WO2017175963A1 - 연골세포 세포외기질 유래 펩타이드 - Google Patents
연골세포 세포외기질 유래 펩타이드 Download PDFInfo
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- WO2017175963A1 WO2017175963A1 PCT/KR2017/001419 KR2017001419W WO2017175963A1 WO 2017175963 A1 WO2017175963 A1 WO 2017175963A1 KR 2017001419 W KR2017001419 W KR 2017001419W WO 2017175963 A1 WO2017175963 A1 WO 2017175963A1
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Images
Classifications
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/18—Peptides; Protein hydrolysates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to novel peptides and their use.
- Extracellular matrix is a component of tissues other than cells, consisting of three-dimensional combinations of various structural functional molecules secreted by cells, and artificial fabrication is impossible because its characteristics and functions are not fully understood. Do. The extracellular matrix plays an important role in maintaining the cellular environment while determining the physical properties of the tissue, ie stretching force, compressive strength and elasticity, and controlling osmotic pressure and ion permeation.
- the cell possesses a number of growth factors and cytokines to determine the function of the cell, especially in the fetus, growth phase, the direction of tissue growth while regulating the differentiation of cells, increase or decrease the cell adhesion, metabolic activity.
- Extracellular matrix is a protein such as collagen or elastin that determines the physical properties of tissues, and glycoproteins such as fibronectin and laminin attach cells and extracellular matrix. It acts like an adhesive, contains many proteoglycans such as chondroitin sulfate to maintain tissue shape and volume, and to actively interact with cells in tissues to maintain and perform tissue or organ specific functions. It serves as a support to maintain the volume so that, but the components and structure of the extracellular matrix has not yet been fully identified.
- proteoglycans such as chondroitin sulfate to maintain tissue shape and volume, and to actively interact with cells in tissues to maintain and perform tissue or organ specific functions. It serves as a support to maintain the volume so that, but the components and structure of the extracellular matrix has not yet been fully identified.
- the present invention is to provide a novel peptide that can prevent or treat ocular surface diseases by inhibiting or improving pathological changes caused by angiogenesis, clouding, fibrosis and inflammation of the cornea.
- the present invention provides a peptide having an amino acid sequence represented by SEQ ID NO: 1.
- the present invention provides a pharmaceutical composition for the prevention or treatment of ocular surface diseases containing a peptide having the amino acid sequence represented by SEQ ID NO: 1 as an active ingredient.
- the present invention provides a health food for preventing or improving ocular surface diseases containing a peptide having the amino acid sequence represented by SEQ ID NO: 1 as an active ingredient.
- the present invention provides a pharmaceutical composition for preventing or treating macular degeneration containing a peptide having the amino acid sequence represented by SEQ ID NO: 1 as an active ingredient.
- the present invention provides a health food for preventing or improving macular degeneration containing a peptide having the amino acid sequence represented by SEQ ID NO: 1 as an active ingredient.
- the present invention provides a pharmaceutical composition for preventing or treating dry eye, which contains an active ingredient of a peptide having an amino acid sequence represented by SEQ ID NO: 1.
- the present invention provides a health food for preventing or improving dry eye containing the active ingredient of the peptide having the amino acid sequence represented by SEQ ID NO: 1.
- the novel peptide of the present invention has the effect of reducing corneal haze, angiogenesis and fibrosis and inhibiting the expression of inflammation-inducing factors in animal models in which pathological changes of the ocular surface are induced by alkaline burns, and tissue changes induced retinal And effectively inhibiting angiogenesis in the choroid, preventing and improving macular degeneration, and inhibiting or improving pathological changes in corneal epithelial cells such as decreased eye tear, irregularities on corneal surface and loss of conjunctival goblet cells.
- the composition containing the same as an active ingredient may be provided as a pharmaceutical composition and health food for preventing or treating eye diseases.
- Figure 2 shows the results of analyzing the purity of hydroxy proline-GQDGLAGPK peptide using HPLC.
- Figure 3 is the result of confirming the molecular weight of hydroxy proline-GQDGLAGPK peptide through Ion-Mass.
- FIG. 4 is a result of confirming the effect of Hyp-GQDGLAGPK in alkaline burn rabbit cornea
- Figure 4B is a graph showing the degree of corneal angiogenesis
- Figure 4C is a graph showing the degree of corneal turbidity
- t -P ⁇ 0.05 vs alkali burn group value was considered significant through the test.
- 5B is a graph showing corneal thickness.
- FIG. 8 shows the effect of Hyp-GQDGLAGPK on inflammatory markers in alkaline burn rabbits.
- Figure 9 shows the results confirming the angiogenesis inhibitory effect in HUVEC cells treated with collagen, GDRGD (CPI) and hydroxy proline-GQDGLAGPK (CPII).
- Figure 13 shows the animal model after laser irradiation, 5 ⁇ g concentration of Avastin or hydroxy proline-GQDGLAGPK (CPII), respectively, and 14 days after laser irradiation RNA extracted from the retina and choroid VEGF, ICAM and MCP-1 gene Real-time RT-PCR results confirming expression levels.
- CPII hydroxy proline-GQDGLAGPK
- FIG. 15 shows NOD.B10.H2b mice in which NOD.B10.H2b mice were treated with physiological saline, Hyp-GQDGLAGPK, collagen, CsA, DQS, and HA. After 3, 5, 7 and 10 days physiological saline, Hyp-GQDGLAGPK, collagen, CsA, DQS and HA were administered to the eye, the tear amount of the mice was measured, and the mean ⁇ standard deviation showed quantitative results.
- & P ⁇ 0.05 vs. CsA treatment group * P ⁇ 0.05 vs. DS 10D group.
- FIG. 16 shows the effects of the Hyp-GQDGLAGPK peptide on corneal surface flexibility.
- Figure 2B shows the cornea of mice treated with saline, Hyp-GQDGLAGPK, collagen, CsA, DQS and HA As a result of confirming the change of the surface smoothness score, the quantitative result was shown as the mean ⁇ standard deviation. * P ⁇ 0.05 vs.
- FIG. 17 shows the effect of Hyp-GQDGLAGPK peptide on corneal epithelial detachment.
- Figure 3B is a quantitative result showing the mean ⁇ standard deviation of corneal epithelial cell detachment ( * P ⁇ 0.05 vs. DS) 10D group).
- FIG. 18 shows the effect of Hyp-GQDGLAGPK peptide on the distribution of conjunctival goblet cells.
- Scale bar 200 ⁇ m
- Figure 4B is a quantitative result showing the mean ⁇ standard deviation of conjunctival goblet cell distribution ( * P ⁇ 0.05 vs. DS 10D group).
- FIG. 19 shows immunohistochemical analysis of TNF- ⁇ , ICAM-1, VCAM-1, MMP-2 and MMP-9 expression levels in lacrimal glands of NOD.B10.H2b mice.
- the present invention provides a peptide having an amino acid sequence represented by SEQ ID NO: 1.
- the peptide may be hydroxy proline (Hyd), and more preferably, hydroxy proline-GQDGLAGPK (Hydroxy proline-GQDGLAGPK).
- the peptide may be derived from collagen type II ⁇ 1, and the collagen type II ⁇ 1 may be isolated from animal chondrocyte-derived extracellular matrix.
- the chondrocyte-derived extracellular matrix may be isolated from the chondrocyte-derived extracellular matrix formed by secretion from animal cartilage tissue and / or cartilage-derived chondrocytes, and the animal may be a pig, a horse, a cow, a sheep, a goat, or a monkey. It may be selected from the group consisting of, but is not limited thereto.
- peptide of the present invention is generally a compound in which two or more ⁇ -amino acids are linked by peptide bonds, and are referred to as dipeptides, tripeptides, tetrapeptides, etc., depending on the number of constituent amino acids. Oligopeptides, which have a number of peptide bonds, are called polypeptides.
- peptides of the present invention are prepared using chemical methods (Peptide Chemistry, A practical Textbook. Mikos Bodansky, Springer-Verlag, Berlin.). For example, peptides are synthesized by solid phase technology (Roberge JY et al (1995) Science 269: 202-204), cleaved in resin and subjected to high performance liquid chromatography (e.g. Creighton (1983) Protein Structures And Molecular Principles, WH Freeman and Co, New York NY).
- the present invention also provides a pharmaceutical composition for the prevention or treatment of ocular surface diseases containing a peptide having the amino acid sequence represented by SEQ ID NO: 1 as an active ingredient.
- the ocular surface disease may be any one selected from the group consisting of corneal haze, corneal neovascularization, corneal inflammation and corneal fibrosis.
- corneal haze appeared immediately after alkali burn, as shown in FIG. 4A, and corneal angiogenesis and cloudiness increased after 7 days of alkali burn, but corneal blood vessels were increased.
- the corneal haze score of the control group was significantly increased to 3.0 ⁇ 0.0 as shown in FIGS. 4B and 4C.
- Figure 4B it was confirmed that the decrease in turbidity in the experimental group treated with the peptide.
- Masson's trichrome staining was performed to determine the effect of Hyp-GQDGLAGPK peptide on the fibrosis of the cornea induced by alkali burns. It was confirmed that brown fibroblast formation was increased in the stromal portion by burns, but the increase in fibroblasts was suppressed in the experimental group treated with the Hyp-GQDGLAGPK peptide.
- the epithelial proliferation, inflammatory cell invasion, interstitial edema and neovascularization were induced by the alkaline burn. It was confirmed.
- corneal sections such as macrophages, TNF ⁇ , ICAM-1, IL-1 ⁇ , IL-6 and MMP-9
- inflammatory markers corneal sections such as macrophages, TNF ⁇ , ICAM-1, IL-1 ⁇ , IL-6 and MMP-9
- alkaline burns increased macrophage expression in epithelium, subepithelial and proliferative substrate, whereas macrophage expression was not observed in the experimental group treated with Hyp-GQDGLAGPK peptide. It was confirmed that it was effectively suppressed.
- Hyp-GQDGLAGPK peptide is effective in preventing or treating ocular surface diseases such as corneal haze, corneal neovascularization, corneal inflammation and corneal fibrosis.
- the peptide having the amino acid sequence represented by SEQ ID NO: 1 may be derived from collagen type II ⁇ 1 isolated from a chondrocyte-derived extracellular matrix (CDEM).
- the chondrocyte-derived extracellular matrix may be isolated from the chondrocyte-derived extracellular matrix formed by secretion from the chondrocyte and / or chondrocyte-derived chondrocytes of the animal, wherein the animal is a pig, a horse, a cow, It may be selected from the group consisting of sheep, goats and monkeys, but is not limited thereto.
- the peptide having the amino acid sequence represented by SEQ ID NO: 1 may be a peptide whose first amino acid is hydroxy proline, and more preferably, hydroxy proline-GQDGLAGPK (Hydroxy proline (Hyp) -GQDGLAGPK). have.
- the peptide having the amino acid sequence represented by SEQ ID NO: 1 may be contained in 0.1 to 50 parts by weight based on 100 parts by weight of the total pharmaceutical composition.
- the pharmaceutical composition may be any one formulation selected from the group consisting of eye drops, injections, granules, tablets, pills, capsules, gels, syrups, suspensions, emulsions, drops and solutions.
- the present invention can provide a health food for preventing or improving ocular surface diseases containing a peptide having the amino acid sequence represented by SEQ ID NO: 1 as an active ingredient.
- the present invention can provide a pharmaceutical composition for preventing or treating macular degeneration containing a peptide having the amino acid sequence represented by SEQ ID NO: 1 as an active ingredient.
- the peptide may be derived from collagen type II ⁇ 1.
- the peptide having the amino acid sequence represented by SEQ ID NO: 1 may be a peptide in which the first amino acid is hydroxy proline, and more preferably, hydroxy proline-GQDGLAGPK (Hydroxy proline-GQDGLAGPK).
- the peptide may prevent or treat macular degeneration by inhibiting neovascularization of the eye, and the macular degeneration may be senile macular degeneration, but is not limited thereto.
- the mouse was irradiated with laser damage to the eyeball, and after 14 days, the eye was extracted and H & E staining was performed.
- choroidal neovascular inhibitory effect of hydroxyproline-GQDGLAGPK (CPII), which showed the best anti-angiogenic activity in the in vitro tube formation experiment, was compared with Avastin, a positive control group, as shown in FIG. 11.
- the lesion size was significantly reduced than that of the control group, and the same concentration of Avastin was found to be similar to the lesion size of the treated positive control group.
- the hydroxy proline-GQDGLAGPK peptide from the above results can exhibit an excellent therapeutic effect on senile macular degeneration caused by angiogenesis.
- the peptide having the amino acid sequence represented by SEQ ID NO: 1 may be contained in 0.1 to 50 parts by weight based on 100 parts by weight of the total pharmaceutical composition.
- the pharmaceutical composition may be any one formulation selected from the group consisting of eye drops, injections, granules, tablets, pills, capsules, gels, syrups, suspensions, emulsions, drops and solutions.
- the present invention can provide a health food for preventing or improving macular degeneration containing a peptide having the amino acid sequence represented by SEQ ID NO: 1 as an active ingredient.
- the present invention also provides a pharmaceutical composition for the prevention or treatment of dry eye containing the peptide having the amino acid sequence represented by SEQ ID NO: 1 as an active ingredient.
- the peptide having the amino acid sequence represented by SEQ ID NO: 1 may be derived from collagen type II ⁇ 1 (collagen type II ⁇ 1).
- the peptide may be a peptide isolated from chondrocyte-derived extracellular matrix (CDEM), and the chondrocyte-derived extracellular matrix may be derived from chondrocytes and / or cartilage-derived chondrocytes of animals. It may be isolated from the chondrocyte-derived extracellular matrix formed by secretion, the animal may be selected from the group consisting of pigs, horses, cattle, sheep, goats and monkeys, but is not limited thereto.
- CDEM chondrocyte-derived extracellular matrix
- the animal may be selected from the group consisting of pigs, horses, cattle, sheep, goats and monkeys, but is not limited thereto.
- the peptide may be a peptide in which the first amino acid is hydroxy proline, and more preferably hydroxy proline-GQDGLAGPK [Hydroxy proline (Hyp) -GQDGLAGPK].
- the peptides may reduce tear formation and dry corneal surface imbalance due to dry stress, and inhibit peeling of corneal epithelial cells and generation of inflammatory factors.
- the amount of tears in the mice exposed to the dry stress was reduced by about 85.5% compared to the normal group (0.22 ⁇ 0.01 ⁇ L) (DS 10D group, 0.03 ⁇ 0.01 ⁇ L, p ⁇ 0.05).
- the tear volume increased by 7.9 times (p ⁇ 0.05) at 10 days after treatment, and the saline treated group (0.08 ⁇ 0.01 ⁇ L) was negative control. It was confirmed that the tear amount was increased by about 1.7 times (p ⁇ 0.05) than that of the collagen treated group (0.13 ⁇ 0.02 ⁇ L), which was about 2.8 times (p ⁇ 0.05).
- the tear amount of the Hyp-GQDGLAGPK treatment group was 1.7 times (p ⁇ 0.05), 1.4, respectively. As folds (p ⁇ 0.05) and 1.6 folds (p ⁇ 0.05) were increased, the effect of Hyp-GQDGLAGPK on tear improvement was found to be more effective than currently available dry eye treatments.
- the peptide may be contained in an amount of 0.1 to 50 parts by weight based on 100 parts by weight of the pharmaceutical composition.
- the pharmaceutical composition may be any one formulation selected from the group consisting of eye drops, injections, granules, tablets, pills, capsules, gels, syrups, suspensions, emulsions, drops and solutions.
- the present invention can provide a health food for preventing or improving dry eye containing the peptide having the amino acid sequence represented by SEQ ID NO: 1 as an active ingredient.
- the pharmaceutical composition for preventing or treating ocular surface diseases comprising the peptide as an active ingredient is suitable carriers, excipients, disintegrants, sweeteners, coatings, expanding agents, commonly used in the manufacture of pharmaceutical compositions, It may further comprise one or more additives selected from the group consisting of lubricants, lubricants, flavors, antioxidants, buffers, bacteriostatics, diluents, dispersants, surfactants, binders and lubricants.
- the carriers, excipients and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil can be used, and solid preparations for oral administration include tablets, pills, powders, granules, capsules.
- solid preparations may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin and the like in the composition.
- excipients such as starch, calcium carbonate, sucrose or lactose, gelatin and the like
- lubricants such as magnesium styrate and talc may also be used.
- Oral liquid preparations include suspensions, solvents, emulsions, syrups, and the like, and may include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin.
- Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.
- non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
- Witsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like may be used as the base material of the suppository.
- the pharmaceutical composition is intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, nasal, inhaled, topical, rectal, oral, intraocular or intradermal Via the route can be administered to the subject in a conventional manner.
- Preferred dosages of the peptides may vary depending on the condition and weight of the subject, the type and extent of the disease, the form of the drug, the route of administration and the duration and may be appropriately selected by those skilled in the art.
- the daily dosage may be 0.01 to 200 mg / kg, specifically 0.1 to 200 mg / kg, more specifically 0.1 to 100 mg / kg.
- Administration may be administered once a day or divided into several times, thereby not limiting the scope of the invention.
- the 'subject' may be a mammal including a human, but is not limited thereto.
- the health food is used in conjunction with other food or food additives in addition to the peptide of the present invention, can be suitably used according to a conventional method.
- the mixed amount of the active ingredient can be suitably determined depending on the purpose of use thereof, for example, prophylactic, health or therapeutic treatment.
- the effective dose of the compound contained in the health food may be used in accordance with the effective dose of the therapeutic agent, but may be less than the above range in the case of long-term intake for health and hygiene purposes or health control purposes It is evident that the component can be used in an amount above the range because there is no problem in terms of safety.
- New Zealand white rabbits weighing 2.0 to 2.5 kg were purchased from Samtako (Osan, Korea), ketamine hydrochloride (30 mg / kg body weight, Huons, Jecheon, Korea) and xylazine hydrochloride (2.5 mg / kg, Bayer) Korea Ltd., Seoul, Korea), the mixture was injected into the muscle and general anesthesia, and local anesthesia using alkaline propracaine eye drops (Alcon Inc., Seoul, Korea).
- Alkaline burn group was administered with saline 4 times daily
- peptide treated group was administered with 10 mg / mL Hyp-GQDGLAGPK peptide 4 times daily
- the left eye was used as a control.
- H & E staining After treatment with each treatment material for 10 days in the above method, H & E staining, Masson's trichrome staining and immunohistochemical staining (immunohistochemistry) were performed to confirm the changes in fibrosis, angiogenesis, inflammation and corneal structure.
- Corneal neovascularization was evaluated from 0 to 3 points. If angiogenesis does not occur, it is assessed as 0 points, 1 point for angiogenesis around the cornea, 2 points for angiogenesis to the edge of the pupil, and 3 points for angiogenesis beyond the edge of the pupil. In the case of corneal angiogenesis evaluation, it was evaluated as 3 points if it was difficult to evaluate the degree of corneal angiogenesis due to the formation of significant haze and extensive gum adhesion.
- corneal haze was evaluated from 0 to 3 points. 0 point for transparent cornea with clear iris, 1 point for partial turbidity in iris area, 2 points for rim of eye and weak part of iris, and 3 points for opacity of iris and eye part completely turbid Evaluated.
- OCT optimal cutting temperature compound
- Tissue sections were cut to 6 ⁇ m thickness and used for immunohistochemical analysis.
- tissue sections were fixed with 3.5% paraformaldehyde, permeated 0.1% Triton X-100, inactivated 2% bovine serum albumin (BSA; all from Sigma, St. Louis, MO), and anti-CD31 ( 1: 1,000; Abcam Inc., Cambridge, MA), anti-bFGF (1: 1,000; Bioss Inc., Woburn, MA), anti-IL-1 ⁇ , anti-IL-6 (1: 1,000; Cloud-Clone Corp , Houston, TX), anti-MMP-9, anti-ICMA-1, anti-TNF ⁇ , anti-macrophage / monocytes (1: 1,000; Abnova Crop., Taipei, Taiwan) and anti-VEGF-A (Abbiotec , San Diego, CA) incubated overnight at 4 ° C with primary antibody.
- BSA bovine serum albumin
- DAB diaminobenzidine
- Sections stained in this manner were photographed with a virtual microscope (NanoZoomer 2.0 RS, Hamamatsu, Japan).
- hydroxyproline-GQDGLAGPK was confirmed by a tubing assay using human vascular endothelial cells (HUVEC).
- HUVEC cells Staining HUVEC cells with calcein-AM and dispensing them in 48-well plates coated with Matrigel, concentration-treated collagen, CPI and CPII with 50 ng / ml recombinant human VEGF and in a 37 ° C. incubator After 4 hours, tube formation was observed with a fluorescence microscope (Leica), and the tube length was analyzed by Image lab software (Bio-Rad Laboratories).
- C57BL / 6 mice were purchased from Orient Bio, and the animal experiments were performed according to the guidelines approved by Inje University College of Medicine (No, 2013-053) and ARVO for animal use for eye and vision studies.
- Six-week-old C57BL / 6 mice were injured in the retinal optic nerve area using a diode green laser (532 nm, 150 mW, 0.1 sec, 50 ⁇ M, photocoagulator).
- CP1, CPII, and positive control Avastin were dissolved in PBS and administered intraocularly for 5 days at 5 mg per day.
- Each experimental group performed the experiment using both eyes of 5 mice each.
- tissue samples treated in this way were stained with hematoxylin & eosin (H & E) and photographed and analyzed using a virtual microscope (NanoZoomer 2.0 RS, Hamamatsu, Japan).
- mice were anesthetized and injected 100 ml retro-orbital with 25 mg / ml FITC-dextran. After 30 minutes, the mice were euthanized and the eyes were extracted, fixed with 10% formalin, and the cornea and lens were removed and mounted flat on the cover glass. New blood vessels stained with FITC-dextran were observed by fluorescence microscopy (Leica), and the lesion size was measured by Image J program.
- RNA was extracted from the retinal and choroid mixtures of extracted mouse eye using RNeasy Mini kit (Qiagen), oligo (dT) primer and reverse transcriptase. CDNA was synthesized using. PCR products were amplified using the specific primer set of Table 1 (Cosmojintech, Korea) and SYBR Green PCR 2X PreMix (Enzynomics). 40 PCR cycles were performed for 15 seconds at 95 ° C, 30 seconds at 60 ° C, and 15 seconds at 72 ° C. Relative quantification was performed using the 2- (DDCT) method [Livak and Schmittgen, 2001; DDCT (CT, target-CT, actin) treatment (CT, target-CT, actin) control].
- Target Primer sequence (5 ' ⁇ 3') Forward direction Reverse VEGF ATGAACTTTCTGCTGTCTTGGGTG TCACCGCCTCGGCTTGTCACA ICAM TGCGTTTTGGAGCTAGCGGACCA CGAGGACCATACAGCACGTGCCAG MCP-1 TGGCAAGATGATCCCAATGA GCAGCACTGTTCGTCACTTCA GAPDH ATGGTGAAGGTCGGTGTGAAC GTGCCGTTGAATTTGCCGTGA
- mice The retina and choroid mixtures of mice were dissolved in Pro-PREP buffer (iNtRON) containing a protease inhibitory cocktail and a phosphatase inhibitory cocktail, and the proteins were extracted.
- Pro-PREP buffer iNtRON
- the extracted protein was quantified using a BCA assay kit (Pierce), mixed with SDS gel loading buffer and boiled at 100 ° C. for 5 minutes for denaturation. Proteins electrophoresed on SDS-PAGE gels were transferred to nitro cellulose membranes (Millipore), after which the membranes were left for 1 hour in 5% skim milk to block nonspecific protein binding, followed by VEGF, Flk-1, Flt- 1, Angiopoetin-2 and ⁇ -actin (Santa Cruz Biotechnology) were treated to perform a general immunoblot. Subsequently, the transreactive protein was detected by ECL kit (Advansta) and multiple Gel DOC system.
- NOD.B10.H2 b mice were purchased from Jackson Laboratory (Bar Harbor, ME, USA). Animal experiments were performed according to the guidelines approved by Inje University School of Medicine (No .; 2014-029) and ARVO for the use of animals for eye and vision studies. 12-16 week old NOD.B10.H2 b mice were exposed to 40-50% ambient humidity and fan ventilation for 18 hours a day under dry stress and injected subcutaneously with 0.5 mg / 0.2 mL muscarinic receptor blocker. In addition, scopolamine hydrobromide (Sigma-Aldrich, St. Louis, MO) was injected alternately into the hips of mice four times a day at 9 am, 12 pm, 3 pm and 6 pm for 10 days. . Mice treated with this method were euthanized after 10 days and did not limit animal behavior and food and water intake during the experiment.
- Tear formation was reported using phenol red-impregnated cotton threads; Zone-Quick; Oasis, Glendora, Calif. (Villareal AL, Farley W, Pflugfelder SC. Effect of topical ophthalmic epinastine and olopatadine on tear volume in mice.Eye Contact Lens. 2006; 32 (6): 272-276.).
- the tear amount was expressed in millimeters by using a medical tweezers for 20 seconds, the thread was placed in the lateral angle and the thread which turned wet and turned red was observed by a microscope (SZX7; Olympus corp, Tokyo, Japan).
- the measured intramillimeter tears were compared to a standard curve represented by cotton thread moistened with a basic solution (1500 mL of 0.9% saline and 5 mL of 5 N NaOH) of anticipated volume of mice for 20 seconds.
- the flexibility of the corneal surface was obtained by reflecting the white ring from the optical fiber ring illumination of stereomicroscope (SZX7; Olympus) after anesthetizing the animal.
- Corneal smoothness was assessed by grading the irregularities of the corneal epithelial cells reflected in the white ring of the digital image.
- the corneal irregularity severity score was calculated by dividing the reflective ring into quadrants and ranking them according to the degree of irregularity. No irregularity is grade 0, quarter equality is grade 1; Irregularities of two quarters; Three quarters of irregularities of grade 3; All four degree of irregularity; All rings were checked with a severity of 5 ratings.
- Protein analysis of extracellular matrix derived from animal chondrocytes was performed in Baek's group of Center of Biomedical Mass Sepctrometry (Diatech Korea Co., Ltd., Seoul, Korea).
- hydroxyproline-GQDGLAGPK (Hydroxy proline-GQDGLAGPK; Hyp-GQDGLAGPK; SEQ ID NO: 1) corresponding to a part of the amino acid sequence of collagen type II ⁇ 1 protein was obtained. ) was synthesized in BIOCELTRAN (Chuncheon, Korea).
- corneal alkali burn Seven days after corneal alkali burn, a clinical evaluation of corneal angiogenesis and clouding was performed.
- corneal haze appeared immediately after alkaline burn, and corneal angiogenesis and haze increased after 7 days of alkali burn.
- Hyp-GQDGLAGPK peptide was effective in inhibiting corneal clouding.
- the corneal thickness increased from 526.6 ⁇ m in the normal range to 960.6 ⁇ m after the alkali burn as shown in FIG. 5B.
- the experimental group treated with the peptide showed that the corneal thickness was reduced to 550.0 ⁇ m (p ⁇ 0.05) compared with the alkaline burn group.
- Masson's trichrome staining was performed to determine the effect of Hyp-GQDGLAGPK peptide on the fibrosis of cornea induced by alkali burns.
- Hyp-GQDGLAGPK peptide was effective in inhibiting corneal fibrosis by inhibiting the increase of fibroblasts.
- H & E staining was performed to confirm the histological changes of the cornea following alkaline burns.
- Hyp-GQDGLAGPK peptide affects angiogenesis
- the alkaline burned cornea was treated with Hyp-GQDGLAGPK peptide, and CD31, FGF and VEGF, which are specific markers of corneal angiogenesis, were used. Corneal sections were immunostained.
- CD31, FGF and VEGF angiogenesis markers were confirmed to be strongly expressed in fibrotic stromal cells following alkaline burns.
- Hyp-GQDGLAGPK peptide was effective in inhibiting corneal angiogenesis.
- the alkaline burn increased the expression of macrophages in the epithelium, subepithelial and proliferative substrates, whereas macrophage expression was effectively suppressed in the experimental group treated with the Hyp-GQDGLAGPK peptide.
- expression of inflammatory cytokines and ICAM-1 adhesion molecules including TNF ⁇ , IL-1 ⁇ , and IL-6 was confirmed, but the expression of the inflammatory factors was reduced in the experimental group treated with peptides.
- the expression of MMP-9 was strongly expressed in the cornea of the alkaline burn group, whereas the expression of MMP-9 was suppressed in the experimental group treated with the peptide.
- Tubing assay using human vascular endothelial cells was performed to confirm the antiangiogenic effect of hydroxyproline-GQDGLAGPK.
- tube formation was increased by about 1.5 times or more than in the VEGF-untreated group, while in the experimental group treated with collagen, CPI, and CPII, all angiogenesis was significantly inhibited.
- CPII inhibited tube formation in a concentration-dependent manner, and decreased almost identical to the degree of angiogenesis in the VEGF-untreated group. It was also found to be similar to the Avastin-treated group for treating age-related macular degeneration.
- the mouse was irradiated with laser in the same manner as in Experimental Example 8, and after 14 days of laser irradiation, the eye was extracted and H & E staining was performed.
- CPII hydroxyproline-GQDGLAGPK
- the lesion size of the CPII treatment group was significantly reduced than the lesion size of the control group, as shown in FIG.
- VEGF which is a representative neovascular gene
- ICAM and MCP-1 genes were found to be about 300-fold and 10-fold increase in expression in the laser treatment group, respectively, but this was also found to be significantly reduced in the CPII treatment group.
- proteins were extracted from the retina and choroid to evaluate the effect of CPII on the expression of angiogenesis-related protein markers, and VEGF, VEGFR-1 (Flt-1), VEGR-2 (Flk-1). ) And immunoblotting of Angiopoietin 2 was performed.
- the degree of tear formation was measured by phenol red-impregnated cotton threads.
- the dry stress was found to be reduced to about 85.5% significant level compared to the normal group (0.22 ⁇ 0.01 ⁇ L) of the NOD.B10.H2 b mice (DS 10D group, 0.03 ⁇ 0.01 ⁇ L, p ⁇ 0.05).
- the hyp-GQDGLAGPK treated group (0.23 ⁇ 0.02 ⁇ L) increased the tear amount by 7.9 times (p ⁇ 0.05) after 10 days of dry stress, compared to the normal saline treated group (0.08 ⁇ 0.01 ⁇ L).
- About 2.8 times (p ⁇ 0.05), compared with the positive control collagen treatment group (0.13 ⁇ 0.02 ⁇ L) tear amount was increased about 1.7 times (p ⁇ 0.05) was confirmed.
- the amount of tears in the Hyp-GQDGLAGPK treatment group was 1.7 times, respectively. (p ⁇ 0.05), 1.4-fold (p ⁇ 0.05) and 1.6-fold (p ⁇ 0.05).
- Hyp-GQDGLAGPK restores the reduced tear amount to a higher level than the currently available dry eye treatment.
- the degree of curvature of the corneal surface of each experimental group was quantified to confirm the flexibility of the corneal surface.
- the degree of curvature of the corneal surface of the mice exposed to dry stress for 10 days was increased by about 13 times (4.33 ⁇ 0.58 points; p ⁇ 0.05) compared to the normal cornea (0.33 ⁇ 0.58 points).
- the curvature of corneal surface was significantly decreased by 53.8% ( p ⁇ 0.05) at 10 days after Hyp-GQDGLAGPK treatment group (2.0 ⁇ 0 points) after removal of dry stress, and the normal saline treatment group (3.33 ⁇ 1.53 points) was negative.
- 40% ( p ⁇ 0.05), and 45.5% ( p ⁇ 0.05) than the collagen treatment group (3.67 ⁇ 1.16 points) that was a positive control group was confirmed.
- Hyp-GQDGLAGPK is more effective in improving the corneal surface flexibility than the dry eye treatment.
- corneas of mice in each experimental group were H & E stained.
- epithelial cell detachment of the cornea increased by 24 times by dry stress (2.29 ⁇ 0.57 / 0.1 mm 2 , p ⁇ 0.05).
- corneal epithelial detachment was decreased by 83.3% ( p ⁇ 0.05) in the Hyp-GQDGLAGPK treated group (0.38 ⁇ 0.17 / 0.1 mm 2 ) after dry stress removal.
- 71.4% ( p ⁇ 0.05) corneal epithelial detachment was reduced compared to the normal control group (1.33 ⁇ 0.17 / 0.1mm 2 ), which was the negative control group, and the collagen treatment group (0.86 ⁇ 0.29 / 0.1mm 2 ) was a positive control group.
- 55.6% ( p ⁇ 0.05) corneal epithelial cell detachment was reduced.
- Hyp-GQDGLAGPK is more effective in reducing the detachment of corneal epithelial cells than the dry eye treatment.
- TNF- ⁇ , ICAM-1, VCAM-1, MMP-2 and MMP-9 was performed in lacrimal glands to evaluate the effect of Hyp-GQDGLAGPK on the expression of inflammatory response factors in dry eye mouse models.
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Abstract
Description
Target | 프라이머 서열( 5’→ 3’) | |
정방향 | 역방향 | |
VEGF | ATGAACTTTCTGCTGTCTTGGGTG | TCACCGCCTCGGCTTGTCACA |
ICAM | TGCGTTTTGGAGCTAGCGGACCA | CGAGGACCATACAGCACGTGCCAG |
MCP-1 | TGGCAAGATGATCCCAATGA | GCAGCACTGTTCGTCACTTCA |
GAPDH | ATGGTGAAGGTCGGTGTGAAC | GTGCCGTTGAATTTGCCGTGA |
Claims (22)
- 서열번호 1로 표시되는 아미노산 서열을 가지는 펩타이드.
- 청구항 1에 있어서, 상기 펩타이드는 첫 번째 아미노산이 히드록시 프롤린(Hydroxy proline; Hyd)인 것을 특징으로 하는 펩타이드.
- 청구항 1에 있어서, 상기 펩타이드는 콜라겐 타입 II α1 유래인 것을 특징으로 하는 펩타이드.
- 청구항 3에 있어서, 상기 콜라겐 타입 II α1은 동물연골세포 유래 세포외기질에서 분리된 것을 특징으로 하는 펩타이드.
- 서열번호 1로 표시되는 아미노산 서열을 가지는 펩타이드를 유효성분으로 함유하는 안구 표면질환 예방 또는 치료용 약학조성물.
- 청구항 5에 있어서, 상기 안구 표면질환은 각막 혼탁, 각막 혈관신생, 각막 염증 및 각막 섬유화로 이루어진 군에서 선택되는 어느 하나인 것을 특징으로 하는 안구 표면질환 예방 또는 치료용 약학조성물.
- 청구항 5에 있어서, 상기 펩타이드는 연골세포 유래 세포외 기질(chondrocyte-derived extracellular matrix; CDEM)에서 분리된 콜라겐 타입 Ⅱα1(collagen type Ⅱ α1) 유래인 것을 특징으로 하는 안구 표면질환 예방 또는 치료용 약학조성물.
- 청구항 5에 있어서, 상기 펩타이드는 약학조성물 총 100 중량부에 대하여 0.1 내지 50 중량부로 함유되는 것을 특징으로 하는 안구 표면질환 예방 또는 치료용 약학조성물.
- 청구항 5에 있어서, 상기 약학조성물은 점안제, 주사제, 과립제, 정제, 환제, 캡슐제, 겔, 시럽, 현탁제, 유제, 점적제 및 액제로 이루어진 군에서 선택된 어느 하나의 제형인 것을 특징으로 하는 안구 표면질환 예방 또는 치료용 약학조성물.
- 서열번호 1로 표시되는 아미노산 서열을 가지는 펩타이드를 유효성분으로 함유하는 안구 표면질환 예방 또는 개선용 건강식품.
- 서열번호 1로 표시되는 아미노산 서열을 가지는 펩타이드를 유효성분으로 함유하는 황반변성 예방 또는 치료용 약학조성물.
- 청구항 11에 있어서, 상기 펩타이드는 콜라겐 타입 Ⅱ α1(collagen type Ⅱα1) 유래인 것을 특징으로 하는 황반변성 예방 또는 치료용 약학조성물.
- 청구항 11에 있어서, 상기 펩타이드는 안구의 신생혈관형성을 억제하는 것을 특징으로 하는 황반변성 예방 또는 치료용 약학조성물.
- 청구항 11에 있어서, 상기 서열번호 1로 표시되는 아미노산 서열을 가지는 펩타이드는 약학조성물 총 100 중량부에 대하여 0.1 내지 50 중량부로 함유되는 것을 특징으로 하는 황반변성 예방 또는 치료용 약학조성물.
- 청구항 11에 있어서, 상기 약학조성물은 점안제, 주사제, 과립제, 정제, 환제, 캡슐제, 겔, 시럽, 현탁제, 유제, 점적제 및 액제로 이루어진 군에서 선택된 어느 하나의 제형인 것을 특징으로 하는 황반변성 예방 또는 치료용 약학조성물.
- 서열번호 1로 표시되는 아미노산 서열을 가지는 펩타이드를 유효성분으로 함유하는 황반변성 예방 또는 개선용 건강식품.
- 서열번호 1로 표시되는 아미노산 서열을 가지는 펩타이드를 유효성분으로 함유하는 건성안 예방 또는 치료용 약학조성물.
- 청구항 17에 있어서, 상기 펩타이드는 콜라겐 타입 Ⅱ α1(collagen type Ⅱα1) 유래인 것을 특징으로 하는 건성안 예방 또는 치료용 약학조성물.
- 청구항 17에 있어서, 상기 펩타이드는 건조 스트레스에 의한 눈물생성 감소 및 각막 표면 불균형을 회복시키고 각막 상피세포의 박리 및 염증성 인자 생성을 억제하는 것을 특징으로 하는 건성안 예방 또는 치료용 약학조성물.
- 청구항 17에 있어서, 상기 펩타이드는 약학조성물 총 100 중량부에 대하여 0.1 내지 50 중량부로 함유되는 것을 특징으로 하는 건성안 예방 또는 치료용 약학조성물.
- 청구항 17에 있어서, 상기 약학조성물은 점안제, 주사제, 과립제, 정제, 환제, 캡슐제, 겔, 시럽, 현탁제, 유제, 점적제 및 액제로 이루어진 군에서 선택된 어느 하나의 제형인 것을 특징으로 하는 건성안 예방 또는 치료용 약학조성물.
- 서열번호 1로 표시되는 아미노산 서열을 가지는 펩타이드를 유효성분으로 함유하는 건성안 예방 또는 개선용 건강식품.
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EP19151372.0A EP3539559B1 (en) | 2016-04-08 | 2017-02-09 | Collagen type ii alpha-1-based peptide for use in the treatment of macular degeneration |
CN201780035505.3A CN109310731B (zh) | 2016-04-08 | 2017-02-09 | 软骨细胞的细胞外基质来源的肽 |
ES17779264T ES2819030T3 (es) | 2016-04-08 | 2017-02-09 | Péptido basado en colágeno tipo II alfa-1 útil para el tratamiento de una enfermedad de la superficie ocular |
EP17779264.5A EP3441081B1 (en) | 2016-04-08 | 2017-02-09 | Collagen type ii alpha-1-based peptide useful for the treatment of an ocular surface disease |
US16/091,998 US10709768B2 (en) | 2016-04-08 | 2017-02-09 | Chondrocyte extracellular matrix-derived peptide |
JP2019503878A JP6770169B2 (ja) | 2016-04-08 | 2017-02-09 | 軟骨細胞の細胞外基質由来ペプチド |
AU2017247626A AU2017247626B2 (en) | 2016-04-08 | 2017-02-09 | Chondrocyte extracellular matrix-derived peptide |
CN201910099020.1A CN110025765B (zh) | 2016-04-08 | 2017-02-09 | 软骨细胞的细胞外基质来源的肽 |
US16/178,618 US10532084B2 (en) | 2016-04-08 | 2018-11-02 | Chondrocyte extracellular matrix-derived peptide |
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KR10-2016-0043305 | 2016-04-08 | ||
KR1020160043305A KR101810163B1 (ko) | 2016-04-08 | 2016-04-08 | 안구 표면질환 예방 또는 치료용 약학조성물 |
KR10-2016-0043298 | 2016-04-08 | ||
KR1020160043300A KR101810158B1 (ko) | 2016-04-08 | 2016-04-08 | 연골세포 세포외기질 유래 펩타이드 |
KR1020160043298A KR101794713B1 (ko) | 2016-04-08 | 2016-04-08 | 황반변성 예방 또는 치료용 약학조성물 |
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US16/178,618 Continuation US10532084B2 (en) | 2016-04-08 | 2018-11-02 | Chondrocyte extracellular matrix-derived peptide |
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EP3539559B1 (en) | 2020-08-26 |
JP6770169B2 (ja) | 2020-10-14 |
US10532084B2 (en) | 2020-01-14 |
US20190111112A1 (en) | 2019-04-18 |
EP3441081B1 (en) | 2020-07-15 |
CN110025765A (zh) | 2019-07-19 |
CN109310731A (zh) | 2019-02-05 |
AU2017247626B2 (en) | 2019-08-29 |
AU2019200063B2 (en) | 2019-10-31 |
ES2819030T3 (es) | 2021-04-14 |
CN109310731B (zh) | 2022-03-29 |
EP3539559A1 (en) | 2019-09-18 |
CN110025765B (zh) | 2022-03-29 |
ES2822289T3 (es) | 2021-04-30 |
AU2019200063A1 (en) | 2019-01-24 |
JP2019519597A (ja) | 2019-07-11 |
US20190100572A1 (en) | 2019-04-04 |
US10709768B2 (en) | 2020-07-14 |
AU2017247626A1 (en) | 2018-11-29 |
JP2019065013A (ja) | 2019-04-25 |
EP3441081A4 (en) | 2019-09-18 |
JP6640311B2 (ja) | 2020-02-05 |
EP3441081A1 (en) | 2019-02-13 |
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