonite, silica, talc, zinc oxide, and the like may be further included.
  • the antiviral composition according to the present invention may further include a solvent, a solubilizer, an emulsifier, and the like.
  • the solvent, solubilizer, and emulsifier include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol, sorbate. fatty acid esters of heartburn, and the like.
  • a liquid diluent such as water, ethanol, propylene glycol, etc., ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, polyoxyethylene sorbitan ester, etc.
  • Suspension agent microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, gum tragacanth and the like may be further included.
  • the pharmaceutical composition according to the present invention may be used alone or in combination with other pharmaceutically active compounds.
  • the pharmaceutical composition may be in the form of a known oral or parenteral administration formulation.
  • the antiviral composition of this embodiment is a filler in addition to the 4-benzoxazolecarboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester, a pharmaceutically acceptable salt, hydrate, solvate, derivative or isomer thereof.
  • extenders, binders, wetting agents, disintegrants, diluents such as surfactants, excipients and/or carriers may be further included.
  • solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in one or more compounds, for example, starch, calcium carbonate, sucrose, lactose. , or gelatin, etc. are mixed and prepared.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid formulations for oral administration may include various excipients, for example, wetting agents, sweetening agents, fragrances, preservatives, etc. in addition to water and liquid paraffin, which are commonly used simple diluents.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • non-aqueous solvent and the suspending solvent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used.
  • injectable esters such as ethyl oleate
  • the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
  • the pharmaceutical composition having antiviral efficacy according to the present invention may be administered to mammals such as rats, mice, livestock, and humans by various routes. Any mode of administration can be envisaged, for example, by oral or parenteral administration (intraperitoneal, rectal, intravenous, intramuscular or subcutaneous injection, or transdermal administration).
  • the parenteral route is preferably transdermal administration, and among them, it may be topical application.
  • the preferred dosage of the antiviral composition according to the present invention varies depending on the patient's condition and weight, the severity of the disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art.
  • the antiviral pharmaceutical composition according to the present invention may be administered in an amount of 0.1 to 100 mg/kg once to several times a day, but is not limited thereto.
  • the parenteral administration dose of the antiviral pharmaceutical composition according to the present invention varies depending on the patient's condition and weight, the degree of disease, drug form, administration route and period, but in the case of external application, 1.0 to 3.0 ml per day is administered once to It can be applied by dividing it into several times, but is not limited thereto.
  • the antiviral composition according to the present invention is a cosmetic composition, for example, a cleansing foam, cleansing cream, or cleansing water, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl Taurate, sarcosinate-based compound, fatty acid amide ether sulfate, alkylamidobetaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative, ethoxylated glycerol fatty acid ester, etc. may be further included. .
  • a cosmetic composition for example, a cleansing foam, cleansing cream, or cleansing water, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl Taurate, sarcos
  • the 4-benzoxazole carboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester may include purchased ones, those isolated from microorganisms, synthesized ones, and the like, For example, it may be extracted from microorganisms and separated, for example, isolated from a Streptomyces sp. strain. Specifically, the compound may be isolated from a Streptomyces sp. strain or a culture of the strain.
  • the Streptomyces sp. strain may be, for example, Streptomyces griseolus SCO-774 having an accession number KCTC14340BP.
  • the Streptomyces griseolus ( Streptomyces griseolus ) SCO-774 strain is a strain having 4-benzoxazole carboxylic acid, 2- (2-hydroxyphenyl) -, methyl ester producing ability, 4-benzoxazole carboxylic acid, 2 -(2-hydroxyphenyl)-, is the first strain confirmed to have the ability to produce methyl ester.
  • the composition having antiviral activity according to the present invention is at least one selected from the group consisting of the cells of the strain, the culture of the strain, the lysate of the strain, the extract of the cell, the extract of the culture, and the extract of the lysate. may include.
  • the compound may be obtained by fractional extraction of the strain or a culture of the strain.
  • a method of extracting the compound having Formula 1 from the Streptomyces sp. strain having the antiviral effect a known microbial extraction method may be used without limitation.
  • the extraction solvent used for extraction may also be extracted by appropriately selecting a solvent known in the art according to the characteristics of the microorganism, including water or organic solvent, for example, water, ethyl acetate, methanol, ethanol, propanol , isopropanol, butanol, acetone, ether, chloroform, methylene chloride, hexane, cyclohexane, and may be extracted with one or more solvents selected from the group consisting of dichloromethane, for example, may be extracted with an ethyl acetate solvent.
  • a solvent known in the art including water or organic solvent, for example, water, ethyl acetate, methanol, ethanol, propanol , isopropanol, butanol, acetone, ether, chloroform, methylene chloride, hexane, cyclohexane, and may be extracted with one or more solvents selected from the group consisting of dichloromethan
  • the compound may be obtained from a small fraction obtained by fractionally extracting the strain or a culture of the strain to obtain a fractional extract, and further fractionating the fractionated extract.
  • the compound may be obtained from a small fraction obtained by fractionally extracting the strain or a culture of the strain to obtain an organic solvent fraction extract from the organic solvent layer, and further fractionating the organic solvent fraction extract.
  • the compound is a small fraction obtained by fractionally extracting the strain or a culture of the strain to obtain an organic solvent fraction extract from the organic solvent layer, and further fractionating the organic solvent fraction extract using reverse phase column chromatography.
  • a small fraction of the extract may be prepared using a fractionation solvent capable of obtaining a large amount of 4-benzoxazole carboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester as active ingredients, for example, water and
  • a fraction fractionated with a mixed solvent of an alcohol eg, a lower alcohol having 1-3 carbon atoms
  • the small fraction may be obtained by further fractionating the fractional extract with 20, 40, 50, 60, 70, 80, or 100% solution of methanol.
  • the compound may be obtained by isolating and purifying the small fraction. Specifically, the compound may be obtained by separating and purifying the small fraction by, for example, HPLC. That is, the compound may be obtained from a second small fraction obtained by fractionally extracting the strain or a culture of the strain, and separating and purifying a small fraction obtained by further separating the fractional extract.
  • the fraction, subfraction, or secondary subfraction may contain useful secondary metabolites, including Formula 1, to exhibit excellent antiviral effects.
  • Another example of the present invention is a strain of Streptomyces having an antiviral effect, a culture of the strain, a lysate of the strain, an extract of the cell, an extract of the culture, and an extract of the lysate. It relates to an antiviral composition comprising at least one selected from.
  • the extract of the culture may be a fractional extract of the culture.
  • the composition may include a fractional extract of the culture.
  • the extract of the culture may include an organic solvent layer, a fraction obtained by separating the organic solvent layer, or both of the fractional extracts of the culture.
  • the dried product and the concentrate mean obtained by drying or concentrating the culture in a conventional manner.
  • the composition may include the compound of Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, isomer, or derivative thereof.
  • the compound having Formula 1 may be isolated from the Streptomyces sp. strain or a culture of the strain.
  • the strain may be isolated from Antarctic marine sediment.
  • the compound having Formula 1 may be isolated from the extract of the SCO774 strain of the genus Streptomyces.
  • the SCO774 strain of Streptomyces or a culture of the strain may be isolated from an extract extracted with ethyl acetate.
  • Another example of the present invention relates to a method for obtaining Formula 1 comprising the step of obtaining an extract by adding ethyl acetate to Streptomyces sp.,.
  • the method may further include the step of removing the organic solvent from the extract.
  • the strain may be a Streptomyces sco774 strain having accession number KCTC14340BP.
  • the composition may have antiviral efficacy against enterovirus.
  • 4-benzoxazolecarboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester of Formula 1 isolated from the Streptomyces sp. strain has antiviral efficacy, specifically, excellent antiviral efficacy against anterovirus appeared to exist.
  • the 4-benzoxazole carboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester can prevent, treat, and improve various infections that can be caused by anteroviruses by inhibiting the growth of anteroviruses.
  • another example of the present invention is a Streptomyces strain having an antiviral effect, a culture of the strain, a lysate of the strain, an extract of the cell, an extract of the culture, and an extract of the lysate. It relates to a composition for preventing or treating enterovirus infection, comprising at least one selected from the group consisting of.
  • the strain may be a Streptomyces sco774 strain having an accession number KCTC14340BP.
  • the infection may be one or more selected from the group consisting of enteritis, hand, foot, and mouth disease, stomatitis, stomatitis herpes, polio, spinal polio, meningitis, and encephalitis.
  • the culture may include a culture medium with a cell-free culture, or a Streptomyces sp. strain, including the culture of the strain and not including the strain.
  • the culture medium may be a known appropriate medium for culturing the strain, but in order to provide optimal conditions for the production of useful secondary metabolites, the culture medium is Marine broth (BD), SYP, seawater contained culture solution (SYP SW: 10 g/L starch, 2 g/L yeast extract, 4 g/L peptone) and the like.
  • the medium form of the marine broth may be both a solid medium and a liquid medium, preferably a liquid medium.
  • the SYP SW medium may be both a solid medium and a liquid medium, preferably a liquid medium.
  • the culture period for obtaining a culture may be about 4 days or more, for example, 4 to 20 days, for example, 6 to 15 days in which the production of effective secondary metabolites is active.
  • starch Soluble starch
  • yeast extract Yeast extract
  • peptone Peptone
  • sea salt sea salt
  • 4 g of starch 1.6 g of yeast extract, 0.3 g of peptone, 7.2 g of agar, 13.9 g of sea salt per 400 mL of distilled water water
  • 4L of distilled water add 4L of distilled water to 40g of starch, 16g of yeast extract, 8g of peptone, and 139g of sea salt based on 4L.
  • Another example of the present invention is composed of a Streptomyces spp. strain having antiviral efficacy, a culture of the strain, a lysate of the strain, an extract of the cell, an extract of the culture, and an extract of the lysate It relates to a composition for preparing a compound having Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, isomer, or derivative thereof, comprising at least one selected from the group.
  • Another example of the present invention is composed of a Streptomyces spp. strain having antiviral efficacy, a culture of the strain, a lysate of the strain, an extract of the cell, an extract of the culture, and an extract of the lysate It relates to a composition for preparing an antiviral composition comprising one or more selected from the group.
  • the antiviral composition may be an antiviral composition against enterovirus.
  • Another example of the present invention relates to a method for producing 4-benzoxazole carboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester using a Streptomyces sp. strain.
  • the preparation method the step of obtaining an extract by adding an extraction solvent to the composition comprising the Streptomyces sp. strain; and isolating and purifying the extract.
  • 4-benzoxazole carboxylic acid useful as an active ingredient of an antiviral composition, 2-(2-hydroxyphenyl)-, methyl ester can be easily obtained.
  • an example of the present invention comprises the steps of fractional extraction of a Streptomyces sp. strain or a culture solution of the strain with an organic solvent; And it relates to a method for preparing a compound having Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, isomer, or derivative thereof, comprising the step of separating and purifying the fractionated extract by chromatography.
  • an example of the present invention relates to a method for preparing an antiviral composition, comprising the step of culturing a Streptomyces sp. strain having antiviral efficacy.
  • the manufacturing method comprises the steps of fractionally extracting the culture of the strain; and separating the fractional extract.
  • the preparation method may further include the step of isolating the fractional extract to obtain a compound having the formula (1).
  • an example of the present invention comprises the steps of fractional extraction of a Streptomyces sp. strain or a culture solution of the strain with an organic solvent; And comprising the step of separating and purifying the fractionated extract by chromatography, comprising the compound of Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, isomer, or derivative thereof, Preparation of an antiviral composition it's about how
  • the extraction solvent may be selected without limitation as long as it is a solvent capable of extracting 4-benzoxazolecarboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester from Streptomyces sp. strain, but an organic solvent, for example, At least one organic solvent selected from the group consisting of ethyl acetate, methanol, ethanol, propanol, isopropanol, butanol, acetone, ether, chloroform, methylene chloride, hexane, cyclohexane, and dichloromethane may be used, for example, ethyl acetate can
  • the extraction may be replaced by a method using an extraction apparatus such as supercritical extraction, high pressure extraction or ultrasonic extraction, or a method using celite or polystyrene or polyamide adsorption resin, but is not limited thereto.
  • the amount of solvent or extraction temperature at the time of extraction can be appropriately changed by those skilled in the art, but it is preferable to extract by adding 1 to 3 times the amount of the solvent by volume of the amount of the culture solution during extraction, and it is preferable to perform extraction at room temperature.
  • the number of extractions is preferably 1 to 3 times, and drying under reduced pressure is preferably performed using a rotary vacuum evaporator, but is not limited thereto.
  • the drying temperature under reduced pressure may be, for example, 20 to 40 °C, for example 30 °C, but is not limited thereto.
  • the strain is obtained by culturing the Streptomyces strain. It may further comprise the step of preparing a composition comprising.
  • an extract is obtained by adding the extraction solvent, and an extraction solvent, preferably an organic solvent, is obtained from the extract. It may further include the step of removing. Removal of the organic solvent may be performed using methods known in the art without limitation.
  • chromatography For the separation and purification method, a known method may be used without limitation, for example, chromatography may be used.
  • the "chromatography” may be used without limitation chromatography according to size, charge, hydrophobicity or affinity, for example, flash chromatography (TLC), may be reversed-phase liquid chromatography.
  • TLC flash chromatography
  • the chromatography may be performed using at least one selected from the group consisting of water and alcohol as a developing solvent.
  • composition for antiviral according to the present invention is a safe material with low cytotoxicity derived from a natural product, and can prevent, treat, and improve viral infection by effectively inhibiting virus proliferation. It can be usefully used in manufacturing.
  • FIG. 1 is a view showing the morphology of a Streptomyces SCO774 strain in a marine solid medium according to an example of the present invention isolated from marine sediments. The back side of the plate is shown, and the lower left is an enlarged view of the strain part.
  • FIG. 2 is a diagram showing the antiviral efficacy of each fraction by fractionating the extract of the SCO774 strain of Streptomyces genus according to an example of the present invention.
  • Figure 3 is a view showing the verification of the membrane protein production of the virus and the activity of the viral protein cleavage enzyme according to the fraction treatment of the SCO774 strain extract of Streptomyces genus according to an example of the present invention by western blot analysis.
  • FIG. 4 is a view showing the HPLC separation result of the F6 fraction of the Streptomyces sp. strain extract according to an example of the present invention. After fractionation of the entire extract of the Streptomyces sp. strain according to an embodiment of the present invention, 4-benzoxazole carboxylic acid, 2-(2-hydroxyphenyl )-, a chromatogram of pure separation of methyl ester. A peak in which 4-benzoxazole carboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester was separated at UV 254 nm was indicated by an arrow.
  • FIG. 5 is a view showing the antiviral efficacy of the secondary fraction of the Streptomyces sp. strain extract according to an example of the present invention.
  • the F6 fraction which has excellent antiviral efficacy, was separated by HPLC, and the concentration-dependent effect of each separated material for inhibiting the growth of anterovirus was confirmed. It can be seen that the substance F6-7 has the best antiviral effect, and this substance was identified as 4-benzoxazolecarboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester.
  • Figure 6a shows 1 H NMR (300 MHz) data of 4-benzoxazolecarboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester, which is a compound isolated from a Streptomyces sp. strain according to an example of the present invention; It is a drawing.
  • 6b is a view showing LC-MS results of 4-benzoxazole carboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester, which are compounds isolated from a Streptomyces sp. strain according to an example of the present invention.
  • 6c is a view showing the UV spectrum results of 4-benzoxazole carboxylic acid, 2-(2-hydroxyphenyl)-, methyl ester, which are compounds isolated from a Streptomyces sp. strain according to an example of the present invention.
  • ISP 1 SW ISP 1 powder 1.6g/L, sea salt 34.74g/L, 1 Primary distilled water 400ml
  • ISP 4 SW ISP 4 powder 3.7g/L, sea salt 34.74g/L, primary distilled water 400ml
  • the isolated strain was named SCO774, and the SCO-774 strain had a morphological pattern similar to that of strains belonging to the genus Streptomyces sp. as shown in FIG. 1 .
  • 1 is a view showing the morphology of SCO774 strain isolated from marine sediment in Marine solid medium, the upper left is the front side of the medium plate, the upper right is the back side of the medium plate, and the lower left is It is an enlarged view of the strain part.
  • SCO774 strain isolated from marine sediment 1 ml of the strain cultured at 27°C for 4 days in a marine broth liquid medium is taken and “Tissue Genomic DNA Isolation kit” (Cosmogenetech co, Ltd.. Seoul, South) Korea) to extract genomic DNA according to the manufacturer's protocol.
  • PCR was performed using primers 518F and 805R for 16S rRNA gene amplification.
  • the PCR product was purified using a “PCR purification kit” (Cosmogenetech co, Ltd. Seoul, South Korea), and the base sequence was analyzed using capillary electrophoresis (Applied Biosystems 3730XL).
  • the primer sequences used for PCR are shown in Table 1.
  • the 16S rRNA gene sequence obtained from the SCO-774 strain was compared with the information of the strains using BLAST search of the GenBank/EMBL/DDBJ database. As a result of identification, the SCO-774 strain of the present invention was identified as a Streptomyces griseolus strain belonging to the genus Streptomyces.
  • the nucleotide sequence of the 16S rRNA genes of the SCO-774 strain of Streptomyces genus according to the present invention is shown in Table 2 (SEQ ID NO: 5):
  • Streptomyces griseolus Streptomyces griseolus ( Streptomyces griseolus ) SCO774 strain was deposited with the Korea Research Institute of Bioscience and Biotechnology on October 21, 2020 and was given an accession number KCTC14340BP.
  • the Streptomyces griseolus SCO774 strain was placed in a 1 liter culture solution (10 g/L starch, 2 g/L yeast extract, 4 g/L peptone) containing seawater in a 2.5L culture vessel at 27°C, 130 for 7 days. Cultured under rpm conditions. Into the Streptomyces SCO774 strain culture medium, 1 L of ethyl acetate was added to separate the two layers according to the polarity, and an ethyl acetate layer was obtained therefrom. Thereafter, the organic solvent was removed from the ethyl acetate layer using a vacuum rotary concentrator to obtain a concentrated ethyl acetate extract.
  • the ethyl acetate extract (4.0 g) was fractionated with a mixed solvent of water and methanol, and a total of 8 fractions (F1 to F7) were fractionated by reverse phase column chromatography using C-18 silica following a stepwise gradient with a methanol concentration of 20 to 100%. and FW).
  • the antiviral efficacy and cytotoxicity of the Streptomyces griseolus SCO774 strain extract was confirmed using HeLa cells.
  • Fractions F6 and F7 of the Streptomyces griseolus SCO774 strain extract were added to the cell culture medium at a concentration of 0.01 ug/ml, 0.1 ug/ml, 1ug/ml, or 10ug/ml, respectively, to HeLa cells cultured in a 96-well cell culture dish After infecting with Entero virus at 10 5 pfu/ml for 18 hours, 10 ⁇ l of Cell Counting Kit 8 (CCK-8), a reagent for detecting proliferation of cells, was added and incubated for 2 hours more. .
  • CCK-8 Cell Counting Kit 8
  • FIG. 2 The results of confirming the antiviral efficacy of the Streptomyces griseolus SCO774 strain extract are shown in FIG. 2 .
  • negative is a negative control group not infected with the virus
  • positive is a positive control group infected with only the virus without drug treatment.
  • the fraction of the SCO774 strain extract had an enterovirus growth inhibitory effect and showed an antiviral effect on enterovirus.
  • the F6 fraction and virus were treated on HeLa cells for 18 hours, and then the cells were lysed using PBS lysis buffer (1x phosphate buffer saline, 1% Triton-X 100) to extract proteins.
  • the extracted protein was heated at 98°C for 10 minutes, loaded on a 10% SDS-PAGE gel, and electrophoresed at 100 volt for 3 hours. Protein transfer was performed on the electrophoresed gel using PVDF membrane. After transfer, the membrane was blocked with 5% skim milk, and the anti-enterovirus VP1, eIF4G1, and GAPDH antibodies were reacted at 4°C for 18 hours, followed by confirmation using ECL solution.
  • the production of membrane proteins indicating virus proliferation was decreased according to the concentration of F6 fraction treatment, and in particular, the destruction of eIF4G1, a transcription initiator of cells cleaved by a virus-producing protein cleavage enzyme, which is evidence of direct virus proliferation, was It can be seen that the excellent antiviral effect is suppressed.
  • the organic solvent was removed from the F6 fraction, the sixth fraction fractionated with 80% MeOH, to obtain 184.9 mg of a residue.
  • the residue was dissolved in 6ml methanol, and high performance liquid chromatography (HPLC) was performed on the solution to separate 7 substances.
  • HPLC separation result of the F6 fraction of the Streptomyces griseolus SCO774 strain extract is shown in FIG. 4 .
  • the conditions of the high performance liquid chromatography used were as follows:
  • the F6-7 peak in the F6 fraction of the Streptomyces griseolus SCO774 strain extract is indicated by an arrow in FIG. 4 .
  • the F6-7 fraction was isolated at a retention time of 12.5 to 13 minutes.
  • the active ingredient of the F6-7 fraction showing the highest antiviral efficacy in Example 3 was identified through NMR, LC-MS and ultraviolet spectrum (IR), and the results are shown in FIGS. 6a, 6b and 6c, respectively.
  • 1 H NMR contains a benzene ring between 6.0 ppm and 8.0 ppm, and it can be seen that 1,2 substituents are included through the coupling pattern.

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Abstract

La présente invention concerne une souche de Streptomyces sp. ayant une efficacité antivirale et une composition antivirale la comprenant.
PCT/KR2021/015945 2020-11-06 2021-11-04 Souche de streptomyces sp. ayant une efficacité antivirale et composition antivirale la comprenant WO2022098133A1 (fr)

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KR10-2020-0148081 2020-11-06
KR1020200148081A KR102540830B1 (ko) 2020-11-06 2020-11-06 항바이러스 효능을 가지는 스트렙토마이세스 속 균주 및 이를 포함하는 항바이러스용 조성물
KR1020200148080A KR102424404B1 (ko) 2020-11-06 2020-11-06 항바이러스용 조성물 및 이의 제조방법
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Citations (3)

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Publication number Priority date Publication date Assignee Title
US20050004188A1 (en) * 2002-11-22 2005-01-06 Kerwin Sean M. UK-1 analogues: methods of preparation and use
US20110256232A1 (en) * 2008-10-28 2011-10-20 Nofima Ingrediens Antimicrobial composition from copepods
KR20140005843A (ko) * 2010-06-25 2014-01-15 인쎄름 (엥스띠뛰 나씨오날 드 라 쌍떼 에 드 라 흐쉐르슈 메디깔) 기도 감염의 치료를 위한 방법 및 약학 조성물

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US20050004188A1 (en) * 2002-11-22 2005-01-06 Kerwin Sean M. UK-1 analogues: methods of preparation and use
US20110256232A1 (en) * 2008-10-28 2011-10-20 Nofima Ingrediens Antimicrobial composition from copepods
KR20140005843A (ko) * 2010-06-25 2014-01-15 인쎄름 (엥스띠뛰 나씨오날 드 라 쌍떼 에 드 라 흐쉐르슈 메디깔) 기도 감염의 치료를 위한 방법 및 약학 조성물

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LOSADA ARMANDO A., CANO-PRIETO CAROLINA, GARCÍA-SALCEDO RAÚL, BRAÑA ALFREDO F., MÉNDEZ CARMEN, SALAS JOSÉ A., OLANO CARLOS: "Caboxamycin biosynthesis pathway and identification of novel benzoxazoles produced by cross-talk in Streptomyces sp. NTK 937", MICROBIAL BIOTECHNOLOGY, WILEY-BLACKWELL PUBLISHING LTD., GB, vol. 10, no. 4, 1 July 2017 (2017-07-01), GB , pages 873 - 885, XP055928468, ISSN: 1751-7915, DOI: 10.1111/1751-7915.12716 *

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