KR101873816B1 - A decapeptide having activity of Epidermal growth factor and production method therefor - Google Patents
A decapeptide having activity of Epidermal growth factor and production method therefor Download PDFInfo
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- KR101873816B1 KR101873816B1 KR1020150131187A KR20150131187A KR101873816B1 KR 101873816 B1 KR101873816 B1 KR 101873816B1 KR 1020150131187 A KR1020150131187 A KR 1020150131187A KR 20150131187 A KR20150131187 A KR 20150131187A KR 101873816 B1 KR101873816 B1 KR 101873816B1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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Abstract
본 발명은 하기 일반식 1로 표시되는 아미노산 서열을 포함하며, 피부를 구성하는 상피세포(epithelial cell) 및 섬유아세포(fibroblast)의 증식활성을 나타내는 펩타이드 및 이의 용도에 관한 것이다:
[일반식 1]
Cys-X1-X2-X3-X4-X5-Gly-X6-Arg-Cys
상기 일반식에서, X1 : 모든 잔기, X2 : Val, Asp 또는 Asn, X3 : 모든 잔기, X4 : Tyr, Arg, Glu 또는 Gln, X5 : Ile 또는 Met 및 X6 : Glu 또는 Gln,
본 발명의 피부세포 증식 펩타이드는 천연형 EGF와 비교하였을 때 피부세포 증식능력이 동일함과 동시에, 저분자량의 특징을 가지고 있어 피부 투과도가 매우 우수한 장점이 있다. 따라서 본 발명의 펩타이드를 포함하는 조성물은, EGF 활성이 요구되는 질환 또는 상태를 치료, 예방 또는 개선하는 데 매우 우수한 효능을 발휘하며, 의약, 의약외품 및 화장품 등에 적용될 수 있다.The present invention relates to peptides exhibiting the proliferative activity of epithelial cells and fibroblasts constituting the skin including the amino acid sequence represented by the following general formula (1), and uses thereof:
[Formula 1]
Cys-X1-X2-X3-X4-X5-Gly-X6-Arg-Cys
Wherein X 1 is any residue, X 2 is Val, Asp or Asn, X 3 is any residue, X 4 is Tyr, Arg, Glu or Gln, X 5 is Ile or Met and X 6 is : Glu or Gln,
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 containing the peptide of the present invention exhibits an extremely 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
본 발명은 상피세포 성장인자의 활성을 가지는 펩타이드와 그의 용도에 관한 것이다. 더욱 상세하게는, 본 발명은 저분자량 구조로 인해 피부투과도가 높으며, 안정성이 증가되어 천연형보다 개선된 상피세포 성장인자 펩타이드에 대한 것이다. 또한 이를 포함하여 피부재생능력이 강화된 화장료 조성물에 대한 것이다.
The present invention relates to peptides having activity of epithelial growth factor and uses thereof. More specifically, the present invention relates to an epithelial cell growth factor peptide which is improved in skin permeability and increased in stability due to its low molecular weight structure, and is more improved than the natural type. The present invention also relates to a cosmetic composition having enhanced skin regeneration ability.
EGF는 53개의 아미노산으로 구성되어 있으며 3개의 이황화결합(disulfide bond)을 가지는 분자량 6,045 달톤의 폴리펩타이드(Cohen, S., J. Bio1. Chem. 237:1555-1562, 1962; Savage, C.R., J. Bio1. Chem. 247:7612-7621, 1972)이며, 1953년 미국의 스텐리 코헨(S. Cohen)에 의하여 처음 발견되어 기능이 밝혀졌다. 주요 기능으로는 EGF 수용체와 결합하여 상피세포와 간엽세포를 포함한 다양한 세포들에 반응하여 상피세포 및 진피세포의 증식 촉진, 진피 구성성분인 콜라겐을 합성하는 섬유아세포의 증식촉진 등이 있다. 이러한 효과로 인하여 EGF는 다양한 적용분야 중에 스킨케어(skin care) 분야에서 가장 많이 사용되고 있다. 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.
나이가 들어감에 따라 피부 등 각 조직에서 EGF를 포함한 성장인자들의 농도는 낮아지며, 세포의 재생 및 분열 기능이 약화되어 주름이 형성되고 탄력이 감소하는 등 노화가 진행된다. 보통 25세를 지난 피부는 성장인자가 감소해 신진대사나 세포의 재생 능력이 점점 늦어지면서 주름이 생겨나게 된다. 건강한 젊은이의 피부 재생 주기는 약 4주간이지만 25세를 지난 피부는 6주로 주기가 늦어져서 피부세포의 재생 능력이 떨어지고 각질층이 두꺼워지면서 피부의 노화 현상이 진행된다. EGF는 세포막에 위치하고 있는 EGF 수용체에 결합하여 신호를 전달함으로써 피부를 구성하는 상피세포와 섬유아세포의 성장 및 분열을 유도하여 피부의 재생을 촉진을 하는 것으로 밝혀져 있으며(Sporn, M. B. et al., Nature. 313:745-747, 1985; Sporn M. B. et al., N. Engl. J. Med. 303:878-880, 1980) 피부세포(NIH3T3 cell line)을 이용한 실험에서도 미량만으로도 성장을 촉진하는 우수한 효과를 나타내었다.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.
따라서 적절한 전달 수단을 이용하여 피부에 EGF를 적용하게 되면 상피세포 및 섬유아세포의 증식을 촉진하게 되고, 섬유아세포의 증식은 섬유아세포가 생산하는 진피 구성성분인 콜라겐 및 엘라스틴의 합성을 촉진하게 되어 피부재생을 돕고 연령과 함께 저하하는 피부 본래의 기능을 회복할 수 있다. 이에 따라 EGF는 미국 화장품협회(CTFA)의 국제 화장품 원료집(ICID)에 등재되었으며, 한국을 포함한 다양한 국가에서 화장품 원료로 사용되고 있다.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.
또한 EGF의 세포재생 기능은 당뇨병성 족부궤양 치료, 화상치료, 창상치료, 위궤양치료, 각막손상치료, 각종 절개수술, 미용목적의 박피수술, 노화된 피부의 개선 등 다양한 분야에 적용되고 있다(미합중국 특허 제140998호; Carpenter et al., Experimental Cell Research. 164:1-10, 1986; Kirkegaard, P. et al., Gastroenterology. 85:1277-1283, 1983; Konturek, S. J. et al., Gastroenterology. 81:438-443, 1981). 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).
지금 사용되고 있는 EGF는 인간 상피세포 성장인자(hEGF)의 성공적 클로닝(Smith, J. et al., Nucleic Acids Res. 10, 4467-4482, 1982) 이후에, 대장균 등 다양한 세포를 이용하여 유전자 재조합 방법으로 생산하여 분리정제 과정을 통하여 순수한 EGF를 공급하고 있다(Urdea, M. S. et al., Proc. Natl. Acad. Sci. USA 80, 7461-7465, 1983; Oka, T, et al., Proc. Natl. Acad. Sci. USA 82, 7212-7216, 1985). 하지만 생산 공정상의 비용부담으로 인하여, 유사 기능을 가지고 있는 기존 고시 원료와 천연물에 비하여 단가가 높은 편에 속한다. 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.
그리고 EGF는 화장품 제형에서 사용되는 수용성 제형 및 유통 온도 등에서 불안정하여 장기간 활성을 유지하기 어려우며(Manning, et al., Pharmaceutical Res. 6:903-917, 1989), 또한 분자량이 상대적으로 커서(>5,000 달톤) 피부 투과율이 낮고, 체내 반감기가 수 분 정도로 짧다고 알려져 있다.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.
따라서 EGF의 기능은 유지하며 안정성 및 피부투과성이 증가된 대체물질의 개발이 절실히 요구되고 있는 실정이다.Therefore, there is a desperate need to develop a substitute material that maintains the function of EGF and increases stability and skin permeability.
[선행 특허 문헌][Prior Patent Literature]
대한민국 특허공개번호 제1020150011877호Korean Patent Publication No. 1020150011877
본 발명은 상기의 필요성에 의하여 안출된 것으로서 본 발명의 목적은 EGF와 동일한 기능 또는 작용을 할 수 있으면서도 EGF 보다 안정성이 우수하고 피부 투과율이 우수한 펩타이드를 제공하는 것이다.The present invention has been made in view of the above needs, 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 excellent in skin permeability.
본 발명의 목적은 EGF 활성을 나타내는 펩타이드를 제공하는 데 있다. 본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명, 청구범위 및 도면에 의해 보다 명확하게 된다.It is an object of the present invention to provide a peptide exhibiting EGF activity. Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.
상기 목적을 당성하기 위하여, 본 발명은 하기 일반식 1로 표시되는 아미노산 서열로 이루어진 펩타이드:In order to achieve the above object, the present invention provides a peptide comprising the amino acid sequence represented by the following general formula 1:
Cys-X1-X2-X3-X4-X5-Gly-X6-Arg-CysCys-X 1 -X 2 -X 3 -X 4 -X 5 -Gly-X 6 -Arg-Cys
[일반식 1][Formula 1]
상기 일반식에서, X1는 발린(Val) 잔기, X2는 발린(Val), 아스파트산(Asp) 또는 아스파라진(Asn) 잔기, X3는 글리신(Gly) 잔기, X4는 타이로신(Tyr), 아르기닌(Arg), 글루탐산(Glu) 또는 글루타민(Gln) 잔기, X5는 아이소루신(Ile) 또는 메티오닌(Met) 잔기이고, X6는 글루탐산(Glu) 또는 글루타민(Gln) 잔기인 것이 바람직하나 이에 한정되지 아니한다.Said general formula, X 1 is valine (Val) residue, X 2 is a valine (Val), aspartic acid (Asp) or asparagine (Asn) residue, X 3 is glycine (Gly) residue, X 4 is tyrosine (Tyr ), arginine (Arg), glutamic acid (Glu) or glutamine (Gln) residue, X 5 is isoleucine (residues Ile) or methionine (Met), X 6 is preferably a glutamic acid (Glu) or glutamine (Gln) residues But not limited to this.
본 발명의 일 구현예에 있어서, 상기 펩타이드는 상피세포 성장인자의 활성을 가지는 것이 바람직하나 이에 한정되지 아니한다.In one embodiment of the present invention, the peptide preferably has epithelial cell growth factor activity, but is not limited thereto.
본 발명의 바람직한 구현예에 있어서, 상기 펩타이드는 서열번호 1 내지 서열번호 48에 기재된 아미노산 서열로 이루어진 군으로부터 선택된 펩타이드 중 하나인 것이 바람직하나 이들 서열에 하나 이상의 치환, 결손, 역위 전좌 등의 돌연변이를 수행하여 본 발명이 목적하고자 하는 효과를 달성하는 모든 돌연변이체도 본 발명의 보호 범위에 포함된다.In a preferred embodiment of the present invention, the peptide is preferably one of the peptides selected from the group consisting of the amino acid sequences set forth in SEQ ID NO: 1 to SEQ ID NO: 48, but mutations such as one or more substitutions, deletions, And all mutants that attain the intended effect of the present invention are also included in the scope of protection of the present invention.
본 발명의 다른 구현예에 있어서, 상기 펩타이드의 N-말단 및 C-말단에 있는 아미노산 잔기 중 적어도 하나는 아세틸기, 아미드기, 포르밀기, 팔미토일기, 미리스틸기, 스테아릴기, 아스코르브산 및 폴리에틸렌글리콜(PEG)로 구성된 군으로부터 선택되는 보호기가 결합되어 있는 것이 바람직하나 이에 한정되지 아니한다.In another embodiment of the present invention, at least one of the N-terminal and C-terminal amino acid residues of the peptide is substituted with an acetyl group, an amide group, a formyl group, a palmitoyl group, a myristyl group, a stearyl group, And polyethylene glycol (PEG), but are not limited thereto.
또 본 발명은 상기 본 발명의 펩타이드의 화장품학적 유효량(cosmetically effective amount); 및 (b) 화장품학적으로 허용되는 담체를 포함하는 화장품 조성물을 제공한다.The present invention also relates to a cosmetically effective amount of said peptide of the invention; And (b) an cosmetically acceptable carrier.
본 발명의 일 구현예에 있어서, 상기 조성물은 피부 상태의 개선의 효능 또는 활성을 가지는 것이 바람직하고, 상기 피부 상태의 개선은 주름개선, 피부탄력 개선, 피부노화 방지, 아토피 질환의 개선, 피부보습 개선, 검버섯 개선 또는 여드름 개선인 것이 바람직하나 이에 한정되지 아니한다.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.
이하 본 발명을 설명한다.Hereinafter, the present invention will be described.
본 발명에서 EGF 유래 펩타이드의 경우 단백질 분자모델링 기술을 이용하여 EGF 와 EGF 수용체와의 활성에 중요한 부위를 선정한 후, 각 아미노산 잔기에 대한 돌연변이를 설정하여 이에 따른 에너지 계산을 수행하여 비교한 결과, 더 강한 interaction을 나타내는 서열을 선택할 수 있었다. 이 분자모델링 결과를 입증하기 위하여 가상화 기술을 통하여 만들어진 펩타이드 서열을 합성하여 세포증식활성을 비교하였다. 본 발명의 바람직한 구현 예에 따르면 EGF와 EGF 수용체의 구조(PDB : 1IVO)에서의 EGF 구조에서 33번 시스테인부터 42번 시스테인까지의 구조를 기반으로 펩타이드의 EGF의 구조를 추출하였다. 위의 방식으로 제작된 EGF펩타이드의 구조를 기반으로 점돌연변이를 in silico(컴퓨터 가상화)기술을 이용하여 제작하였고 이를 수용체와의 도킹 실험을 통하여 더 강한 결합을 가지는 펩타이드의 서열을 발견할 수 있었다. In the present invention, in the case of the peptide derived from EGF, a region important for the activity of EGF and EGF receptor was selected using a protein molecule modeling technique, mutation was set for each amino acid residue, 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, the structure of the EGF of the peptide is extracted based on the structure from the
본 발명의 바람직한 구현예의 따르면 34번 발린의 경우 곁사슬(side chain)만 EGF의 수용체와 상호작용(interaction)을 하기 때문에 다른 어떠한 아미노산 잔기가 오더라고 결합에는 문제가 없다. 35번의 발린의 경우 아스파라진 과 아스파트산(Asp)으로 치환 또는 발린으로;. 36번 글라이신의 경우 외부로 노출되어 있는 부분으로 어떠한 결합 상호작용이 없다 어떠한 잔기가 오더라도 문제는 없다. 37번 타이로신의 경우 아르지닌 아스파라진 아스파트산(Asp)으로 치환 또는 타이로신으로; 38번 아이소루이신의 경우 메사이오닌 트립토판으로 치환 또는 아이소루신 사용; 40번 글루타민산의 경우 글루타민 또는 글루타민산의 사용이 가능한 데카펩타이드(일반식 1)를 포함한다.According to a preferred embodiment of the present invention, in the case of
본 발명의 펩타이드는 그 자체로서 천연 EGF 보다 매우 우수한 안정성을 나타내지만, 아미노산의 변형에 의해 안정성이 향상될 수 있다. 본 발명의 바람직한 구현예에 따르면, 상기 일반식 1의 펩타이드의 N-말단 및 C-말단에 있는 아미노산 잔기 중 적어도 하나는 아스코르브산기, 아세틸기, 아미드기, 포르밀기, 팔미토일기, 미리스틸기, 스테아릴기 및 폴리에틸렌글리콜(PEG)등 으로 구성된 군으로부터 선택되는 보호기가 결합되어 있다. 이러한 보호기는 본 발명의 펩타이드의 안정성을 증가시키는 역할을 한다.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
본 발명의 다른 변형 예에 따르면, 상기 일반식 1의의 펩타이드의 C-말단은 아미노기로 변형되어 있으며, 이는 펩타이드의 안정성을 증가시키는 작용을 한다.According to another variant of the present invention, the C-terminal of the peptide of the
본 발명은 피부투과도가 개선되고 안정성이 증가된 상피세포성장인자의 펩타이드를 제안하며, 이를 포함한 피부상태 개선용 화장료 조성물을 제공한다. The present invention proposes peptides of epithelial growth factor with improved skin permeability and increased stability, and provides a cosmetic composition for skin condition improvement containing the peptides.
본 발명의 피부재생용 화장료 조성물은 다음의 서열을 가지는 서열 일반식 1에서 선택된 하나 이상의 펩타이드를 주성분으로 포함하여 구성됨을 특징으로 한다.The cosmetic composition for skin regeneration of the present invention is characterized in that it comprises at least one peptide selected from the sequence represented by the general formula (1) having the following sequence as a main component.
본 발명의 다른 양태에 따르면, 본 발명은 상기 EGF-유래 펩타이드를 유효성분으로 포함하는 피부 질환 예방 또는 치료용 약학적 조성물을 제공한다.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.
바람직하게는, 본 발명의 조성물은 피부 염증, 급만성 습진, 접촉성 피부염, 아토피성 피부염, 지루성 피부염, 만성 단순태선, 간찰진, 박탈 피부염, 구진상 두드러기, 건선, 일광 피부염 및 여드름과 같은 피부 질환의 예방 또는 치료에 이용된다. 또한, 본 발명의 조성물은 창상 치료용 조성물을 제공할 수 있다.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.
바람직하게는, 본 발명의 조성물은 폐쇄창(closed wound) 및 개방창(open wound)의 치료에 이용된다. 폐쇄창의 예는 좌상(contusion or Burise)을 포함하고, 개방창의 예는 찰과상(abrasion), 열상(laceration), 결출상(Avulsion), 관통상(penetrated wound) 및 총상(gun shot wound)을 포함한다.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.
본 발명의 조성물은 (a) 상술한 본 발명의 EGF-유래 펩타이드의 약학적 유효량; 및 (b) 약학적으로 허용되는 담체를 포함하는 약학적 조성물이다.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.
본 명세서에서 사용되는 용어 "약학적 유효량"은 상술한 EGF-유래 펩타이드의 효능 또는 활성을 달성하는 데 충분한 양을 의미한다.As used herein, the term "pharmaceutically effective amount" means an amount sufficient to achieve efficacy or activity of the EGF-derived peptides described above.
본 발명의 약학적 조성물에 포함되는 약학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약제학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences(19th ed., 1995)에 상세히 기재되어 있다.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).
본 발명의 약학적 조성물은 경구 또는 비경구, 바람직하게는 비경구로 투여할 수 있고, 비경구 투여인 경우에는 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 국소 투여, 경피 투여 등으로 투여할 수 있다.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, .
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 한편, 본 발명의 약제학적 조성물의 바람직한 1일 투여량은 0.001-1000 ug/kg 체중이다.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 0.001-1000 ug / kg body weight.
본 발명의 약제학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 대용량 용기내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액 또는 유화액 형태이거나 엑스제, 분말제, 과립제, 정제, 캅셀제 또는 젤(예컨대, 하이드로젤) 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.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 Can be manufactured by inserting it into a large-capacity 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 .
본 발명의 다른 양태에 따르면, 본 발명은 상기 EGF-유래 펩타이드를 유효성분으로 포함하는 피부 상태 개선용 화장료 조성물을 제공한다.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.
하기의 실시예에서 입증된 바와 같이, 본 발명의 EGF-유래 펩타이드는 천연 EGF와 동일한 활성을 갖고, 매우 우수한 열안정성 및 수용액에서의 안정성을 갖는다. 따라서 본 발명의 조성물은 피부 상태의 개선에 매우 유효하다.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 in improving the skin condition.
바람직하게는, 본 발명의 조성물은 주름개선, 피부탄력 개선, 피부노화 방지, 피부보습 개선, 검버섯 제거 또는 여드름 치료와 같은 피부 상태의 개선에 이용된다.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.
본 발명의 조성물은 (a) 상술한 본 발명의 EGF-유래 펩타이드의 화장품학적 유효량(cosmetically effective amount); 및 (b) 화장품학적으로 허용되는 담체를 포함하는 화장료 조성물이다.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.
본 명세서에서 사용되는 용어 "화장품학적 유효량"은 상술한 본 발명의 조성물의 피부 개선 효능을 달성하는 데 충분한 양을 의미한다.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.
본 발명의 화장품 조성물은 당업계에서 통상적으로 제조되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어, 용액, 현탁액, 유탁액, 페이스트, 겔, 크림, 로션, 파우더, 비누, 계면활성제-함유 클린싱, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션 및 스프레이 등으로 제형화될 수 있으나, 이에 한정되는 것은 아니다. 보다 상세하게는, 유연 화장수, 영양 화장수, 영양 크림, 마사지 크림, 에센스, 아이 크림, 클렌징 크림, 클렌징 폼, 클렌징 워터, 팩, 스프레이 또는 파우더의 제형으로 제조될 수 있다.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.
본 발명의 제형이 페이스트, 크림 또는 겔인 경우에는 담체 성분으로서 동물성유, 식물성유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크 또는 산화아연 등이 이용될 수 있다.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 .
본 발명의 제형이 파우더 또는 스프레이인 경우에는 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄 히드록시드, 칼슘 실리케이트 또는 폴리아미드 파우더가 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본, 프로판/부탄 또는 디메틸 에테르와 같은 추진체를 포함할 수 있다.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.
본 발명의 제형이 용액 또는 유탁액인 경우에는 담체 성분으로서 용매, 용해화제 또는 유탁화제가 이용되고, 예컨대 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌글리콜, 1,3-부틸글리콜 오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르가 있다.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.
본 발명의 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상의 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라칸트 등이 이용될 수 있다.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.
본 발명의 제형이 계면-활성제 함유 클린징인 경우에는 담체 성분으로서 지방족 알코올 설페이트, 지방족 알코올 에테르 설페이트, 설포숙신산 모노에스테르, 이세티오네이트, 이미다졸리늄 유도체, 메틸타우레이트, 사르코시네이트, 지방산 아미드 에테르 설페이트, 알킬아미도베타인, 지방족 알코올, 지방산 글리세리드, 지방산 디에탄올아미드, 식물성 유, 라놀린 유도체 또는 에톡실화 글리세롤 지방산 에스테르 등이 이용될 수 있다.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.
본 발명의 조성물들은 상술한 본 발명의 EGF 펩타이드를 유효성분으로 포함하기 때문에, 이 둘 사이에 공통된 내용은 본 명세서의 과도한 복잡성을 피하기 위하여 그 기재를 생략한다.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.
본 발명에 따른 피부투과도가 개선된 상피세포성장인자의 펩타이드를 포함한 화장료 조성물을 첨부한 도면을 참고로 하여 이하 상세히 기술되는 실시예에 의하여 그 특징들을 이해할 수 있을 것이다.
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.
본 발명에 의하면, 본 발명의 EGF 펩타이드들이 포함된 화장료 조성물은, 펩타이드들의 피부투과도의 향상으로 인하여 천연형 EGF를 첨가한 화장료 조성물보다 뛰어난 피부재생 효과를 보인다.
According to the present invention, the cosmetic composition containing the EGF peptides of the present invention exhibits an excellent skin regeneration effect than the cosmetic composition containing natural EGF due to the improvement of the skin permeability of the peptides.
도 1은 in silico modeling 기법을 이용하여 각각 아미노산 잔기의 돌연변이를 주었을 때의 도킹에너지 비교 결과
도 2는 아미노산 잔기의 돌연변이의 따른 세포증식실험
도 3은 컴퓨터 시뮬레이션 방법을 통한 결합에너지 계산
도 4는 각 펩타이드들의 NIH-3T3세포 증식능 비교 그림,
도 5는 세포증식능 평가를 통하여 데카펩타이드와 천연형 EGF의 안정성을 비교한 그림,
도 6은 시간에 따른 데카펩타이드의 피부투과도 측정결과를 나타낸 그림,FIG. 1 shows a comparison of docking energies when amino acid residues are mutated using in silico modeling technique
FIG. 2 is a graph showing cell proliferation experiments due to mutation of amino acid residues
Fig. 3 is a graph showing the combined energy calculation
FIG. 4 shows the comparison of NIH-3T3 cell proliferation ability of each peptide,
FIG. 5 is a graph comparing the stability of decapeptide and native EGF by evaluating cell proliferation ability,
FIG. 6 is a graph showing skin permeability measurement results of decapeptide over time,
이하, 비한정적인 실시예를 통하여 본 발명을 더욱 상세하게 설명한다. 단 하기의 실시예는 본 발명을 예시하기 위한 의도로 기재한 것으로서 본 발명의 범위는 하기 실시예에 의하여 한정되는 것은 아니다.
Hereinafter, the present invention will 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 limited by the following examples.
실시예Example 1: 분자 1: molecule 모델링modelling
PDB(Protein data bank)에 등록된 EGF와 EGF receptor의 구조인 1IVO와 복합체의 논문(OGISO, Hideo, et al. Cell, 110.6: 775-787,2002.)을 이용하여 interaction site에 대한 분석을 실시하였다. 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) Respectively.
이중 EGF receptor와 강하게 결합하는 33번 시스테인부터 42번 시스테인까지의 구조를 얻은 후 이를 Felxpepdock(Raveh B, et al,. Proteins 78:2029-40,2010.)을 이용하여 도킹을 진행한다. 이러한 도킹의 에너지와 형태 구조를 실제 구조와 비교분석하는 평가를 선행 진행하였다. 이후 PIC(Protein interaction Calculator)를 이용, 각각의 interaction의 에너지, RMSD(root-mean-square deviation) 및 경향성을 분석하였다. 이러한 경향성을 토대로 아미노산 잔기들의 점돌연변이를 가상화 기술을 통하여 제작한 후 이를 Flexpepdock을 이용하여 도킹을 진행한 후 천연형 EGF의 33부터 42번까지 도킹에너지를 비교분석하였다. 이러한 펩타이드들이 실제로 세포활성을 갖는지 확인하기 위하여 NIH-3T3세포 증식능 실험을 진행하였다(도 2). 세포증식능 실험의 자세한 설명은 실시예 4에서 설명하기로 한다. 이러한 분석결과를 기반으로 표 1에 나와 있는 서열을 결정하였고 이에 따른 에너지를 계산하였다(도 3).After the structure from
표 1은 본 발명의 아미노산 서열 표로 각각의 펩타이드 1 내지 48은 각각 서열번호 1 내지 48에 해당됨.
Table 1 is an amino acid sequence listing of the present invention, wherein each of the
실시예Example 2: 2: CysCys -Val-Val--Val-Val- GlyGly -- TyrTyr -- IleIle -- GlyGly -- GluGlu -- ArgArg -- CysCys (( EGFEGF 데카펩타이드Decapeptide )의 합성) Synthesis of
상기의 서열을 갖는 펩타이드 제작을 위해, 먼저 Fmoc-Rink 아미드 레진(GL Biochem사, Cat No. 49001) 10 mmole을 반응용기에 넣고, 메틸렌 클로라이드 (MC) 50 ml를 가하여 20분간 교반한 후 다시 용매를 제거하였다. 탈보호용액(20%의 피페리딘/DMF) 60 ml를 반응용기에 넣고 30분간 상온에서 교반한 후 용액을 제거하고 DMF로 3회, MC로 1회 세척하였다. 새로운 반응기에 50 ml의 DMF 용액을 넣고 이어, Nsc-Cys(acm)-OH 15mmole, HoBt 15 mmole 및 HBTU 15 mmole을 넣은 후 교반하여 잘 용해시켰다. 용해된 아미노산 혼합용액을 탈보호된 레진이 있는 반응용기에 넣고, 20mmole의 DIPEA(N,N'-Diisopropyl ethylamine)를 넣고 2시간 동안 상온에서 교반하며 반응시켰다. 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-Cys (acm) -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.
반응액을 제거하고, DMF 용액으로 3회 5분씩 교반하여 미반응 잔류물을 제거하였다. 반응 레진을 소량 취하여 카이저테스트(Ninhydrine test)를 이용하여 반응 정도를 점검하였다. 탈보호 용액으로 상기와 같이 동일하게 2번 탈보호 반응시켜 Cys(acm)-Rink 아미드 레진을 제조하였다. DMF와 MC로 세척하고, 다시 한 번 카이저 테스트를 수행한 다음 상기와 동일하게 아미노산 부착 실험을 수행하였다. 선정된 아미노산 서열에 의거하여, Nsc-Arg(pbf)-OH, Nsc-Glu(tBu)-OH, Nsc-Gly-OH, Nsc-Ile-OH, Nsc-Tyr(tBu)-OH, Nsc-Gly-OH, Nsc-Val-OH, Nsc-Val-OH, Nsc-Cys(acm)-OH 순으로 연쇄 반응을 시킨 후 탈보호용액(20%의 피페리딘/DMF) 60 ml를 반응용기에 넣고 30분간 상온에서 교반한 후 용액을 제거하고 DMF로 3회, MC로 1회 세척하였다. DMF 60ml(20%-Acetic anhydride)를 넣고 상온에서 30분간 교반하면서 용액을 제거하고 DMF로 3회, MC로 3회 세척하고, 질소 공기를 흘려 건조하여 Cys(acm)-Val-Val-Gly-Tyr(tBu)-Ile-Gly-Glu(tBu)-Arg(pbf)-Cys(acm)-Rink 아미드 레진을 제조하였다.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. Cyst (acm) -Rink amide resin was prepared by the same deprotection reaction twice as the above-described deprotection solution. Washed with DMF and MC, and once again subjected to a Kaiser test, amino acid adhesion experiments were carried out in the same manner as described above. (TBu) -OH, Nsc-Gly (tBu) -OH, Nsc-Gly-OH, Nsc-Ile-OH, Nsc- (20% piperidine / DMF) was added to the reaction vessel after the chain reaction was carried out in the order of -OH, Nsc-Val-OH, Nsc-Val-OH and Nsc- After stirring for 30 minutes at room temperature, the solution was removed and washed three times with DMF and once with MC. (ACM) -Val-Val-Gly-Gly-Boc-Gly-Boc-Boc-Gly- Tyr (tBu) -Ile-Gly-Glu (tBu) -Arg (pbf) -Cys (acm) -Rink amide resin.
제조된 아미드 레진을 둥근 바닥 플라스크에 넣었다. 미리 조제한 탈루용액(TFA 81.5%, 증류수 5 %, 티오아니졸 5%, 페놀 5%, EDT 2.5% 및 TIS1%) 100 ml을 넣은 후, 상온에서 흔들어주며 2시간 반응을 유지하였다. 필터링을 하여 레진을 여과한 다음, 레진을 소량의 TFA 용액으로 세척한 후 모액과 합하였다. 감압을 이용하여 전체 볼륨이 절반 정도 남도록 증류하고, 300 ml의 차가운 에테르를 가하여 침전을 유도한 후, 원심 분리하여 침전을 모으고, 2번 더 차가운 에테르로 세척하였다. 모액을 제거하고 질소 하에서 건조하여 정제 전 데카펩타이드 (Cys-Val-Val-Gly-Tyr-Ile-Gly-Glu-Arg-Cys-NH2)를 수득하였다. 정제 전 데카펩타이드를 ID 5cm preparative LC를 통해 정제 및 동결건조하여 분말형태로 수득하였다. 정제 후 얻은 분말은 HPLC로 분석하여 순도와 질량 값을 측정하였다.
The amide resin prepared was placed in a round bottom flask. 100 ml of a previously prepared solution (TFA 81.5%, distilled
실시예Example 3: 다른 3: Other 펩타이드들의Peptides 합성 synthesis
펩타이드 1 ~ 48번까지의 서열을 갖는 펩타이드 제작을 위해 상기 실시예 2와 동일한 방법으로 합성하되, 아미노산은 서열에 부합되는 아미노산을 사용하였다. 또한 상기 표 1의 펩타이드에 N-말단 및 C-말단에 있는 아미노산 잔기에 아세틸기, 아미드기, 아스코르브산기를 양 말단에 합성한 후 이를 분석하였다. 합성된 펩타이드들의 순도와 질량값을 HPLC로 분석 측정하였다(표 2).The peptide was synthesized in the same manner as in Example 2, except that amino acids corresponding to the amino acid sequences were used for the production of peptides having sequences of
peptide
peptide
표 2는 펩타이드군을 HPLC로 분석하여 순도와 질량을 분석한 표 Table 2 shows the peptides group analyzed by HPLC and the purity and mass were analyzed
(Ac-아세틸기, As-아스코르빌기, Pl-팔미토일기)(Ac-acetyl group, As-ascorbyl group, Pl-palmitoyl group)
실시예Example 4 : NIH-3 4: NIH-3 T3T3 섬유아세포에 대한 성장효과 분석 Analysis of growth effects on fibroblasts
본 발명의 펩타이드들에 대한 섬유아세포의 성장효과를 분석하기 위해, NIH-3T3 섬유아세포주를 이용한 MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] 분석법을 이용하여 측정하였다. NIH-3T3 세포는 한국세포주은행에서 구입하였으며, 열처리된 10% BCS(bovine calf serum), 100 units/의 페니실린, 100 mg/의 스트렙토마이신이 포함된 DMEM(Dulbeco"s Modified Eagle"s Medium) 배지(D-MEM high Glucose,with L-glutamine, Sodium Pyruvate, USA)를 이용하여 유지하였다. 96-웰 조직 배양용 평판에 각 웰 당 2 x 103 세포가 되도록 NIH-3T3 세포를 분주하고 24시간 동안 37℃, 7% CO2 조건 하에서 배양하였다. 24시간 뒤 0.5% BCS, 페니실린 1%를 포함한 DMEM 배양액으로 배지를 교환한 뒤, 표준을 잡기위한 대조군(control)과 사람의 EGF, 그리고 여러 시료 펩타이드들을 물과 10% DMSO에 용해한 후 각각의 농도로 처리하고, 24시간 배양하였다. 배양 후 10 ul의 MTT 용액(EZ-CYTOX, Cell Viability, Proliferation & Cytotoxicity Assay Kit, Dogen, KOR, Cat 786-213)을 첨가하고 1시간 반응시킨 후, 450 nm에서 흡광도를 측정하여 세포의 생존상태를 측정하였다.(도 4) 이 때 펩타이드의 양끝 보호기의 유무에 따른 활성도 차이가 확인되지 않았다. 이에 이 둘 사이에 공통된 내용은 본 명세서의 과도한 복잡성을 피하기 위하여 그 기재를 생략한다.
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 (Dulbecco's Modified Eagle's Medium) medium containing 10% heat-treated bovine calf serum (BCS), 100 units / penicillin, 100 mg / (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. 4). 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.
실시예Example 5 : 5: 천연형Natural type EGFEGF 와 Wow EGFEGF 데카펩타이드의Decapeptide 안정성 분석 Stability analysis
본 발명에서 활성과 안정도를 고려하여 선정된 EGF 데카펩타이드의 대한 안정성을 분석하기 위해 20 mM sodium phosphate(pH7.0) 완충액에 EGF 데카펩타이드를 1.1 μg/ml의 농도가 되도록 용해시켰다. 천연형 EGF와의 안정성 비교를 위하여 대장균으로부터 생산 된 천연형 EGF도 20 mM sodium phosphate(pH7.0) 완충액에 1.1 μg/ml의 농도가 되도록 용해시켰다. 그리고 각각 37℃ 환경에서 방치하여 일주일 간격으로 하였다. 이를 대상으로 실시예 4의 NIH-3T3 cell line을 이용한 세포증식능 실험을 진행하여 천연형 EGF와 EGF 데카펩타이드의 안정성을 확인하였다. 이때 0일의 샘플 활성을 100% 기준으로 진행하였다. In order to analyze the stability of the selected EGF decapeptide in consideration of activity and stability, EGF decapeptide was dissolved in 20 mM sodium phosphate (pH 7.0) buffer to a concentration of 1.1 μg / ml. In order to compare the stability with the native EGF, the native EGF produced from Escherichia coli was dissolved in 20 mM sodium phosphate (pH 7.0) buffer to a concentration of 1.1 μg / ml. And left at 37 ° C in an environment of a week. The cell proliferation assay using the NIH-3T3 cell line of Example 4 was carried out to confirm the stability of natural EGF and EGF decapeptide. At this time, 0 day sample activity was performed on the basis of 100%.
도 5에서 볼 수 있듯이 일주일 간격으로 샘플링된 결과에서 천연형 EGF의 활성은 일주일이 지남에 따라 급격하게 떨어져 35일이 경과 된 날에 0일째 기준 60%정도의 활성을 보이는 반면에 EGF 데카펩타이드의 활성은 미미하게 떨어져 35일이 경과 된 후에도 85%이상의 활성을 확인할 수 있었다. 이를 토대로 천연형 EGF에 비하여 EGF 데카펩타이드의 안정도가 보다 뛰어나다는 것을 알 수 있었다. 표 3에 각 펩타이드들의 시간에 따른 안정도 측정한 결과를 표기하였다. 이때 보호기의 유무에 따라 안정도가 유의하게 증가하는 양상은 보였으나 큰 차이가 나타나지 않았다. 이에 이 둘 사이에 공통된 내용은 본 명세서의 과도한 복잡성을 피하기 위하여 그 기재를 생략한다.As can be seen in FIG. 5, the activity of native EGF was abruptly dropped over a week, and the activity of EGF decapeptide was about 35% on the
peptide Day
peptide
표 3은 각 펩타이드들의 시간에 따른 안정도(%)를 나타낸 표Table 3 is a table showing the stability (%) of each peptide over time
실시예Example 6 : 6: 천연형Natural type EGFEGF 와 Wow EGFEGF 데카펩타이드의Decapeptide 피부투과도 테스트 Skin permeability test
본 발명의 EGF 데카펩타이드에 대한 피부투과도를 확인하기 위하여 인공피부 Neoderm E (테고사이언스)와 PBS(Sigma사. Cat No. P-5368)을 준비하였다. Franz cell에 자기교반봉 (magnetic bar)을 넣고 5 ml PBS를 넣어준다. Franz cell위에 Neoderm E의 각질층(stratum corneum)이 위쪽을 향하도록 올린다. Neoderm E의 위에 Franz cell 뚜껑을 올리고 고정쇠(clamp)로 완전히 고정시킨 후, Franz cell service system에 Franz cell을 위치시킨다. Neoderm E위에 천연형 EGF와 EGF 데카펩타이드 각각 50 μg/ml의 시료 중에 500 μl 넣은 후 파라필름(parafilm)으로 봉인하고 600 rpm에서 교반기를 작동한다. 주사기를 이용하여 8시간, 12시간 별로 샘플링하여 분석할 시료를 150 μl씩 취하여 ELISA kit를 이용하여 농도를 측정하였다. 이 때 보호기의 유무에 따라 피부투과도에 있어서 눈에 띄는 차이가 나타나지 않았다. 이에 이 둘 사이에 공통된 내용은 본 명세서의 과도한 복잡성을 피하기 위하여 그 기재를 생략한다.
Artificial skin Neoderm E (Tego Science) and PBS (Sigma Co. Cat No. P-5368) were prepared to confirm the skin permeability of the EGF decapeptide of the present invention. Place magnetic bar in Franz cell and add 5 ml of PBS. Place the stratum corneum of Neoderm E on 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. Add 500 μl of each of the natural EGF and EGF decapeptide to 50 μg / ml of Neoderm E, seal it with parafilm, and operate the agitator 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.
peptide Time
peptide
표 4는 시간에 따른 펩타이드들의 피부투과도를 나타낸 표
Table 4 is a table showing skin permeability of peptides over time
<110> PnP Biopharm Co., Ltd. <120> A decapeptide having activity of Epidermal growth factor and production method therefor <130> HY151135 <160> 48 <170> KopatentIn 2.0 <210> 1 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 1 Cys Val Val Gly Tyr Ile Gly Glu Arg Cys 1 5 10 <210> 2 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 2 Cys Val Val Gly Tyr Ile Gly Gln Arg Cys 1 5 10 <210> 3 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 3 Cys Val Val Gly Tyr Met Gly Glu Arg Cys 1 5 10 <210> 4 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 4 Cys Val Val Gly Tyr Met Gly Gln Arg Cys 1 5 10 <210> 5 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 5 Cys Val Val Gly Arg Ile Gly Glu Arg Cys 1 5 10 <210> 6 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 6 Cys Val Val Gly Arg Ile Gly Gln Arg Cys 1 5 10 <210> 7 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 7 Cys Val Val Gly Arg Met Gly Glu Arg Cys 1 5 10 <210> 8 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 8 Cys Val Val Gly Arg Met Gly Gln Arg Cys 1 5 10 <210> 9 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 9 Cys Val Val Gly Glu Ile Gly Glu Arg Cys 1 5 10 <210> 10 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 10 Cys Val Val Gly Glu Ile Gly Gln Arg Cys 1 5 10 <210> 11 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 11 Cys Val Val Gly Glu Met Gly Glu Arg Cys 1 5 10 <210> 12 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 12 Cys Val Val Gly Glu Met Gly Gln Arg Cys 1 5 10 <210> 13 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 13 Cys Val Val Gly Gln Ile Gly Glu Arg Cys 1 5 10 <210> 14 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 14 Cys Val Val Gly Gln Ile Gly Gln Arg Cys 1 5 10 <210> 15 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 15 Cys Val Val Gly Gln Met Gly Glu Arg Cys 1 5 10 <210> 16 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 16 Cys Val Val Gly Gln Met Gly Gln Arg Cys 1 5 10 <210> 17 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 17 Cys Val Asp Gly Tyr Ile Gly Glu Arg Cys 1 5 10 <210> 18 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 18 Cys Val Asp Gly Tyr Ile Gly Gln Arg Cys 1 5 10 <210> 19 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 19 Cys Val Asp Gly Tyr Met Gly Glu Arg Cys 1 5 10 <210> 20 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 20 Cys Val Asp Gly Tyr Met Gly Gln Arg Cys 1 5 10 <210> 21 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 21 Cys Val Asp Gly Arg Ile Gly Glu Arg Cys 1 5 10 <210> 22 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 22 Cys Val Asp Gly Arg Ile Gly Gln Arg Cys 1 5 10 <210> 23 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 23 Cys Val Asp Gly Arg Met Gly Glu Arg Cys 1 5 10 <210> 24 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 24 Cys Val Asp Gly Arg Met Gly Gln Arg Cys 1 5 10 <210> 25 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 25 Cys Val Asp Gly Glu Ile Gly Glu Arg Cys 1 5 10 <210> 26 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 26 Cys Val Asp Gly Glu Ile Gly Gln Arg Cys 1 5 10 <210> 27 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 27 Cys Val Asp Gly Glu Met Gly Glu Arg Cys 1 5 10 <210> 28 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 28 Cys Val Asp Gly Glu Met Gly Gln Arg Cys 1 5 10 <210> 29 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 29 Cys Val Asp Gly Gln Ile Gly Glu Arg Cys 1 5 10 <210> 30 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 30 Cys Val Asp Gly Gln Ile Gly Gln Arg Cys 1 5 10 <210> 31 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 31 Cys Val Asp Gly Gln Met Gly Glu Arg Cys 1 5 10 <210> 32 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 32 Cys Val Asp Gly Gln Met Gly Gln Arg Cys 1 5 10 <210> 33 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 33 Cys Val Asn Gly Tyr Ile Gly Glu Arg Cys 1 5 10 <210> 34 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 34 Cys Val Asn Gly Tyr Ile Gly Gln Arg Cys 1 5 10 <210> 35 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 35 Cys Val Asn Gly Tyr Met Gly Glu Arg Cys 1 5 10 <210> 36 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 36 Cys Val Asn Gly Tyr Met Gly Gln Arg Cys 1 5 10 <210> 37 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 37 Cys Val Asn Gly Arg Ile Gly Glu Arg Cys 1 5 10 <210> 38 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 38 Cys Val Asn Gly Arg Ile Gly Gln Arg Cys 1 5 10 <210> 39 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 39 Cys Val Asn Gly Arg Met Gly Glu Arg Cys 1 5 10 <210> 40 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 40 Cys Val Asn Gly Arg Met Gly Gln Arg Cys 1 5 10 <210> 41 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 41 Cys Val Asn Gly Glu Ile Gly Glu Arg Cys 1 5 10 <210> 42 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 42 Cys Val Asn Gly Glu Ile Gly Gln Arg Cys 1 5 10 <210> 43 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 43 Cys Val Asn Gly Glu Met Gly Glu Arg Cys 1 5 10 <210> 44 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 44 Cys Val Asn Gly Glu Met Gly Gln Arg Cys 1 5 10 <210> 45 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 45 Cys Val Asn Gly Gln Ile Gly Glu Arg Cys 1 5 10 <210> 46 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 46 Cys Val Asn Gly Gln Ile Gly Gln Arg Cys 1 5 10 <210> 47 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 47 Cys Val Asn Gly Gln Met Gly Glu Arg Cys 1 5 10 <210> 48 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 48 Cys Val Asn Gly Gln Met Gly Gln Arg Cys 1 5 10 ≪ 110 > PnP Biopharm Co., Ltd. <120> A decapeptide having activity of Epidermal growth factor production method therefor <130> HY151135 <160> 48 <170> Kopatentin 2.0 <210> 1 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Peptide <400> 1 Cys Val Val Gly Tyr Ile Gly Glu Arg Cys 1 5 10 <210> 2 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 2 Cys Val Val Gly Tyr Ile Gly Gln Arg Cys 1 5 10 <210> 3 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 3 Cys Val Val Gly Tyr Met Gly Glu Arg Cys 1 5 10 <210> 4 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 4 Cys Val Val Gly Tyr Met Gly Gln Arg Cys 1 5 10 <210> 5 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 5 Cys Val Val Gly Arg Ile Gly Glu Arg Cys 1 5 10 <210> 6 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 6 Cys Val Val Gly Arg Ile Gly Gln Arg Cys 1 5 10 <210> 7 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 7 Cys Val Val Gly Arg Met Gly Glu Arg Cys 1 5 10 <210> 8 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 8 Cys Val Val Gly Arg Met Gly Gln Arg Cys 1 5 10 <210> 9 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 9 Cys Val Val Gly Glu Ile Gly Glu Arg Cys 1 5 10 <210> 10 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 10 Cys Val Val Gly Glu Ile Gly Gln Arg Cys 1 5 10 <210> 11 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 11 Cys Val Val Gly Glu Met Gly Glu Arg Cys 1 5 10 <210> 12 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 12 Cys Val Val Gly Glu Met Gly Gln Arg Cys 1 5 10 <210> 13 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 13 Cys Val Val Gly Gln Ile Gly Glu Arg Cys 1 5 10 <210> 14 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 14 Cys Val Val Gly Gln Ile Gly Gln Arg Cys 1 5 10 <210> 15 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 15 Cys Val Val Gly Gln Met Gly Glu Arg Cys 1 5 10 <210> 16 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 16 Cys Val Val Gly Gln Met Gly Gln Arg Cys 1 5 10 <210> 17 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 17 Cys Val Asp Gly Tyr Ile Gly Glu Arg Cys 1 5 10 <210> 18 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 18 Cys Val Asp Gly Tyr Ile Gly Gln Arg Cys 1 5 10 <210> 19 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 19 Cys Val Asp Gly Tyr Met Gly Glu Arg Cys 1 5 10 <210> 20 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 20 Cys Val Asp Gly Tyr Met Gly Gln Arg Cys 1 5 10 <210> 21 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 21 Cys Val Asp Gly Arg Ile Gly Glu Arg Cys 1 5 10 <210> 22 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 22 Cys Val Asp Gly Arg Ile Gly Gln Arg Cys 1 5 10 <210> 23 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 23 Cys Val Asp Gly Arg Met Gly Glu Arg Cys 1 5 10 <210> 24 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 24 Cys Val Asp Gly Arg Met Gly Gln Arg Cys 1 5 10 <210> 25 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 25 Cys Val Asp Gly Glu Ile Gly Glu Arg Cys 1 5 10 <210> 26 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 26 Cys Val Asp Gly Glu Ile Gly Gln Arg Cys 1 5 10 <210> 27 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 27 Cys Val Asp Gly Glu Met Gly Glu Arg Cys 1 5 10 <210> 28 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 28 Cys Val Asp Gly Glu Met Gly Gln Arg Cys 1 5 10 <210> 29 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 29 Cys Val Asp Gly Gln Ile Gly Glu Arg Cys 1 5 10 <210> 30 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 30 Cys Val Asp Gly Gln Ile Gly Gln Arg Cys 1 5 10 <210> 31 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 31 Cys Val Asp Gly Gln Met Gly Glu Arg Cys 1 5 10 <210> 32 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 32 Cys Val Asp Gly Gln Met Gly Gln Arg Cys 1 5 10 <210> 33 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 33 Cys Val Asn Gly Tyr Ile Gly Glu Arg Cys 1 5 10 <210> 34 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 34 Cys Val Asn Gly Tyr Ile Gly Gln Arg Cys 1 5 10 <210> 35 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 35 Cys Val Asn Gly Tyr Met Gly Glu Arg Cys 1 5 10 <210> 36 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 36 Cys Val Asn Gly Tyr Met Gly Gln Arg Cys 1 5 10 <210> 37 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 37 Cys Val Asn Gly Arg Ile Gly Glu Arg Cys 1 5 10 <210> 38 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 38 Cys Val Asn Gly Arg Ile Gly Gln Arg Cys 1 5 10 <210> 39 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 39 Cys Val Asn Gly Arg Met Gly Glu Arg Cys 1 5 10 <210> 40 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 40 Cys Val Asn Gly Arg Met Gly Gln Arg Cys 1 5 10 <210> 41 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 41 Cys Val Asn Gly Glu Ile Gly Glu Arg Cys 1 5 10 <210> 42 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 42 Cys Val Asn Gly Glu Ile Gly Gln Arg Cys 1 5 10 <210> 43 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 43 Cys Val Asn Gly Glu Met Gly Glu Arg Cys 1 5 10 <210> 44 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 44 Cys Val Asn Gly Glu Met Gly Gln Arg Cys 1 5 10 <210> 45 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 45 Cys Val Asn Gly Gln Ile Gly Glu Arg Cys 1 5 10 <210> 46 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 46 Cys Val Asn Gly Gln Ile Gly Gln Arg Cys 1 5 10 <210> 47 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 47 Cys Val Asn Gly Gln Met Gly Glu Arg Cys 1 5 10 <210> 48 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 48 Cys Val Asn Gly Gln Met Gly Gln Arg Cys 1 5 10
Claims (10)
(a) a cosmetically effective amount of the peptide of any one of claims 1 to 4; And (b) a pharmaceutically acceptable carrier.
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| KR1020150131187A KR101873816B1 (en) | 2015-09-16 | 2015-09-16 | A decapeptide having activity of Epidermal growth factor and production method therefor |
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