WO2021162463A1 - Composition pour prévenir, traiter et soulager la dermatite atopique, comprenant un composé conjugué de flavone-resvératrol - Google Patents
Composition pour prévenir, traiter et soulager la dermatite atopique, comprenant un composé conjugué de flavone-resvératrol Download PDFInfo
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- WO2021162463A1 WO2021162463A1 PCT/KR2021/001805 KR2021001805W WO2021162463A1 WO 2021162463 A1 WO2021162463 A1 WO 2021162463A1 KR 2021001805 W KR2021001805 W KR 2021001805W WO 2021162463 A1 WO2021162463 A1 WO 2021162463A1
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- atopic dermatitis
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
- A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
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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
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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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
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/318—Foods, ingredients or supplements having a functional effect on health having an effect on skin health and hair or coat
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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
- A23V2250/00—Food ingredients
- A23V2250/30—Other Organic compounds
Definitions
- the present invention relates to a composition for preventing, treating and improving atopic dermatitis comprising a flavone-resveratrol conjugate compound.
- Human skin consists of three layers: the epidermis, dermis, and subcutaneous fat tissue. It acts as a protective barrier.
- the epidermal layer is divided into a stratum corneum, a stratum granulosum, a stratum spinosum, and a stratum basale.
- Cells constituting the epidermal layer include various cells such as keratinocytes, Langelhans cells, and Merkel cells, and the majority of these cells are keratinocytes. Keratinocytes proliferate in the basal layer, and as they differentiate, they rise to the stratum corneum and become corneocytes, forming the keratin of the skin, thereby protecting the skin from the harmful external environment.
- Atopic dermatitis is a chronic recurrent skin inflammatory disease accompanied by severe itching as the skin barrier weakens and the skin becomes dry due to allergic symptoms caused by immune hypersensitivity reaction (J Clin Invest 2012;122:440). -447).
- the skin barrier is damaged due to an inflammatory reaction, exposure to other antigens is easily made, and the vicious cycle of chronic inflammation, itching, and dry skin is repeated (N Engl J Med 2008;358:1483-1494).
- the cause of atopic dermatitis has not yet been clearly identified, it is considered that a variety of genetic, environmental, immunological, and skin structural factors act in a complex way (J Clin Invest 2004;113:651-657).
- Thymic stromal lymphopoietin secreted by keratinocytes
- interleukin-4 secreted by CD4+helper type 2 T-lymphocytes (Th2)
- interleukin-4 IL-4
- IFN ⁇ interferon-gamma
- Th1-lymphocytes Th1-lymphocytes
- TNF ⁇ Tumor necrosis factor-alpha
- IL-4 and IL-33 activate various inflammatory cells such as monocytes/macrophages, dendritic cells, keratinocytes, eosinophils, basophils, and mast cells to generate interleukin-31 (IL-31).
- monocytes/macrophages dendritic cells
- keratinocytes keratinocytes
- eosinophils basophils
- mast cells to generate interleukin-31 (IL-31).
- TSLP is a cytokine secreted in large amounts from keratinocytes in an inflammatory environment of the skin.
- Interleukin-4 activates dendritic cells and CD4+helper type 2 T-lymphocytes (Th2), which are important for innate immunity response.
- Th2 CD4+helper type 2 T-lymphocytes
- TSLP mediates the progression of chronic atopic dermatitis patients to complex asthma disease, and activates TRPA-1 positive-sensory neurons to induce severe itchiness (Cell.
- TSLP expression was increased in keratinocytes in the skin of atopic dermatitis patients, and spontaneous atopic-like dermatitis occurred in transgenic mice overexpressing TSLP (J Exp Med 2005:202; 541-549).
- the expression of TSLP is regulated by the transcription factor EGR-1.
- Interleukin-31 secreted from Th2 lymphocytes is a representative cytokine that induces histamine-independent itch by directly stimulating sensory nerves or acting on keratinocytes to promote beta-endorphin production (Br J Dermatol). 2012;167:794-803). Interleukin-31 promotes the expression of beta-endorphin precursor pro-opiomelanocortin (POMC) gene in keratinocytes.
- POMC pro-opiomelanocortin
- Atopic dermatitis is a chronic disease that cannot be treated well enough to be called an incurable disease, so once it is onset, it is a chronic disease that must be continuously managed and treated for several to several decades.
- Most of the existing commercialized first-line treatments were mainly steroid-based external treatments that relieve severe itching and suppress cytokine production due to hypersensitivity immune response.
- steroids for infants and young children may cause various side effects such as weakened immunity and skin atrophy or growth retardation.
- immunosuppressants such as calcineurin-inhibiting cyclosporin, which are nonsteroidal agents, have been developed and commercialized.
- EGR-1 a transcription factor expressed in keratinocytes
- cytokines TSLP, interleukin-1 ⁇ , interleukin-6, interleukin-17, interleukin-23
- CXCL1, CCL5 chemokines
- T-lymphocytes and mast cells inflammatory cells
- beta-endorphin a precursor of beta-endorphin
- EGR-1 which can suppress the expression of cytokines causing atopic dermatitis and genes causing itch, and flavone-resveratrol, which is a low molecular weight compound for alleviating the occurrence and symptoms of atopic dermatitis.
- the present invention provides a pharmaceutical composition for preventing or treating atopic dermatitis, comprising a compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, as an active ingredient.
- the compound of Formula 1 is a flavone-resveratrol conjugate compound, as 2-(6-(4-methoxystyryl)-2,4-dimethoxyphenyl)-3-hydroxy-6-nitro-4H-chromen-4-one (AB1711).
- the material may be synthesized by the inventors of the present invention or may be derived from nature, but is not limited thereto, and the AB1711 compound synthesized according to the synthesis method described in Example 1 of the present invention may be used.
- the present inventors found that the AB1711 directly binds to the transcription factor EGR-1 and blocks the DNA-binding ability of EGR-1, thereby inhibiting the production of various cytokines and chemokines that cause atopic dermatitis, It was confirmed that it performs the function of suppressing expression.
- the compound AB1711 of Formula 1 of the present invention directly binds to EGR-1 and blocks the ability of EGR-1 to bind to the DNA sequence of the 5'-transcription regulatory region of the target gene, thereby preventing atopic dermatitis.
- TSLP, IL-1 ⁇ , IL-6, IL-17, IL-23 which are cytokines that induce Since it has an effect of inhibiting the expression of POMC (Ppro-opiomelanocortin), a precursor of ⁇ -endorphin that transmits a signal to the brain, it may have therapeutic and symptom relief effects for atopic dermatitis. That is, since it has not only a therapeutic effect of atopic dermatitis, but also an improvement effect that can prevent it, and further relieve symptoms, it can be used as an effective drug for the treatment of atopic dermatitis.
- POMC Pro-opiomelanocortin
- prevention refers to any action that suppresses or delays the onset of skin wrinkles or atopic dermatitis by administration of the composition of the present invention
- treatment refers to skin wrinkles or atopic dermatitis by the composition of the present invention. It refers to any action in which the symptoms caused by dermatitis are improved or changed to a beneficial effect.
- improvement refers to any action in which the symptoms of skin wrinkles and atopic dermatitis suspected and affected individuals are improved or beneficial by using the composition.
- the AB1711 compound of Formula 1 may be used in the form of a salt, preferably a pharmaceutically acceptable salt.
- the salt is preferably an acid addition salt formed with a pharmaceutically acceptable free acid, and an organic acid and an inorganic acid may be used as the free acid.
- the organic acid is not limited thereto, but citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, glutamic acid and aspartic acid.
- the inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.
- the addition salt according to the present invention is prepared by a conventional method, that is, the compound is dissolved in a water-miscible organic solvent, for example, acetone, methanol, ethanol, or acetonitrile, and an equivalent or excess of an organic acid is added or an aqueous solution of an inorganic acid is added. It can be prepared by precipitation or crystallization, or by evaporation of the solvent or excess acid followed by suction filtration of the dried or precipitated salt.
- a water-miscible organic solvent for example, acetone, methanol, ethanol, or acetonitrile
- the present invention may include within the scope of the present invention not only the compound or a pharmaceutically acceptable salt thereof, but also solvates, hydrates and stereoisomers having the same efficacy, which can be prepared therefrom.
- the pharmaceutical composition comprising the AB1711 compound of the present invention or a pharmaceutically acceptable salt thereof may further include an appropriate carrier, excipient or diluent commonly used in the preparation of the pharmaceutical composition.
- the content of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof included in the composition is not particularly limited, but may be included in an amount of 0.001 to 50% by weight based on the total weight of the composition, preferably 0.1 to 10 It may be included in weight %.
- the pharmaceutical composition is any one selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, internal solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-drying agents and suppositories It may have a dosage form, and may be oral or parenteral various dosage forms.
- commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants may be used.
- Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin. and the like.
- excipients for example, starch, calcium carbonate, sucrose or lactose, gelatin. and the like.
- lubricants commonly used in addition to excipients may be included.
- Liquid formulations for oral administration include suspensions, internal solutions, emulsions, syrups, etc., and various excipients such as wetting agents, sweetening agents, fragrances, preservatives, etc. in addition to commonly used simple diluents such as water and liquid paraffin. have.
- Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories.
- Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
- injectable esters such as ethyl oleate.
- As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
- the pharmaceutical composition of the present invention may be formulated as a pharmaceutical or quasi-drug.
- Drug refers to a general drug, and is not limited to its formulation.
- Quasi-drugs refer to textiles, rubber products, or similar products used for the purpose of treating, alleviating, treating, or preventing diseases of humans or animals, which have weak effects on the human body or do not act directly on the human body, and are not instruments or machines.
- Products that are similar to those used for sterilization, insecticide and similar purposes for infection prevention, and are used for the purpose of diagnosing, treating, alleviating, treating or preventing diseases of humans or animals; It refers to items that are not machines or devices, and items used for the purpose of pharmacologically affecting the structure and function of humans or animals, excluding those that are not instruments, machines, or devices, and includes external preparations for skin and personal care products.
- composition of the present invention can be administered in a pharmaceutically effective amount.
- the term “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is dependent on the individual type and severity, age, sex, and disease. It can be determined according to the type, drug activity, drug sensitivity, administration time, administration route and excretion rate, treatment period, factors including concurrent drugs, and other factors well known in the medical field.
- the composition of the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, and may be administered simultaneously or sequentially with conventional therapeutic agents. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
- the preferred dosage of the composition of the present invention varies depending on the patient's condition and weight, the degree of disease, the drug form, the route and period of administration, and a suitable total daily amount may be determined by the treating physician within the scope of correct medical judgment, In general, an amount of 0.001 to 1000 mg/kg, preferably 0.05 to 200 mg/kg, and more preferably 0.1 to 100 mg/kg may be administered once a day or divided into several times a day.
- composition is not particularly limited as long as it is an individual for the purpose of preventing, treating, and alleviating symptoms of atopic dermatitis, and it is applicable to both humans and animals.
- the mode of administration may include without limitation as long as it is a conventional method in the art, and a method through topical application, oral administration, etc. may be used, but is not limited thereto.
- the present invention provides a health functional food composition for the prevention or improvement of atopic dermatitis, containing the compound represented by the formula (1) and a pharmaceutically acceptable salt thereof as an active ingredient.
- the composition of the present invention When the composition of the present invention is included in health functional food, the composition may be added as it is or used together with other health functional food or health functional food ingredients, and may be appropriately used according to a conventional method.
- the mixing amount of the active ingredient may be suitably determined according to the purpose of use.
- the composition of the present invention may be added in an amount of preferably 20 parts by weight or less, more preferably 10 parts by weight or less, based on the raw material, and is used for health control and hygiene purposes. In the case of long-term ingestion, the amount may be less than or equal to the above range.
- the type of health functional food that can contain the composition of the present invention, and there are various functional foods, gum, candy, jelly, beverage, tea, drink, alcoholic beverage and vitamin complex, and the like, and It may include all health functional foods, and may include feed or feed additives for animals.
- the health functional food composition of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin , alcohol, a carbonation agent used in carbonated beverages, and the like.
- the present invention provides a cosmetic composition for the prevention or improvement of atopic dermatitis, comprising the compound represented by Formula 1 and a cosmetically acceptable salt thereof as an active ingredient.
- the cosmetic composition of the present invention may include, without limitation, commonly acceptable ingredients in addition to the active ingredients, for example, conventional adjuvants such as antioxidants, stabilizers, solubilizers, vitamins, pigments and fragrances, and carriers. have.
- the cosmetic composition according to the present invention includes solutions, external ointments, creams, foams, nourishing lotions, softening lotions, packs, soft water, emulsions, makeup bases, essences, soaps, liquid detergents, bathing agents, sunscreen creams, sun oils, suspensions, It may be prepared in formulations such as emulsion, paste, gel, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, patch and spray, but is not limited thereto.
- the cosmetic composition of the present invention may further include one or more cosmetically acceptable carriers to be formulated in general skin cosmetics, and conventional ingredients include, for example, oil, water, surfactant, humectant, lower alcohol, A thickener, a chelating agent, a colorant, a preservative, a fragrance, etc. may be appropriately mixed, but the present invention is not limited thereto.
- the cosmetically acceptable carrier included in the cosmetic composition of the present invention may be included in various ways depending on the formulation.
- the content thereof is not limited thereto, but the total weight of the composition It may be included in the range of 0.001 to 5% by weight, and may be included in an amount greater than or equal to the minimum to exhibit efficacy for atopic dermatitis.
- the present invention provides a composition for preventing, treating, and improving atopic dermatitis, including the AB1711 compound or a salt thereof, which is a flavone-resveratrol conjugate compound, and various inflammatory cytokines and chemokines that induce atopic dermatitis and beta- By inhibiting the DNA binding ability of EGR-1, a transcription factor involved in the expression of an endorphin precursor, it can have a preventive, therapeutic and ameliorating effect on atopic dermatitis.
- FIG. 1 is a schematic diagram of the synthesis process of the AB1711 compound of the present invention.
- Figure 2 shows the results of analyzing the binding state of the AB1711 compound of the present invention and the EGR-1 protein by molecular docking method.
- A Binding of EGR-1 and AB1711 compound using LigPlot program
- B Three-dimensional image of binding of EGR-1 and AB1711 compound using PyMol program.
- FIG. 3 shows the results of analyzing the effect of the AB1711 compound of the present invention in blocking the DNA binding ability of EGR-1 by targeting the EGR-1 protein using the EMSA method.
- A Results of EMSA analysis of the EGR-1 binding DNA sequence position of the AB1711 compound and the EGR-1 protein (EGR1::DNA complex) and not (Free probe).
- B The result of quantitatively measuring the band intensity of the EGR-1 and DNA-bound complex using the ImagJ program
- Figure 4 shows the results of confirming the fact that the AB1711 compound of the present invention does not induce EGR-1 expression non-specifically by immunoblot method.
- A Immunoblot method.
- B The result of quantitative measurement of the EGR-1 band intensity of the immunoblot using the ImagJ program.
- EGR-1 plays a role in regulating the expression of various cytokines and chemokines causing atopic dermatitis in an inflammatory environment using HaCaT cells in which expression of the transcription factor EGR-1 is knocked down.
- A, B mRNA expression analysis using RT-PCR method.
- C The result of quantitative measurement of each gene mRNA band intensity in RT-PCR using the ImagJ program.
- FIG. 6 shows the results of confirming that the AB1711 compound of the present invention has the effect of inhibiting the expression of atopic dermatitis-induced cytokines and chemokines regulated by EGR-1 by targeting EGR-1.
- A Analysis of mRNA expression using RT-PCR method.
- B The result of quantitative measurement of each gene mRNA band intensity in RT-PCR using the ImagJ program.
- FIG. 7 shows the results of confirming that the AB1711 compound of the present invention has the effect of inhibiting the expression of the EGR-1 regulated POMC gene that causes itching in atopic dermatitis.
- A, B EGR-1 protein expression analysis using immunoblot method.
- C, D Result of quantitative measurement of POMC mRNA band intensity in RT-PCR using ImagJ program.
- E RT-PCR quantitative measurement of the POMC gene mRNA band intensity in Fig. 7D using the ImagJ program.
- Figure 10 confirms that the AB1711 compound of the present invention has the effect of reducing the infiltration of mast cells increased by the inflammatory response in the skin of mice induced atopic dermatitis by applying DNCB, an atopic-inducing drug.
- A Toluidine blue staining of rat skin tissue.
- B Measurement of mast cells stained with toluidine blue in FIG. A.
- the flavone-resveratrol conjugate compound AB1711 of the present invention is named as 2-(6-(4-methoxystyryl)-2,4-dimethoxyphenyl)-3-hydroxy-6-nitro-4H-chromen-4-one, It is synthesized according to the steps described. Hereinafter, the synthesis process of AB1711 was described in detail step by step.
- This structure contains amino acid residues between E335 - D423, and includes ZnF1 (338 - 362), ZnF2 (368 - 390), and ZnF3 (396 - 418) between E335 - D423. Since 4r2a.pdb does not contain a ligand, the binding site was determined using the MOLCAD module included in the Sybyl program: F377, S378, H382, T385, H386, T389, R407. The size (62, 56, 70) and center (-4.421, -10.84, -19.227) of the docking box were determined to include the determined binding site, and an in silico docking experiment was performed with the Autodock vina program.
- oligonucleotides included in 4r2a.pdb were removed using Sybyl program.
- Nine protein-ligand complexes were obtained from docking using Autodock vina.
- the binding energy of the obtained protein-ligand complexes was between -6.3 and -5.0 kcal/mol.
- the complex with the lowest energy was selected and analyzed by LigPlot (FIG. 2A).
- AB1711 compound showed hydrophobic interaction with 10 amino acid residues (R357, H358, R360, I361, G364, K366, R375, F377, R379), and hydrogen-bond (H) with two amino acid residues (S378, H382). -bond) was formed.
- the hydroxyl group of S378 formed 1-position oxygen of the flavonol moiety, and the nitrogen of the imidazole group of H382 formed 6-position oxygen and H-bond).
- a three-dimensional image (3D image) of the binding complex between EGR-1 and AB1711 compound was obtained using the PyMOL program, and the result of binding of the AB1711 compound to ZnF2 and ZnF3 of EGR-1 was confirmed (FIG. 2B).
- EMSA Electrophoretic Mobility
- EGR-1 protein used in the EMSA experiment a cell extract in which human EGR-1 protein was overexpressed in Sf21 insect cells was used.
- the flashBAC Baculovirus expression system (Mirus Bio, Madison, WI, USA) was purchased and used.
- IPLB-Sf21 insect cells purchased from Clontech Company (Mountain View, CA, USA) were cultured in Grace Insect Medium (Gibco Company, Grand Island, NY, USA) with 10% fetal bovine serum (Hyclone Company, Logan, UT, USA). ) was incubated.
- the coding DNA sequence of EGR-1 in the EGR-1 expression plasmid (pcDNA3.1zeo/EGR1) was cut and isolated with Hind III and Bgl II restriction enzymes, and then transferred to the pOET1 transfer plasmid (Mirus Bio company; Madison, WI, USA). inserted to construct a pOET1/EGR1 plasmid.
- 100 ng of transfer vector (pOET/EGR1), 100 ng viral DNA (flashBACTM, Mirus Bio) and 1.2 ⁇ l of TransIT®-Insect Transfection Reagent (Mirus Bio) was added. After culturing the cell culture plate at 28° C. for 5 days, it was harvested, and finally an Sf21 cell extract in which EGR-1 was mass-produced was obtained, and used for the following EMSA experiment.
- EGR-1 binding biotin-nucleotide probe (5'-biotin-AGA GTG TGT CTC CTT CGC ACA CAT C-3'; hereinafter referred to as 'EGR-1 binding probe') is available from Macrogen (Macrogen, Seoul, Korea). It was synthesized and used.
- EGR-1::DNA complex was measured using the ImageJ program (National Institutes of Health, Bethesda, MD, USA).
- the AB1711 compound of the present invention inhibited the binding ability of EGR-1 and the EGR-1 binding probe in a concentration-dependent manner ( FIG. 3A ).
- the amount of EGR-1 and DNA-binding complex was quantitatively measured using the ImageJ program.
- the complex formation of EGR-1 and EGR-1 binding probe was reduced by about 51.2% compared to the control group, and when 3 ⁇ L was added, the complex formation decreased by about 96.5% compared to the control group became (Fig. 3B). Therefore, it was confirmed that the AB1711 compound of the present invention binds to EGR-1 and blocks the binding of EGR-1 to the target DNA.
- HaCaT cells a human dermal keratinocyte line for use in the experiment, were purchased from Cell Lines Service GmbH (Eppelheim, Germany) and cultured in DMEM containing 10% fetal bovine serum (Gibco BRL, USA) and antibiotics (Gibco BRL, USA). was used to incubate.
- the culture vessel used 75T-flask and 6-well plate, and cultured in a 37°C incubator supplied with 5% CO2. The culture medium was changed every 3 to 4 days, and when the cells were excessively proliferated, subculture was performed.
- HaCaT cells of an appropriate passage number were transferred to a 6-well plate, and when they proliferated more than 90% of the culture vessel area, 50 ⁇ M and 100 ⁇ M concentrations of AB1711 were treated. After 30 minutes, TNF ⁇ at a concentration of 5 ng/ml was treated, and cells were harvested after culturing for an additional hour. The amount of EGR-1 expression was analyzed by performing an immunoblot method (FIG. 4A). As a result of quantitative measurement using the ImageJ program, as shown in FIG. 4B, AB1711 slightly increased the expression of EGR-1 increased by TNF ⁇ to a statistically insignificant degree.
- AB1711 has no effect on the cellular neurotransmitter system that non-specifically affects EGR-1 expression, and specifically only the DNA binding ability of EGR-1. It was confirmed that it was selectively blocked.
- TNF ⁇ secreted from various stromal cells and inflammatory cells in the skin inflammatory environment stimulates keratinocytes to secrete inflammatory cytokines and chemokines such as TSLP, IL-1 ⁇ , IL-6, CXCL1, CCL2, and CCL5 to activate Th2 lymphocytes.
- cytokines and chemokines such as TSLP, IL-1 ⁇ , IL-6, CXCL1, CCL2, and CCL5 to activate Th2 lymphocytes.
- Atopic dermatitis worsens by attracting various inflammatory immune cells to the inflamed area.
- RT-PCR reverse transcription-polymerase chain reaction
- HaCaT/shCT Scrambled shRNA-injected HaCaT control cells
- HaCaT/shEgr1 cells were used (J Biol Chem 2011; 286:26860-26872).
- RT-PCR Reverse Transcription-Polymerase Chain Reaction
- RNA extraction for measuring the amount of gene mRNA was extracted using TRIzol RNA Isolation Reagents purchased from TRIzol Life Technologies Korea.
- complementary DNA cDNA
- cDNA complementary DNA
- PCR was performed with 0.0125 ⁇ g of double-stranded cDNA.
- Primer bases for gene amplification were synthesized by Macrogen (Seoul, Korea), and the primer sequences are shown in Table 1 below.
- GPDH glyceraldehyde-3-phosphate dehydrogenase
- the final PCR product was confirmed by electrophoresis on a 1% agarose gel and staining with EtBr (ethidium bromide).
- EtBr ethidium bromide
- the amount of GAPDH was normalized, the control was set to “1”, and the relative change was converted.
- GAPDH and gene PCR bands were quantified using ImageJ program.
- EGR-1 expression was increased when HaCaT/shCT control cells were treated with TNF ⁇ , but it was confirmed that EGR-1 expression by TNF ⁇ was significantly reduced in HaCaT/shEgr1 cells expressing shEgr1 compared to control cells ( 5A). As a result, it was confirmed that EGR-1 expression was knocked down in HaCaT/shEgr1 cells.
- EGR-1 plays an important role in Th2 lymphocyte activity and influx of inflammatory cells in an inflammatory environment.
- the AB1711 compound of the present invention targets EGR-1 and suppresses the expression of inflammatory cytokines and chemokines causing atopic dermatitis regulated by EGR-1 was analyzed.
- the AB1711 compound of the present invention is In order to confirm whether the expression of atopic dermatitis-induced cytokines and chemokines produced by TNF ⁇ is inhibited, the reverse transcription-polymerase chain reaction (RT-PCR) described in [Example 5] is used. and analyzed.
- RT-PCR reverse transcription-polymerase chain reaction
- HaCaT/shEgr1 cells in which the keratinocytes, HaCaT/shCT and EGR-1 expression were knocked down were pre-treated with AB1711 at concentrations of 50 ⁇ M and 100 ⁇ M, and then treated with TNF ⁇ after 30 minutes. It was confirmed that the expression of inflammatory cytokines and chemokines, which are EGR-1 targets, produced by TNF ⁇ stimulation, is reduced by AB1711 of the present invention ( FIG. 6A ).
- the AB1711 compound of the present invention could effectively block the expression of various cytokines and chemokine genes involved in the occurrence and worsening of atopic dermatitis by targeting EGR-1 of keratinocytes.
- Beta-endorphin similar to morphine, when secreted in the brain, is well known as a happy hormone that relieves mental stress, prevents human aging, destroys cancer cells, and strengthens memory.
- beta-endorphin produced in keratinocytes of the skin acts as a neurotransmitter that stimulates skin sensory nerves and makes itching feel independent of histamine (J Inv Dermatol 2007;127:2228-2235).
- Interleukin-31 is known to increase the gene expression of POMC, a precursor of beta-endorphin (Br J Dermatol 2012; 167:794-803).
- the POMC gene expression inhibition effect was analyzed.
- RT-PCR was performed as described in ⁇ 5.1.2> above.
- the POMC primer sequences are shown in Table 2 below.
- GAPDH an anti-susceptibility gene
- AB1711 compound of the present invention targeting EGR-1 had the effect of inhibiting POMC mRNA expression by interleukin-31 was analyzed using RT-PCR.
- HaCaT cells were pre-treated with AB1711 at concentrations of 50 ⁇ M and 100 ⁇ M, stimulated with interleukin-31 1 hour later, harvested 24 hours after treatment, and analyzed for changes in POMC mRNA expression using RT-PCR.
- AB1711 reduced POMC mRNA expression increased by interleukin-31 in a concentration-dependent manner in a statistically significant manner ( FIG. 7D ).
- the AB1711 compound of the present invention effectively blocks the expression of the POMC gene, which causes the itch of atopic dermatitis by targeting EGR-1 of keratinocytes.
- mice 7-week-old male BALB/c mice were purchased from Orient Bio (Orient Co., Seongnam, Korea) and acclimatized for 1 week in an animal laboratory where temperature 20 ⁇ 2°C, humidity 50 ⁇ 10%, and light-dark cycle were maintained for 12 hours.
- Orient Bio Orient Co., Seongnam, Korea
- acclimatized for 1 week in an animal laboratory where temperature 20 ⁇ 2°C, humidity 50 ⁇ 10%, and light-dark cycle were maintained for 12 hours.
- the experimental group applied 100 ⁇ L of 4% SDS and 0.5% DNCB in the same way as the control group, and after about 2-3 hours, an ointment containing 5% AB1711 was prepared in the same area to observe the symptom relief effect.
- the control group applied only the ointment (vehicle) without AB1711.
- Table 3> shows the ingredients used to prepare the experimental ointment.
- AB1711 has the effect of reducing the blood IgE concentration.
- a paraffin block was prepared. After the paraffin block was cut to a thickness of 5 ⁇ m, hematoxylin/eosin staining was performed. As a result, it was observed that the skin thickness was significantly increased in the tissues of the positive control group (DNCB) induced with atopic dermatitis compared to the negative control group, and in the tissues of the experimental group to which the ointment containing AB1711 (DNCB+AB1711) was applied. It was observed that the thickness of the skin tissue was significantly reduced compared to the positive control group (FIG. 9A).
- AB1711 of the present invention can alleviate skin inflammation symptoms by inhibiting the proliferation of skin keratinocytes.
- the number of infiltrating mast cells in the TB-stained tissue of [FIG. 10A] was measured.
- the number of infiltrated mast cells in the untreated negative control (Naive Control) tissue was 23 ⁇ 6 per 2.5 cm 2 and 113 ⁇ 8 in the atopic dermatitis-induced positive control (DNCB) tissue.
- DNCB+AB1711 atopic dermatitis-induced positive control
- the application of the AB1711 of the present invention can alleviate the symptoms of skin inflammation by reducing the number of mast cells infiltrating into the skin inflammation site.
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Abstract
La présente invention concerne une composition pour prévenir, traiter et soulager la dermatite atopique, comprenant AB1711, qui est un composé conjugué de flavone-resvératrol, ou un sel de celui-ci, la composition pouvant prévenir, traiter et atténuer la dermatite atopique par inhibition de l'EGR-1, qui est un facteur de transcription impliqué dans l'expression de la POMC qui est un précurseur de diverses cytokines, chimiokines et bêta-endorphines qui provoquent la dermatite atopique.
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KR20060120101A (ko) * | 2003-10-10 | 2006-11-24 | 리스버로직스 코퍼레이션 | Egr-1 인핸서 요소와 관련된 질환의 치료 |
KR20120121684A (ko) * | 2011-04-27 | 2012-11-06 | 주식회사 에버미라클 | 퀘세틴 및 아스트라갈린을 함유하는 항가려움 조성물 |
KR101640165B1 (ko) * | 2014-10-08 | 2016-07-15 | 한국원자력의학원 | 3-하이드록시-3'',4''-디메톡시플라본을 포함하는 뇌종양 전이 억제용 조성물 |
KR102174194B1 (ko) * | 2020-02-14 | 2020-11-04 | 주식회사 아제라바이오텍 | 플라본-레스베라트롤 접합체 화합물을 포함하는 아토피 피부염 예방, 치료 및 개선용 조성물 |
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