KR20170024469A - A peptide having activity of Epidermal growth factor activity and production method therefor - Google Patents
A peptide having activity of Epidermal growth factor activity and production method therefor Download PDFInfo
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- KR20170024469A KR20170024469A KR1020150119794A KR20150119794A KR20170024469A KR 20170024469 A KR20170024469 A KR 20170024469A KR 1020150119794 A KR1020150119794 A KR 1020150119794A KR 20150119794 A KR20150119794 A KR 20150119794A KR 20170024469 A KR20170024469 A KR 20170024469A
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- peptide
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- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 230000037373 wrinkle formation Effects 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
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- 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
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07K14/475—Growth factors; Growth regulators
- C07K14/485—Epidermal growth factor [EGF], i.e. urogastrone
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- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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Abstract
The present invention relates to peptides showing the proliferative activity of keratinocytes and fibroblasts constituting the skin and their uses, including the amino acid sequence represented by the following general formula: X1-Leu-X2-Glu -X3-Glu-X4, wherein X 1 in : Met, Ile, Phe, His , Lys, Arg, Glu, or Ile, X 2: Lys, Arg , His, or Asn, X 3: Trp, Gly His, Tyr, or Arg, X 4 : Leu, Asp, Asn, or Phe. The skin cell proliferative peptide of the present invention has the same skin cell proliferative capacity as the native EGF and has a low molecular weight characteristic, and thus has excellent skin permeability. Therefore, the composition comprising the peptide of the present invention exhibits a very excellent effect for treating, preventing or ameliorating a disease or condition for which EGF activity is required, and can be applied to medicines, quasi-drugs and cosmetics.
Description
The present invention relates to a peptide having an epithelial growth factor activity and, more particularly, to a peptide having an epithelial cell growth factor activity and a use thereof. More particularly, the present invention relates to a peptide having a low molecular weight structure and high skin permeability, Peptides and cosmetic compositions having enhanced skin regeneration ability including the same.
EGF has a molecular weight of 6,045 daltons (Cohen, S., J. Bio. Chem. 237: 1555-1562, 1962; Savage, CR, J Biotechnol. Chem. 247: 7612-7621, 1972) and was first discovered and characterized by S. Cohen in the United States in 1953. Major functions include binding to the EGF receptor and promoting proliferation of epithelial cells and dermal cells in response to various cells including epithelial cells and mesenchymal cells, and promoting the proliferation of fibroblasts that synthesize collagen as a component of the dermis. Because of this effect, EGF is most widely used in the skin care field among various application fields.
As the age increases, the concentration of growth factors including EGF decreases in each tissue such as skin, aging progresses such as weakening of cell regeneration and division function, wrinkle formation and decrease of elasticity. The skin, which is usually over 25 years of age, will have wrinkles as the growth factor decreases and the metabolism or cell regeneration becomes slower. The skin regeneration cycle of healthy young people is about 4 weeks, but the skin after 25 years of age is delayed by 6 weeks, the skin cell regeneration ability is lowered and the stratum corneum is thickened and the aging of the skin progresses. It has been shown that EGF binds to the EGF receptor located in the cell membrane and transmits a signal to induce growth and division of epithelial cells and fibroblasts constituting the skin to promote skin regeneration (Sporn, MB et al., Nature (NIH3T3 cell line) was used to test the effect of the microorganism on growth, Respectively.
Therefore, when EGF is applied to the skin using an appropriate delivery means, it promotes the proliferation of epithelial cells and fibroblasts, and the proliferation of fibroblasts promotes the synthesis of collagen and elastin, which are components of the dermis produced by fibroblasts, It helps regenerate and restores the original function of the skin that deteriorates with age. As a result, EGF has been listed on the International Cosmetic Ingredient Collection (ICID) of the American Cosmetics Association (CTFA) and is being used as cosmetic ingredients in a variety of countries including Korea.
In addition, the cell regenerating function of EGF has been applied to various fields such as diabetic foot ulcer treatment, burn treatment, wound healing, gastric ulcer treatment, corneal injury treatment, various incision surgery, cosmetic purpose skin peeling, and aging skin improvement Konturek, SJ et al., Gastroenterology. 81 (1986), < RTI ID = 0.0 > : 438-443, 1981).
The EGF currently in use can be prepared by a variety of methods including gene recombination method using a variety of cells such as Escherichia coli after successful cloning of human epithelial cell growth factor (hEGF) (Smith, J. et al., Nucleic Acids Res. 10, 4467-4482, Natl. Acad. Sci. USA 80, 7461-7465, 1983; Oka, T, et al., Proc. Natl. Acad Sci USA 82, 7212-7216, 1985). However, due to the cost burden on the production process, the unit price is higher than the conventional raw materials and natural products having similar functions.
EGF is unstable in water-soluble formulations used in cosmetic formulations and distribution temperature, and thus it is difficult to maintain long-term activity (Manning, et al., Pharmaceutical Res. 6: 903-917, 1989) Dalton) It is known that the skin permeability is low and the half-life of the body is short as several minutes.
Therefore, there is a desperate need to develop a substitute material that maintains the function of EGF and increases stability and skin permeability.
DISCLOSURE OF THE INVENTION The present invention has been accomplished to solve the above-mentioned problems, and it is an object of the present invention to provide a peptide having the same function or action as EGF, but superior in stability to EGF and superior skin permeability.
In order to achieve the above object, the present invention provides a peptide comprising an amino acid sequence represented by a general formula of an amino acid and exhibiting EGF activity:
General Formula 1:
X 1 -Leu-X 2 -Glu-X 3 -Glu-X 4
In this formula,
X 1 : Met, Ile, Phe, His, Lys, Arg, Glu, or Ile
X 2 : Lys, Arg, His, or Asn
X 3 : Trp, Gly His, Tyr, or Arg
X 4 : Leu, Asp, Asn, or Phe residue, but is not limited thereto.
The present invention provides a peptide consisting of an amino acid sequence represented by the following general formula:
General Formula 1:
X 1 -Leu-X 2 -Glu-X 3 -Glu-X 4
In the above general formula, X 1 : Is Met or Ile, X 2: a Lys or Arg, X 3 : Trp or Gly, X 4 : Leu or Asp residues, but is not limited thereto.
In one embodiment of the present invention, the peptide comprises a peptide wherein X 1 is a Met residue, X 2 is a Lys residue, X 3 is a Trp residue, X 4 is a Leu residue;
X 1 is a Met residue, X 2 is a Lys residue, X 3 is a Trp residue, X 4 is an Asp residue
Wherein said peptide has the following structure: X 1 is a Met residue, X 2 is a Lys residue, X 3 is a Gly residue, X 4 is a Leu residue;
X 1 is a Met residue, X 2 is a Lys residue, X 3 is a Gly residue, X 4 is an Asp residue;
X 1 is a Met residue, X 2 is an Arg residue, X 3 is a Trp residue, X 4 is a Leu residue;
X 1 is a Met residue, X 2 is an Arg residue, X 3 is a Trp residue, X 4 is an Asp residue;
X 1 is a Met residue, X 2 is an Arg residue, X 3 is a Gly residue, X 4 is a Leu residue;
X 1 is a Met residue, X 2 is an Arg residue, X 3 is a Gly residue, X 4 is an Asp residue;
X 1 is an Ile residue, X 2 is a Lys residue, X 3 is a Trp residue, X 4 is a Leu residue;
X 1 is an Ile residue, X 2 is a Lys residue, X 3 is a Trp residue, X 4 is an Asp residue;
X 1 is an Ile residue, X 2 is a Lys residue, X 3 is a Gly residue, X 4 is a Leu residue;
X 1 is an Ile residue, X 2 is a Lys residue, X 3 is a Gly residue, X 4 is an Asp residue;
X 1 is an Ile residue, X 2 is an Arg residue, X 3 is a Trp residue, X 4 is a Leu residue;
X 1 is an Ile residue, X 2 is an Arg residue, X 3 is a Trp residue, X 4 is an Asp residue;
X 1 is an Ile residue, X 2 is an Arg residue, X 3 is a Gly residue, X 4 is a Leu residue, or
X 1 is preferably an Ile residue, X 2 is an Arg residue, X 3 is a Gly residue, and X 4 is an Asp residue, but is not limited thereto.
The present invention also provides a peptide comprising an Arg residue at the C-terminus of the peptide of the present invention.
In one embodiment of the present invention, the sequence of the peptide of the present invention is preferably composed of the amino acid sequence of one of SEQ ID NOS: 1 to 32, but is not limited thereto.
In another embodiment of the present invention, at least one of the N-terminal and C-terminal amino acid residues of the peptide of the present invention is an acetyl group, an amide group, a formyl group, a palmitoyl group, , A stearyl group, an ascorbic acid group, and a polyethylene glycol (PEG), but is not limited thereto.
(A) a cosmetically effective amount of said peptide of the invention; And (b) an cosmetically acceptable carrier.
In one embodiment of the present invention, the composition preferably has an effect or activity of improving the skin condition, and the improvement of the skin condition may include improvement of wrinkles, improvement of skin elasticity, prevention of skin aging, improvement of atopic diseases, Amelioration, acne improvement, or acne improvement, but is not limited thereto.
Hereinafter, the present invention will be described.
In the present invention, in the case of the peptide derived from EGF, a site important for the activity of EGF and EGF receptor was selected using a protein molecule modeling technique, mutation for each amino acid residue was set, energy calculation was performed, We could select a sequence that showed strong interaction. To verify the molecular modeling results, we synthesized peptide sequences prepared by virtualization technology and compared cell proliferation activities.
According to a preferred embodiment of the present invention, in the EGF structure in the structure of EGF and EGF receptor (PDB: 1IVO), 52 amino acid residues deleted from the structure of arginine 41 to glutamic acid 51 by homology modeling of peptides Restoration of leucine and
According to a preferred embodiment of the present invention, substitution of the 46th aspartic acid with mesaionine, isoleucine, phenylalanine, histidine, lysine, arginine, Substitution or use of arginine, histidine, or asparagine of
The peptides of the present invention exhibit much better stability than natural EGFs themselves, but the stability can be improved by modification of amino acids. According to a preferred embodiment of the present invention, at least one of the amino acid residues at the N- and C-termini of the peptide of the
According to another variant of the present invention, the C-terminus of the peptide of the
According to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating skin diseases comprising the EGF-derived peptide as an active ingredient.
Preferably, the composition of the present invention is used for the treatment of skin such as skin inflammation, acute chronic eczema, contact dermatitis, atopic dermatitis, seborrheic dermatitis, chronic simplex poisoning, biliary cysts, deprived dermatitis, bulimia nervosa, psoriasis, It is used for the prevention or treatment of diseases. In addition, the composition of the present invention can provide a composition for treating wound.
Preferably, the composition of the present invention is used for the treatment of closed wounds and open wounds. Examples of closed windows include contusion or burys and examples of open windows include abrasion, laceration, avulsion, penetrated wound, and gun shot wound.
The composition of the present invention comprises (a) a pharmaceutically effective amount of the above-mentioned EGF-derived peptide of the present invention; And (b) a pharmaceutically acceptable carrier.
As used herein, the term "pharmaceutically effective amount" means an amount sufficient to achieve efficacy or activity of the EGF-derived peptides described above.
The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).
The pharmaceutical composition of the present invention may be administered orally or parenterally, preferably parenterally. In the case of parenteral administration, the pharmaceutical composition may be administered by intravenous infusion, subcutaneous injection, muscle injection, intraperitoneal injection, local administration, .
The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . On the other hand, the preferred daily dosage of the pharmaceutical composition of the present invention is 0.001-100 mg / kg.
The pharmaceutical composition of the present invention may be prepared in a unit dosage form by formulating it with a pharmaceutically acceptable carrier or excipient according to a method which can be easily carried out by those having ordinary skill in the art to which the present invention belongs Into a multi-dose container. The formulations may be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of excipients, powders, granules, tablets, capsules or gels (e.g., hydrogels), and may additionally contain dispersing or stabilizing agents .
According to another aspect of the present invention, there is provided a cosmetic composition for improving skin condition comprising the EGF-derived peptide as an active ingredient.
As demonstrated in the following examples, the EGF-derived peptides of the present invention have the same activity as native EGF and have excellent thermal stability and stability in aqueous solution. Therefore, the composition of the present invention is very effective for improving the skin condition.
Preferably, the composition of the present invention is used for the improvement of skin conditions such as wrinkle improvement, skin elasticity improvement, skin aging prevention, skin moisturization improvement, black spot removal or acne treatment.
The composition of the present invention comprises (a) a cosmetically effective amount of the above-mentioned EGF-derived peptide of the present invention; And (b) an cosmetically acceptable carrier.
The term "cosmetically effective amount" as used herein means an amount sufficient to achieve the skin-improving effect of the composition of the present invention described above.
The cosmetic composition of the present invention may be prepared in any form conventionally produced in the art and may be in the form of a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant- , Oil, powder foundation, emulsion foundation, wax foundation and spray, but is not limited thereto. More specifically, it can be manufactured in the form of a soft lotion, a nutritional lotion, a nutritional cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray or a powder.
When the formulation of the present invention is a paste, cream or gel, an animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as the carrier component .
When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. In the case of a spray, in particular, / Propane or dimethyl ether.
When the formulation of the present invention is a solution or an emulsion, a solvent, a dissolving agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, , 3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid esters.
In the case where the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.
When the formulation of the present invention is an interfacial active agent-containing cleansing, the carrier component may include aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives, or ethoxylated glycerol fatty acid esters.
Since the compositions of the present invention include the above-mentioned EGF peptide of the present invention as an active ingredient, the description common to both of them is omitted in order to avoid the excessive complexity of the present specification.
The characteristics of the cosmetic composition including peptides of epithelial cell growth factor with improved skin permeability according to the present invention will be understood by referring to the accompanying drawings, which are described in detail below.
According to the present invention, the cosmetic composition containing the EGF peptides of the present invention shows skin regeneration effect superior to the cosmetic composition containing natural EGF due to the improvement of the skin permeability of the peptides.
FIG. 1 is a graph showing the result of docking energy comparison when amino acid residues are mutated using in silico modeling technique,
FIG. 2 shows the docking energy contribution of each amino acid residue when a peptide is bound to a receptor,
FIG. 3 is a graph showing an experiment of cell proliferation due to mutation of amino acid residues,
FIG. 4 is a graph showing numerical values of binding energy calculated by a computer simulation method of each peptide,
FIG. 5 shows the comparison of the NIH-3T3 cell proliferation ability of each peptide,
FIG. 6 is a graph comparing the stability of the heptapeptide and native EGF through the evaluation of cell proliferation ability,
FIG. 7 is a graph comparing the stability of octapeptide and native EGF through cell proliferation assay,
8 is a graph showing the results of measurement of skin permeability of heptapeptide over time,
FIG. 9 is a graph showing the results of measurement of skin permeability of octapeptide over time,
The present invention will now be described in more detail by way of non-limiting examples. The following examples are intended to illustrate the present invention and the scope of the present invention is not to be construed as being limited by the following examples.
Example 1: molecule modelling
Analysis of the interaction site was performed using a paper (OGISO, Hideo, et al., 110.6: 775-787, 2002) of a complex with 1IVO, a structure of EGF and EGF receptor registered in PDB (Protein data bank) do. The structure of 41R to 51E, which strongly binds to the EGF receptor, is taken, and Leu and Arg, which are missing in the PDB structure, are attached to the 52 and 53 fragments, respectively, and this is called Felxpepdock (Raveh B, et al, Proteins 78: 2029-40,2010 .) To proceed with docking. We then analyze the energy, RMSD (root-mean-square deviation) and tendency of each interaction using the PIC (Protein interaction Calculator). Based on this tendency, the peptide candidates are prepared by virtualization techniques such as point mutation, deletion mutation and insertion mutation of amino acid residues and analyzed using Flexpepdock. The results are shown in Fig. Based on the mutations shown in FIG. 1, the contribution of the docking energy of each amino acid residue upon binding of the peptide to the receptor was analyzed to evaluate the importance of mutation of amino acid residues (FIG. 2). NIH-3T3 cell proliferative capacity experiments were conducted to confirm that these peptides actually have cell activity (FIG. 3). A detailed description of the cell proliferation ability experiment will be described in Example 5. Based on the results of the analysis, the sequences shown in Table 1 were determined and the energy corresponding thereto was calculated (Fig. 4).
Table 1 shows the amino acid sequence of the peptides of the present invention (
Example 2: Met-Leu- Lys - Glu -Trp- Glu -Leu ( EGF Heptapeptide ) Synthesis of
10 mmole of Fmoc-Rink amide resin (GL Biochem, Cat No. 49001) was added to the reaction vessel, and 50 ml of methylene chloride (MC) was added thereto. The mixture was stirred for 20 minutes, . 60 ml of the deprotection solution (20% piperidine / DMF) was added to the reaction vessel and stirred for 30 minutes at room temperature. The solution was then removed and washed three times with DMF and once with MC. To the new reactor, 50 ml of DMF solution was added, followed by 15 mmole of Nsc-Leu-OH, 15 mmole of HoBt and 15 mmole of HBTU, followed by stirring and dissolution. The dissolved amino acid mixture solution was placed in a reaction vessel with the deprotected resin, and 20 mmole of DIPEA (N, N'-Diisopropyl ethylamine) was added thereto, followed by stirring at room temperature for 2 hours.
The reaction solution was removed, and the mixture was stirred with DMF solution three times for 5 minutes to remove unreacted residues. A small amount of the reaction resin was taken and the degree of reaction was checked using a Ninhydrine test. The reaction solution was subjected to the same deprotection reaction twice as described above to prepare a Leu-Rink amide resin. Washed with DMF and MC, once again subjected to the Kaiser test, and then subjected to the same experiment as described above. (TBu) -OH, Nsc-Trp (Boc) -OH, Nsc-Glu (tBu) -OH, Nsc-Lys (20% piperidine / DMF) were added to the reaction vessel, and the mixture was stirred at room temperature for 30 minutes. Then, the solution was removed, and the solution was washed three times with DMF and three times with MC And washed once. (20% -Acetic anhydride), and the solution was removed with stirring at room temperature for 30 minutes. The solution was washed three times with DMF, three times with MC, and dried with flowing nitrogen air to obtain Met-Leu-Lys (Boc) -Glu tBu) -Trp (Boc) -Glu (tBu) -Leu-Rink amide resin.
The amide resin prepared was placed in a round bottom flask. 100 ml of a previously prepared solution (TFA 81.5%, distilled
Example 3: Met-Leu- Lys - Glu -Trp- Glu -Leu- Arg ( EGF Octapeptide ) Synthesis of
10 mmole of Fmoc-Rink amide resin (GL Biochem, Cat No. 49001) was added to the reaction vessel, and 50 ml of methylene chloride (MC) was added thereto. The mixture was stirred for 20 minutes, . 60 ml of the deprotection solution (20% piperidine / DMF) was added to the reaction vessel and stirred for 30 minutes at room temperature. The solution was then removed and washed three times with DMF and once with MC. 50 ml of DMF solution was added to the new reactor, followed by 15 mmole of Nsc-Arg (Pbf) -OH, 15 mmole of HoBt and 15 mmole of HBTU, followed by stirring and dissolution. The dissolved amino acid mixture solution was placed in a reaction vessel with the deprotected resin, and 20 mmole of DIPEA (N, N'-Diisopropyl ethylamine) was added thereto, followed by stirring at room temperature for 2 hours.
The reaction solution was removed, and the mixture was stirred with DMF solution three times for 5 minutes to remove unreacted residues. A small amount of the reaction resin was taken and the degree of reaction was checked using a Ninhydrine test. (Pbf) -Rink amide resin was prepared by the same deprotection reaction twice as the above-described deprotection solution. Washed with DMF and MC, once again subjected to the Kaiser test, and then subjected to the same experiment as described above. (TBu) -OH, Nsc-Trp (Boc) -OH, Nsc-Glu (tBu) -OH, Nsc-Lys (Boc) -OH, Nsc-Leu-OH and Nsc-Met-OH. The reaction mixture was stirred for 30 minutes at room temperature, and the solution was removed. DMF (20 ml) , And once with MC. (Boc) -Glu (tBu) -Trp (Boc) -Glu (tBu) -Leu-Arg (Pbf) -Rink amide resin was prepared.
The amide resin prepared was placed in a round bottom flask. 100 ml of a previously prepared solution (TFA 81.5%, distilled
Example 4: Other Peptides synthesis
For the production of peptides having sequences of
Table 2 shows the peptides group analyzed by HPLC and the purity and mass were analyzed
(Ac-acetyl group, As-ascorbyl group, Pl-palmitoyl group)
Example 5: NIH-3 T3 Analysis of growth effects on fibroblasts
In order to analyze the growth effect of fibroblasts on the peptides of the present invention, MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl- 2H-tetrazolium bromide] assay. NIH-3T3 cells were purchased from Korean Cell Line Bank and cultured in DMEM supplemented with 10% bovine calf serum (BCS), 100 units / ml penicillin, 100 mg / ml streptomycin (Dulbeco's Modified Eagle's Medium ) Medium (D-MEM high glucose, with L-glutamine, sodium pyruvate, USA). NIH-3T3 cells were plated at a density of 2 x 10 3 cells per well on a 96-well tissue culture plate and cultured for 24 hours at 37 ° C and 7% CO 2 . After 24 hours, the medium was replaced with a DMEM medium containing 0.5% BCS and 1% penicillin. The control, human EGF, and various sample peptides were dissolved in water and 10% DMSO, And cultured for 24 hours. After incubation, 10 μl of MTT solution (EZ-CYTOX, Cell Viability, Proliferation and Cytotoxicity Assay Kit, Dogen, KOR, Cat 786-213) was added and incubated for 1 hour. Absorbance was measured at 450 nm, (Fig. 5). At this time, no difference in activity was observed depending on the presence or absence of the protective groups at both ends of the peptide. The common description between them is omitted in order to avoid the excessive complexity of the present specification.
Example 6: Natural type EGF Wow EGF Heptapeptide , EGF Octapeptide Stability analysis
In order to analyze the stability of EGF heptapeptide and EGF octapeptide in consideration of activity and stability in the present invention, EGF heptapeptide and EGF octapeptide were added to 20 mM sodium phosphate (pH 7.0) buffer at a concentration of 1.1 ug / ml . In order to compare the stability with natural EGF, natural EGF produced from E. coli was also dissolved in 20 mM sodium phosphate (pH 7.0) buffer to a concentration of 1.1 ug / ml. And left at 37 ° C in an environment of a week. As a result, cell proliferation experiments using the NIH-3T3 cell line of Example 4 were carried out to confirm the stability of natural type EGF, EGF hepta peptide and EGF octapeptide. At this time, 0 day sample activity was performed on the basis of 100%.
As can be seen from FIGS. 6 and 7, the activity of native EGF was abruptly dropped over a week and was found to be about 60% on the
Peptides
Table 3 is a table showing the stability (%) of each peptide over time
Example 7: Natural type EGF Wow EGF Heptapeptide , EGF Octapeptide Skin permeability test
Artificial skin Neoderm E (Tego Science) and PBS (Sigma Co. Cat No. P-5368) were prepared to confirm the skin permeability of the EGF heptapeptide and EGF octapeptide of the present invention. Add magnetic bar to Franz cell and add 5 ml of PBS. Place the stratum corneum of Neoderm E on top of the Franz cell so that it faces upwards. Place the Franz cell lid on top of the Neoderm E and fully secure it with a clamp, then place the Franz cell in the Franz cell service system. On the Neoderm E, 500 μl of natural EGF, EGF heptapeptide and EGF octapeptide are added to each sample of 50 μg / ml, sealed with parafilm, and the agitator is operated at 600 rpm. Using a syringe, 150 μl of each sample was sampled for 8 hours and 12 hours, and the concentration was measured using an ELISA kit. At this time, there was no noticeable difference in skin permeability depending on the presence or absence of a protecting group. The common description between them is omitted in order to avoid the excessive complexity of the present specification.
Peptides
Table 4 is a table showing skin permeability of peptides over time
≪ 110 > PnP Biopharm Co., Ltd. <120> A peptide having activity of Epidermal growth factor activity production method therefor <130> HY151024 <160> 32 <170> Kopatentin 2.0 <210> 1 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 1 Met Leu Lys Glu Trp Glu Leu 1 5 <210> 2 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 2 Met Leu Lys Glu Trp Glu Asp 1 5 <210> 3 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 3 Met Leu Lys Glu Gly Glu Leu 1 5 <210> 4 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 4 Met Leu Lys Glu Gly Glu Asp 1 5 <210> 5 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 5 Met Leu Arg Glu Trp Glu Leu 1 5 <210> 6 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 6 Met Leu Arg Glu Trp Glu Asp 1 5 <210> 7 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 7 Met Leu Arg Glu Gly Glu Leu 1 5 <210> 8 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 8 Met Leu Arg Glu Gly Glu Asp 1 5 <210> 9 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 9 Ile Leu Lys Glu Trp Glu Leu 1 5 <210> 10 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 10 Ile Leu Lys Glu Trp Glu Asp 1 5 <210> 11 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 11 Ile Leu Lys Glu 1 5 <210> 12 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 12 Ile Leu Lys Glu Gly Glu Asp 1 5 <210> 13 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 13 Ile Leu Arg Glu Trp Glu Leu 1 5 <210> 14 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 14 Ile Leu Arg Glu Trp Glu Asp 1 5 <210> 15 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 15 Ile Leu Arg Glu Gly Glu Leu 1 5 <210> 16 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 16 Ile Leu Arg Glu Gly Glu Asp 1 5 <210> 17 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 17 Met Leu Lys Glu Trp Glu Leu Arg 1 5 <210> 18 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 18 Met Leu Lys Glu Trp Glu Asp Arg 1 5 <210> 19 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 19 Met Leu Lys Glu Gly Glu Leu Arg 1 5 <210> 20 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 20 Met Leu Lys Glu Gly Glu Asp Arg 1 5 <210> 21 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 21 Met Leu Arg Glu Trp Glu Leu Arg 1 5 <210> 22 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 22 Met Leu Arg Glu Trp Glu Asp Arg 1 5 <210> 23 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 23 Met Leu Arg Glu Gly Glu Leu Arg 1 5 <210> 24 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 24 Met Leu Arg Glu Gly Glu Asp Arg 1 5 <210> 25 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 25 Ile Leu Lys Glu Trp Glu Leu Arg 1 5 <210> 26 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 26 Ile Leu Lys Glu Trp Glu Asp Arg 1 5 <210> 27 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 27 Ile Leu Lys Glu Gly Glu Leu Arg 1 5 <210> 28 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 28 Ile Leu Lys Glu Gly Glu Asp Arg 1 5 <210> 29 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 29 Ile Leu Arg Glu Trp Glu Leu Arg 1 5 <210> 30 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 30 Ile Leu Arg Glu Trp Glu Asp Arg 1 5 <210> 31 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 31 Ile Leu Arg Glu Gly Glu Leu Arg 1 5 <210> 32 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 32 Ile Leu Arg Glu Gly Glu Asp Arg 1 5
Claims (23)
[Formula 1]
X 1 -Leu-X 2 -Glu-X 3 -Glu-X 4
In the above general formula, X 1 : Is Met or Ile, X 2: a Lys or Arg, X 3 : Trp or Gly, X 4 : Leu or Asp.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
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| KR1020150119794A KR101831977B1 (en) | 2015-08-25 | 2015-08-25 | A peptide having activity of Epidermal growth factor activity and production method therefor |
| PCT/KR2016/009325 WO2017034301A1 (en) | 2015-08-25 | 2016-08-23 | Peptide having the activity of epithelial growth factor, and use therefor |
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| KR1020150119794A KR101831977B1 (en) | 2015-08-25 | 2015-08-25 | A peptide having activity of Epidermal growth factor activity and production method therefor |
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| KR101831977B1 KR101831977B1 (en) | 2018-02-23 |
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| WO (1) | WO2017034301A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101943081B1 (en) * | 2017-08-31 | 2019-01-29 | (주)케어젠 | Peptides Having Activity for Wrinkle Relief and Uses Thereof |
| KR20190024916A (en) * | 2019-01-14 | 2019-03-08 | (주)케어젠 | Peptides Having Activity for Wrinkle Relief and Uses Thereof |
| KR20190024915A (en) * | 2019-01-14 | 2019-03-08 | (주)케어젠 | Peptides Having Activity for Wrinkle Relief and Uses Thereof |
| KR20190024914A (en) * | 2019-01-14 | 2019-03-08 | (주)케어젠 | Peptides Having Activity for Wrinkle Relief and Uses Thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5183805A (en) * | 1990-08-13 | 1993-02-02 | Board Of Regents, The University Of Texas System | Bioactive egf peptides for promotion of tissue regeneration and cancer therapy |
| KR100824396B1 (en) | 2006-10-10 | 2008-04-22 | (주)케어젠 | Peptides Having Activities of Epidermal Growth Factor and Its Uses |
| WO2009126718A2 (en) * | 2008-04-08 | 2009-10-15 | Arizona Board Of Regents And On Behalf Of Arizona State University | Tumor-associated biomarkers from the dark proteom |
| US20140357512A1 (en) | 2013-06-03 | 2014-12-04 | Acetylon Pharmaceuticals, Inc. | Histone deacetylase (hdac) biomarkers in multiple myeloma |
| KR101519118B1 (en) * | 2013-07-23 | 2015-05-12 | (주)피앤피바이오팜 | Highly stabilized epidermal growth factor mutants |
-
2015
- 2015-08-25 KR KR1020150119794A patent/KR101831977B1/en active IP Right Grant
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101943081B1 (en) * | 2017-08-31 | 2019-01-29 | (주)케어젠 | Peptides Having Activity for Wrinkle Relief and Uses Thereof |
| WO2019045248A3 (en) * | 2017-08-31 | 2019-04-18 | (주)케어젠 | Peptide exhibiting wrinkle-improving activity and uses thereof |
| US11103436B2 (en) | 2017-08-31 | 2021-08-31 | Caregen Co., Ltd. | Peptide exhibiting wrinkle-improving activity and uses thereof |
| US11672749B2 (en) | 2017-08-31 | 2023-06-13 | Caregen Co., Ltd. | Peptide exhibiting wrinkle-improving activity and uses thereof |
| KR20190024916A (en) * | 2019-01-14 | 2019-03-08 | (주)케어젠 | Peptides Having Activity for Wrinkle Relief and Uses Thereof |
| KR20190024915A (en) * | 2019-01-14 | 2019-03-08 | (주)케어젠 | Peptides Having Activity for Wrinkle Relief and Uses Thereof |
| KR20190024914A (en) * | 2019-01-14 | 2019-03-08 | (주)케어젠 | Peptides Having Activity for Wrinkle Relief and Uses Thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2017034301A1 (en) | 2017-03-02 |
| KR101831977B1 (en) | 2018-02-23 |
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