KR20240072327A - A peptide having an excellent collagen proliferation effect and a composition for improving skin wrinkles comprising the same - Google Patents
A peptide having an excellent collagen proliferation effect and a composition for improving skin wrinkles comprising the same Download PDFInfo
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- KR20240072327A KR20240072327A KR1020220150317A KR20220150317A KR20240072327A KR 20240072327 A KR20240072327 A KR 20240072327A KR 1020220150317 A KR1020220150317 A KR 1020220150317A KR 20220150317 A KR20220150317 A KR 20220150317A KR 20240072327 A KR20240072327 A KR 20240072327A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
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- 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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- 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
- 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
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Abstract
본 발명은 콜라겐 증식 활성을 갖는 펩타이드 및 이를 포함하는 피부 주름개선용 조성물에 관한 것이다.
본 발명에 따른 펩타이드는 하기 화학식 I의 구조를 갖는다.
[화학식 I]
본 발명의 신규한 펩타이드는 콜라겐 증식 효과가 뛰어나므로, 인체 적용시 본래의 기능을 효과적으로 발휘할 수 있어, 의약, 화장품, 기능성 식품 분야에서 유용하게 이용될 수 있다.The present invention relates to a peptide having collagen proliferation activity and a composition for improving skin wrinkles containing the same.
The peptide according to the present invention has the structure of formula (I) below.
[Formula I]
Since the novel peptide of the present invention has an excellent collagen proliferation effect, it can effectively exert its original function when applied to the human body, and can be usefully used in the fields of medicine, cosmetics, and functional foods.
Description
본 발명은 콜라겐 증식 활성을 갖는 펩타이드 및 이를 포함하는 피부 주름개선용 조성물에 관한 것이다.The present invention relates to a peptide having collagen proliferation activity and a composition for improving skin wrinkles containing the same.
펩타이드는 바이오의 핵심소재로 단백질의 기능적 최소 단위이며, 아미노산이 2개로부터 50개 이하로 구성된다. 소량으로 우수한 효능을 보일 뿐만 아니라 독성이 없어 의약품, 식품 및 화장품의 주요 원료로 많이 활용되고 있다. 특히 인체에 안전하고 효과가 좋은 펩타이드 화장품 소재는 날로 사용량이 늘어날 뿐만 아니라 새로운 소재의 개발은 수입대체 효과 등 당 산업에서 매우 중요하다고 할 수 있다.Peptides are core biomaterials and the minimum functional unit of proteins, and consist of 2 to 50 amino acids. Not only does it show excellent efficacy in small amounts, but it is also non-toxic, so it is widely used as a major raw material for medicines, foods, and cosmetics. In particular, not only is the use of peptide cosmetic materials that are safe and effective for the human body increasing day by day, but the development of new materials is very important in the industry, including the import substitution effect.
화장품 원료로 사용하는 펩타이드의 효능은 주로 콜라겐 증식, 미백 및 항염등의 효능을 단독으로 가지는 소재가 주를 이루고 있으며 비교적 고가 소재이기 때문에 사용량에 제한이 있는 실정이다. 이러한 항산화, 항염, 콜라겐 증식, 미백 등 다양한 효능을 하나의 펩타이드를 통해 발현할 수 있을 뿐만 아니라 비교적 짧은 서열로 구성되어 대량 생산을 통해 상업화가 가능하다면 관련 분야에서 다양하게 활용 가능하다. The effectiveness of peptides used as cosmetic raw materials mainly consists of materials that have effects such as collagen proliferation, whitening, and anti-inflammatory, and because they are relatively expensive materials, the amount of use is limited. Not only can various effects such as antioxidant, anti-inflammatory, collagen proliferation, and whitening be expressed through a single peptide, but it is composed of a relatively short sequence, so if it can be commercialized through mass production, it can be used in a variety of related fields.
피부 주름을 생기게 하는 내부적 요소로는 나이와 노화 유전자, 피부 속 탄력 섬유, 결합 조직, 근육 퇴화, 피하지방 감소, 혈액순환 저하, 피지 분비 감소, 수분 감소 등이 있다.Internal factors that cause skin wrinkles include age and aging genes, elastic fibers in the skin, connective tissue, muscle degeneration, decrease in subcutaneous fat, decreased blood circulation, decreased sebum secretion, and decreased moisture.
이와 같은 피부 주름개선용으로 사용되는 대표적인 원료로는 레티놀, 레티닐팔미테이트, 아데노신, 폴리에톡실레이티드 레틴아마이드 등으로 식품의약품안전처에서 주름 개선 기능을 인정한 것들이다. 이런 성분은 대부분 피부 주름의 원인인 콜라겐 부족, 탄력섬유 손상 등의 문제를 해결해 피부 재생을 돕는다.Representative raw materials used to improve skin wrinkles include retinol, retinyl palmitate, adenosine, and polyethoxylated retinamide, which are recognized by the Ministry of Food and Drug Safety for their wrinkle-improving function. Most of these ingredients help skin regeneration by solving problems such as lack of collagen and damage to elastic fibers, which are causes of skin wrinkles.
그러나 이와 같은 기능성 원료들은 주로 천연물 추출물이나 케미칼에 한정되어 있어 보다 인체 친화적인 소재가 절실하게 필요한 상황이다.However, these functional raw materials are mainly limited to natural extracts or chemicals, so more human-friendly materials are desperately needed.
한국등록특허 제10-1173412호에는 유기농 에버라스팅의 미생물 발효를 통한 저분자 펩타이드를 함유하는 피부 보호 및 주름개선 화장료 조성물을 개시하고 있으나, 미생물 발효에 의한 것으로 고분자량의 펩타이드를 특정하여 사업화가 용이하지 못한 단점이 있다.Korean Patent No. 10-1173412 discloses a skin protection and wrinkle improvement cosmetic composition containing low-molecular-weight peptides obtained through microbial fermentation of Organic Everlasting. However, commercialization is not easy due to the specification of high-molecular-weight peptides due to microbial fermentation. There is a downside to this.
또한, 한국등록특허 제10-0753472호에는 사람 콜라겐 Ⅰ형의 Ｃ-말단에서 유래된 펩타이드에 ＴＡＴ 펩타이드가 결합된 융합펩타이드를 포함하는 피부주름개선 화장료 조성물을 개시하고 있으나, 서열이 길고 수율이 낮아 상업화 하기에는 많은 문제점이 있다.In addition, Korean Patent No. 10-0753472 discloses a skin wrinkle-improving cosmetic composition containing a fusion peptide in which a TA peptide is bound to a peptide derived from the C-terminus of human collagen type I, but the sequence is long and the yield is low. There are many problems with commercialization.
이에, 본 발명자들은 상기 문제점을 해결하기 위하여 노력한 결과, 신규 아미노산 서열을 갖는 펩타이드가 프로콜라겐을 생성함으로서, 우수한 콜라겐 증식 효과를 갖는다는 것을 확인하고, 본 발명을 완성하게 되었다.Accordingly, as a result of efforts to solve the above problem, the present inventors confirmed that a peptide with a novel amino acid sequence produces procollagen and has an excellent collagen proliferation effect, thereby completing the present invention.
본 발명의 목적은 우수한 콜라겐 증식 효능을 갖는 신규 펩타이드 및 이의 용도를 제공하는 데 있다.The purpose of the present invention is to provide a novel peptide with excellent collagen proliferation effect and its use.
본 발명의 다른 목적은 주름개선용 조성물을 제공하는 데 있다.Another object of the present invention is to provide a composition for improving wrinkles.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 I의 구조를 갖는 펩타이드를 제공한다.In order to achieve the above object, the present invention provides a peptide having the structure of formula (I) below.
[화학식 I][Formula I]
본 발명에 있어서, 상기 펩타이드는 프로콜라겐 생성 활성을 갖는 것을 특징으로 한다.In the present invention, the peptide is characterized as having procollagen producing activity.
본 발명은 또한, 상기 펩타이드를 포함하는 피부 주름개선용 조성물을 제공한다.The present invention also provides a composition for improving skin wrinkles containing the above peptide.
본 발명에 있어서, 상기 조성물은 약학용, 화장용 또는 건강기능식품용 피부 주름개선용 조성물인 것을 특징으로 한다.In the present invention, the composition is characterized as a composition for improving skin wrinkles for pharmaceutical, cosmetic or health functional food purposes.
본 발명의 신규한 펩타이드는 프로콜라겐 생성 활성이 우수하여 피부 주름개선 효과가 뛰어나므로, 인체 적용시 본래의 기능을 효과적으로 발휘할 수 있어, 의약, 화장품, 기능성 식품 분야에서 유용하게 이용될 수 있다.The novel peptide of the present invention has excellent procollagen production activity and has an excellent skin wrinkle improvement effect, so it can effectively exert its original function when applied to the human body, and can be usefully used in the fields of medicine, cosmetics, and functional foods.
도 1은 본 발명에 따른 펩타이드의 분자량 측정(MALDI-TOF MS) 결과이다.
도 2는 본 발명에 따른 펩타이드의 순도를 측정한 HPLC Chromatorgam 결과이다.
도 3은 본 발명에 따른 펩타이드의 HS68 세포에 대한 독성을 평가한 결과이다.
도 4는 본 발명에 따른 펩타이드의 프로콜라겐 생성 활성을 평가한 결과이다. Figure 1 shows the results of molecular weight measurement (MALDI-TOF MS) of a peptide according to the present invention.
Figure 2 shows the HPLC Chromatorgam results measuring the purity of the peptide according to the present invention.
Figure 3 shows the results of evaluating the toxicity of the peptide according to the present invention to HS68 cells.
Figure 4 shows the results of evaluating the procollagen production activity of the peptide according to the present invention.
본 명세서에서 특별한 표시가 없는 한, 아미노산 및 보호기의 지정에 사용되는 약어는 IUPAC-IUB의 생화학 용어 위원회 (Commission of Biochemical Nomenclature)에서 권장하는 용어에 기초한다 (Bioche mistry, 11:1726-1732(1972); Pure & Appl. Chem., Vol. 56, No. 5, pp. 595-624, 1984).Unless otherwise specified herein, the abbreviations used to designate amino acids and protecting groups are based on the terminology recommended by the Commission of Biochemical Nomenclature of IUPAC-IUB ( Bioche mistry, 11:1726-1732 (1972) ); Pure & Chem., Vol. 56, pp. 595-624.
본 명세서에서 용어 “펩타이드”는 펩타이드 결합에 의해 아미노산 잔기들이 서로 결합되어 형성된 선형의 분자를 의미한다.As used herein, the term “peptide” refers to a linear molecule formed by linking amino acid residues together through peptide bonds.
본 명세서에서 사용한 용매, 시약, 보호기 및 아미노산의 약어는 다음과 같다:The abbreviations for solvents, reagents, protecting groups and amino acids used herein are as follows:
Arg: 아르기닌 (Arginine)Arg: Arginine
AcOH: 아세틱 엑시드 (Acetic acid)AcOH: Acetic acid
Boc: 터트-부틸옥시카르보닐기 (tert-Butyloxycarbonyl)Boc: tert-Butyloxycarbonyl group (tert-Butyloxycarbonyl)
DCM: 디클로로메탄 (Dichloromethane)DCM: Dichloromethane
DMF: 디메틸포름아미드 (N,N-Dimethylformamide)DMF: Dimethylformamide (N,N-Dimethylformamide)
DMSO: 디메틸설폭시드 (Dimethylsulfoxide)DMSO: Dimethylsulfoxide
DTT: 디티올쓰레이톨 (Dithiolthreitol)DTT: Dithiolthreitol
EDT: 1,2-에탄디티올 (1,2-Ethanedithiol)EDT: 1,2-Ethanedithiol
Fmoc: 9-플루오레닐옥시카보닐 (9-Fluorenyloxycarbonyl)Fmoc: 9-Fluorenyloxycarbonyl
Gly: 글라이신 (Glycine)Gly: Glycine
His: 히스티딘 (Histidine)His: Histidine
HPLC: 고성능액체크로마토그래피 (High Performance Liquid Chromatography)HPLC: High Performance Liquid Chromatography
OtBu: O-터트-부틸(O-tert-Butyl)OtBu: O-tert-Butyl
t-Bu: 터트-부틸 (tert-Butyl)t-Bu: tert-Butyl
Trt: 트리페닐메틸 (또는 트리틸) (Triphenylmethyl or Trityl)Trt: Triphenylmethyl or Trityl
Pbf: 2,2,4,6,7-펜타메틸-디히드로벤조퓨란-5-설포닐 (2,2,4,6,7-Pentamethyl-dihydrobenzofuran-5-sulfonyl)Pbf: 2,2,4,6,7-Pentamethyl-dihydrobenzofuran-5-sulfonyl (2,2,4,6,7-Pentamethyl-dihydrobenzofuran-5-sulfonyl)
Pmc: 2,2,5,7,8-펜타메틸크로만-6-설포닐 (2,2,5,7,8-Pentamethylchroman-6-sulfonyl)Pmc: 2,2,5,7,8-Pentamethylchroman-6-sulfonyl (2,2,5,7,8-Pentamethylchroman-6-sulfonyl)
Mtr: 4-메톡시-2,3,6-트리메틸페닐-설포닐 (4-Methoxy-2,3,6-trimethylphenyl-sulfonyl)Mtr: 4-Methoxy-2,3,6-trimethylphenyl-sulfonyl (4-Methoxy-2,3,6-trimethylphenyl-sulfonyl)
TIS: 트리이소프로필실란 (Triisopropylsilane)TIS: Triisopropylsilane
Tos: 파라-톨루엔설포닐 (para-Toluenesulfonyl)Tos: para-Toluenesulfonyl
Trp: 트립토판 (Tryptophan)Trp: Tryptophan
TES: 트라이에틸실란 (Triethylsilane)TES: Triethylsilane
TFA: 트라이플루오로아세틱 엑시드 (Trifluoroacetic acid)TFA: Trifluoroacetic acid
TIPS: 트리이소프로필실란 (Triisopropylsilane)TIPS: Triisopropylsilane
본 발명에서는 피부주름 개선 효과를 갖는 펩타이드를 연구, 개발하는 과정에서 특정 서열을 갖는 펩타이드가 프로콜라겐을 생성함으로서, 우수한 콜라겐 증식 효과를 갖는다는 것을 확인하였다.In the process of researching and developing peptides with skin wrinkle improvement effects, the present invention confirmed that peptides with a specific sequence produce procollagen and have an excellent collagen proliferation effect.
따라서, 본 발명은 일 관점에서 하기 화학식 I의 구조를 갖는 펩타이드에 관한 것이다. Accordingly, in one aspect, the present invention relates to a peptide having the structure of formula (I):
[화학식 I][Formula I]
상기 화학식 I의 펩타이드는 H-His-Arg-Trp-Arg-His-Gly-His-Lys-OH의 서열을 가진 신규한 펩타이드이다.The peptide of Formula I is a novel peptide with the sequence H-His-Arg-Trp-Arg-His-Gly-His-Lys-OH.
본 발명에 있어서, 상기 화학식 I의 신규 펩타이드는 당 업계에 알려진 기술을 사용하여 제조할 수 있다. 대표적인 합성방법을 아래에 설명하고 있으나, 본 발명이 이러한 예에 제한되는 것은 아니며, 당 업계에 알려진 기술의 범위 내에서 당 업자가 적절히 변형하여 사용할 수 있다.In the present invention, the novel peptide of Formula I can be prepared using techniques known in the art. Representative synthetic methods are described below, but the present invention is not limited to these examples, and those skilled in the art may appropriately modify and use them within the scope of techniques known in the art.
상기 목적을 달성하기 위하여, 본 발명은 (a) H-Lys(Boc)-O-Resin(2-Chlorotrityl)에 Fmoc-His(Trt)-OH를 결합하여 화학식 I-a로 표시되는 H-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl)을 얻는 단계; (b) 상기 단계 (a)에서 수득한 레진에 아미노산 (Fmoc-His(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-His(Trt)-OH, Fmoc-Gly-OH)을 순서적으로 결합하여 화학식 I-b로 표시되는 보호기를 가진 레진에 결합된 펩타이드를 얻는 단계; (c) 상기 단계 (b)에서 수득한 보호화된 펩타이드가 결합된 레진으로부터 탈 보호화 공정을 거쳐 화학식 I-c로 표시되는 탈보호화된 Crude 펩타이드를 수득하는 단계; 및 (d) 상기 단계 (c)에서 수득한 비 정제 (Crude)된 펩타이드를 고성능액체크로마토그래피 (HPLC)로 정제하여 화학식 I로 표시되는 펩타이드를 얻는 단계를 포함하는 펩타이드의 제조방법을 제공한다.In order to achieve the above object, the present invention combines Fmoc-His(Trt)-OH with (a) H-Lys(Boc)-O-Resin(2-Chlorotrityl) to form H-His(Trt) represented by formula I-a. )-Lys(Boc)-O-Resin(2-Chlorotrityl); (b) Amino acids (Fmoc-His(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Arg(Pbf)-OH) in the resin obtained in step (a) , Fmoc-His(Trt)-OH, Fmoc-Gly-OH) to obtain a peptide bound to a resin having a protecting group represented by Formula I-b; (c) obtaining a deprotected crude peptide represented by Formula I-c through a deprotection process from the resin to which the protected peptide obtained in step (b) is bound; and (d) purifying the crude peptide obtained in step (c) by high-performance liquid chromatography (HPLC) to obtain a peptide represented by Formula I.
[화학식 I-a] [Formula I-a]
[화학식 I-b][Formula I-b]
[화학식 I-c][Formula I-c]
[화학식 I][Formula I]
본 발명에 있어서, 상기 화학식 I로 표시되는 펩타이드는 고체상 합성법으로 합성하는 것을 특징으로 한다.In the present invention, the peptide represented by Formula I is characterized by being synthesized by solid phase synthesis.
상기 화학식 I-b에서 R₁은 당 업계에서 통상적으로 방향족의 아민 보호기를 이용할 수 있다. 상기 아민 보호기는 메톡시메틸 (Methoxymethyl)기, 벤질옥시메틸 (Benzyloxymethyl)기, 트리페닐메틸 (Triphenylmethyl)기, 터트-부틸디메틸실릴 (tert-Butyldimethylsilyl)기, 트리페닐실릴 (Triphenylsily)기, 트리이소프로필실릴 (Triispropylsilyl)기, 파라-메톡시벤질 (para-Methylxybenzyl)기, 테트라히드로피란 (Tetrahydropyran)기, 테트라히드로퓨란 (Tetrahydrofuran)기, 터트-부틸 (tert-Butyl)기, 디페닐메틸 (Diphenylmethyl)기, 2-클로로트리틸 (2-Chlorotrityl)기, 벤질 (Benzyl)기, 4-메톡시벤질 (4-Methoxybenzyl)기, 알릴 (Allyl)기, 터트-부틸옥시카르보닐 (tert-Butyloxycarbonyl)기, 아세틸 (Acetyl)기, 벤조일 (Benzoyl)기 등을 예시할 수 있으며, 메톡시메틸 (Methoxymethyl)기, 벤질옥시메틸 (Benzyloxymethyl)기, 트리페닐메틸 (Triphenylmethyl)기, 터트-부틸디메틸실릴 (tert-Butyldimethylsilyl)기, 트리페닐실릴 (Triphenylsily)기 또는 트리이소프로필실릴 (Triisopropylsilyl)기를 이용하는 것이 바람직하며, 2-클로로트리틸 (2-Chlorotrityl)기 또는 트리페닐메틸 (Triphenylmethyl)기를 이용하는 것이 보다 바람직하며, 아민 보호기가 트리페닐메틸 (Triphenylmethyl)기를 이용하는 것이 가장 바람직하지만 이에 국한되는 것은 아니다.In the above formula (I-b), R₁ can commonly use an aromatic amine protecting group in the industry. The amine protecting group is methoxymethyl group, benzyloxymethyl group, triphenylmethyl group, tert-Butyldimethylsilyl group, triphenylsilyl group, triiso Triispropylsilyl group, para-Methylxybenzyl group, Tetrahydropyran group, Tetrahydrofuran group, tert-Butyl group, Diphenylmethyl ) group, 2-Chlorotrityl group, Benzyl group, 4-Methoxybenzyl group, Allyl group, tert-Butyloxycarbonyl Group, acetyl (Acetyl) group, benzoyl (Benzoyl) group, etc. can be exemplified, methoxymethyl group, benzyloxymethyl group, triphenylmethyl group, tert-butyldimethylsilyl ( It is preferable to use a tert-Butyldimethylsilyl group, a triphenylsilyl group, or a triisopropylsilyl group, and it is more preferable to use a 2-Chlorotrityl group or a triphenylmethyl group. It is most preferable that the amine protecting group uses a triphenylmethyl group, but it is not limited to this.
상기 화학식 I-b에서, R₂는 당 업계에서 통상적으로 이용하는 구아니딘 (Guanidine) 보호기를 이용할 수 있다. 상기 구아니딘 보호기는 터트-부틸옥시카보닐기 (tert-Butyloxycarbonyl), 벤질옥시카보닐기 (Benzyloxycarbonyl), 메톡시메틸기 (Methoxymethyl), 벤질옥시메틸기 (Benzyloxymethyl), 트리페닐메틸기 (Triphenylmethyl), 벤질기 (Benzyl), 알릴기 (Allyl), 터트-부틸디메틸실릴기 (tert-Butylmethylsillyl), 트리페닐실릴기 (Triphenylsillyl), 디메틸페닐기 (Dimethylphenyl), 트리이소프로필실릴기 (Triisopropylsillyl), 니트로기 (Nitro), Pmc (2,2,5,7,8-pentamethylchroman-6-sulfonyl), Mtr ((4-methoxy-2,3,6-trimethylphenyl)sulfonyl), Pbf (2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl) 또는 Tos (para-toluenesulfonyl) 기를 이용할 수 있으며, 바람직하게는 Pmc (2,2,5,7,8-pentamethylchroman-6-sulfonyl), Mtr ((4-methoxy-2,3,6-trimethylphenyl)sulfonyl), Pbf (2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl)이며, 구아니딘의 보호기가 Pbf (2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl)가 가장 바람직하지만 이에 국한되는 것은 아니다.In Formula I-b, R₂ may use a guanidine protecting group commonly used in the industry. The guanidine protecting group is tert-Butyloxycarbonyl, benzyloxycarbonyl, methoxymethyl, benzyloxymethyl, triphenylmethyl, and benzyl. , Allyl, tert-Butylmethylsilyl, Triphenylsilyl, Dimethylphenyl, Triisopropylsilyl, Nitro, Pmc ( 2,2,5,7,8-pentamethylchroman-6-sulfonyl), Mtr ((4-methoxy-2,3,6-trimethylphenyl)sulfonyl), Pbf (2,2,4,6,7-pentamethyldihydrobenzofuran-5 -sulfonyl) or Tos (para-toluenesulfonyl) groups can be used, preferably Pmc (2,2,5,7,8-pentamethylchroman-6-sulfonyl), Mtr ((4-methoxy-2,3,6- trimethylphenyl)sulfonyl), Pbf (2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl), and the protecting group of guanidine is most preferably Pbf (2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl) But it is not limited to this.
상기 화학식 I-b에서 R₃는 당 업계에서 통상적으로 이용하는 트립토판의 이민 보호기를 이용할 수 있다. 상기 이민 보호기는 메톡시메틸 (Methoxymethyl)기, 벤질옥시메틸 (Benzyloxymethyl)기, 트리페닐메틸 (Triphenylmethyl)기, 터트-부틸디메틸실릴 (tert-Butyldimethylsilyl)기, 트리페닐실릴 (Triphenylsily)기, 트리이소프로필실릴 (Triispropylsilyl)기, 파라-메톡시벤질 (para-Methylxybenzyl)기, 테트라히드로피란 (Tetrahydropyran)기, 테트라히드로퓨란 (Tetrahydrofuran)기, 터트-부틸 (tert-Butyl)기, 디페닐메틸 (Diphenylmethyl)기, 2-클로로트리틸 (2-Chlorotrityl)기, 벤질 (Benzyl)기, 4-메톡시벤질 (4-Methoxybenzyl)기, 알릴 (Allyl)기, 터트-부틸옥시카르보닐 (tert-Butyloxycarbonyl)기, 아세틸 (Acetyl)기, 벤조일 (Benzoyl)기 등을 예시할 수 있으며, 메톡시메틸 (Methoxymethyl)기, 벤질옥시메틸 (Benzyloxymethyl)기, 벤질옥시카르보닐 (Benzyloxycarbonyl), 파라-메톡시벤질옥시카르보닐 (para-Methoxybenzyloxycarbonyl), 트리페닐메틸 (Triphenylmethyl)기, 터트-부틸디메틸실릴 (tert-Butyldimethylsilyl)기, 트리페닐실릴 (Triphenylsily)기 또는 트리이소프로필실릴 (Triisopropylsilyl)기를 이용하는 것이 바람직하며, 터트-부틸 (tert-Butyl) 또는 터트-부틸옥시카르보닐 (tert-Butyloxycarbonyl)기를 이용하는 것이 보다 바람직하며, 이민 보호기가 터트-부틸옥시카르보닐 (tert-Butyloxycarbonyl)기를 이용하는 것이 가장 바람직하지만 이에 국한되는 것은 아니다.In the above formula (I-b), R₃ can use the imine protecting group of tryptophan commonly used in the industry. The imine protecting group is a methoxymethyl group, a benzyloxymethyl group, a triphenylmethyl group, a tert-Butyldimethylsilyl group, a triphenylsilyl group, and a triiso Triispropylsilyl group, para-Methylxybenzyl group, Tetrahydropyran group, Tetrahydrofuran group, tert-Butyl group, Diphenylmethyl ) group, 2-Chlorotrityl group, Benzyl group, 4-Methoxybenzyl group, Allyl group, tert-Butyloxycarbonyl Group, acetyl (Acetyl) group, benzoyl (Benzoyl) group, etc. can be exemplified, methoxymethyl group, benzyloxymethyl group, benzyloxycarbonyl (Benzyloxycarbonyl), para-methoxybenzyloxy group. It is preferable to use carbonyl (para-Methoxybenzyloxycarbonyl), triphenylmethyl, tert-Butyldimethylsilyl, triphenylsilyl, or triisopropylsilyl. -It is more preferable to use a tert-Butyl or tert-Butyloxycarbonyl group, and it is most preferable for the imine protecting group to use a tert-Butyloxycarbonyl group, but it is limited to this. no.
상기 화학식 I-b에서, R₄는 당 업계에서 통상적으로 이용하는 아민 보호기를 이용할 수 있다. 상기 아민 보호기는 메톡시메틸 (Methoxymethyl)기, 벤질옥시메틸 (Benzyloxymethyl)기, 트리페닐메틸 (Triphenylmethyl)기, 터트-부틸디메틸실릴 (tert-Butyldimethylsilyl)기, 트리페닐실릴 (Triphenylsily)기, 트리이소프로필실릴 (Triispropylsilyl)기, 파라-메톡시벤질 (para-Methylxybenzyl)기, 테트라히드로피란 (Tetrahydropyran)기, 테트라히드로퓨란 (Tetrahydrofuran)기, 터트-부틸 (tert-Butyl)기, 디페닐메틸 (Diphenylmethyl)기, 2-클로로트리틸 (2-Chlorotrityl)기, 벤질 (Benzyl)기, 4-메톡시벤질 (4-Methoxybenzyl)기, 알릴 (Allyl)기, 터트-부틸옥시카르보닐 (tert-Butyloxycarbonyl)기, 아세틸 (Acetyl)기, 벤조일 (Benzoyl)기 등을 예시할 수 있으며, 메톡시메틸 (Methoxymethyl)기, 벤질옥시메틸 (Benzyloxymethyl)기, 벤질옥시카르보닐 (Benzyloxycarbonyl), 파라-메톡시벤질옥시카르보닐 (para-Methoxybenzyloxycarbonyl), 트리페닐메틸 (Triphenylmethyl)기, 터트-부틸디메틸실릴 (tert-Butyldimethylsilyl)기, 트리페닐실릴 (Triphenylsily)기 또는 트리이소프로필실릴 (Triisopropylsilyl)기를 이용하는 것이 바람직하며, 터트-부틸 (tert-Butyl) 또는 터트-부틸옥시카르보닐 (tert-Butyloxycarbonyl)기를 이용하는 것이 보다 바람직하며, 아민 보호기가 터트-부틸옥시카르보닐 (tert-Butyloxycarbonyl)기를 이용하는 것이 가장 바람직하지만 이에 국한되는 것은 아니다.In the above formula (I-b), R₄ can use an amine protecting group commonly used in the art. The amine protecting group is methoxymethyl group, benzyloxymethyl group, triphenylmethyl group, tert-Butyldimethylsilyl group, triphenylsilyl group, triiso Triispropylsilyl group, para-Methylxybenzyl group, Tetrahydropyran group, Tetrahydrofuran group, tert-Butyl group, Diphenylmethyl ) group, 2-Chlorotrityl group, Benzyl group, 4-Methoxybenzyl group, Allyl group, tert-Butyloxycarbonyl Group, acetyl (Acetyl) group, benzoyl (Benzoyl) group, etc. can be exemplified, methoxymethyl group, benzyloxymethyl group, benzyloxycarbonyl (Benzyloxycarbonyl), para-methoxybenzyloxy group. It is preferable to use carbonyl (para-Methoxybenzyloxycarbonyl), triphenylmethyl, tert-Butyldimethylsilyl, triphenylsilyl, or triisopropylsilyl. -It is more preferable to use a tert-Butyl or tert-Butyloxycarbonyl group, and it is most preferable for the amine protecting group to use a tert-Butyloxycarbonyl group, but it is limited to this. no.
이하, 상기 합성 방법을 단계별로 좀 더 상세히 설명한다.Hereinafter, the synthesis method will be described step by step in more detail.
고체상 펩타이드 합성방법은;The solid phase peptide synthesis method is;
1) 라이신이 결합된 레진을 Swelling하고 보호화된 두 번째 서열의 아미노산을 레진에 붙이는 단계;1) Swelling the lysine-bound resin and attaching the protected amino acid of the second sequence to the resin;
2) 아미노산 보호기(N-말단의 아미노기)를 염기(피페리딘)로 처리하여 제거하고 레진을 세척하는 단계;2) removing the amino acid protecting group (N-terminal amino group) by treating it with a base (piperidine) and washing the resin;
3) 결합을 위한 시약과 함께 보호화된 아미노산을 세척된 레진에 반응시켜 결합하는 단계;3) reacting the protected amino acid with a binding reagent to the washed resin to bind it;
4) 상기 2) 및 3)의 단계를 반복하여 서열 순서대로 합성하는 단계;4) repeating steps 2) and 3) to synthesize in sequence order;
5) 레진 및 구성 아미노산들의 보호기를 동시에 제거하는 단계; 5) simultaneously removing the protecting groups of the resin and constituent amino acids;
6) 펩타이드를 용매로 고체화하여 얻은 다음 정제하는 단계; 및6) Solidifying the peptide with a solvent and then purifying it; and
7) 정제된 펩타이드를 농축하고 동결건조하여 수득하는 단계를 포함할 수 있다. 7) It may include the step of concentrating and freeze-drying the purified peptide.
단계 1)에 있어서, 사용할 수 있는 레진으로는 2-클로로트리틸클로라이드 레진 (2-Chlorotritylchloride Resin), 왕 레진 (Wang Resin), 디에이치피피 레진 (DHPP Resin, 4-(1’,1’-dimethyl-1’-hydroxypropyl)phenoxyacetyl alanyl aminomethyl polystyrene), 피디디엠 레진 (PDDM Resin, Diphenyldiazomethane Resin), 사스린 레진 (SASRIN Resin, 2-Methoxy-4-alkoxybenzyl alcohol Resin)으로 구성된 군에서 선택되는 1 이상의 것을 들 수 있다. In step 1), resins that can be used include 2-Chlorotritylchloride Resin, Wang Resin, and DHPP Resin, 4-(1',1'- At least one selected from the group consisting of dimethyl-1'-hydroxypropyl)phenoxyacetyl alanyl aminomethyl polystyrene), PDDM Resin (Diphenyldiazomethane Resin), and SASRIN Resin (2-Methoxy-4-alkoxybenzyl alcohol Resin) I can hear it.
단계 1)에 있어서, 사용되는 용매로는 디클로로메탄 (Dichloromethane), N,N-디메틸포름아마이드 (N,N-Dimethylformamide), N,N-디메틸아세트아마이드 (N,N-Dimethylacetamide), N-메틸피롤리돈 (N-Methylpyrrolidone), 클로로포름 (Chloroform), 1,2-디클로로에탄 (1,2-Dichloroethane), 테트라히드로퓨란 (Tetrahydrofurane), 1,4-디옥산 (1,4-Dioxane), 아세토니트릴 (Acetonitrile), 메탄올 (Methanol), 에탄올 (Ethanol), 이소프로판올 (Isopropanol), 에틸렌 글리콜 (Ethylene glycol), 메틸 아세테이트 (Methyl acetate), 에틸 아세테이트 (Ethyl acetate) 등으로 구성된 군에서 선택되는 1 이상의 것을 들 수 있다.In step 1), the solvents used are dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl. N-Methylpyrrolidone, Chloroform, 1,2-Dichloroethane, Tetrahydrofurane, 1,4-Dioxane, Aceto At least one selected from the group consisting of Acetonitrile, Methanol, Ethanol, Isopropanol, Ethylene glycol, Methyl acetate, Ethyl acetate, etc. I can hear it.
단계 2)에 있어서, 사용되는 보호기를 제거하는 염기로는 피페리딘 (Piperidine), 피롤리딘 (Pyrrolidine), 피페라진 (Piperazine), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), 4-메틸피페리딘 (4-Methylpiperidine), 몰포린 (Morpholine), 1-메틸-3-부틸이미다졸리윰 테트라플로오로보란 (1-methyl-3-butyl imidazolium BF4), 에탄올아민 (Ethanolamine), 시클로헥실아민 (Cyclohexylamine), 트리스(2-아미노에틸)아민 (Tris(2-aminoethyl)amine), 1,3-디시클로헥산비스-(메틸아민) (1,3-Dicyclohexanebis-(methylamine)), 1,4-비스-(3-아미노프로필)피페라진 (1,4-Bis-(3-aminopropyl)piperazine), 디에틸아민 (Diethylamine), 4-디메틸아미노피리딘 (4-Dimethylaminopyridine) 등의 유기 염기 및 수산화 리튬 (Lithium hydroxide), 수산화 나트륨 (Sodium Hydroxide), 수산화 칼슘 (Calcium Hydroxide), 수산화 칼륨 (Potassium Hydroxide) 등의 무기염기로 구성된 군에서 선택되는 1 이상의 것을 들 수 있다.In step 2), the bases used to remove the protecting group include Piperidine, Pyrrolidine, Piperazine, DBU (1,8-diazabicyclo[5.4.0]undec-7 -ene), 4-Methylpiperidine, Morpholine, 1-methyl-3-butyl imidazolium tetrafluoroborane (1-methyl-3-butyl imidazolium BF4), ethanol Ethanolamine, Cyclohexylamine, Tris(2-aminoethyl)amine, 1,3-Dicyclohexanebis-(methylamine) (1,3-Dicyclohexanebis- (methylamine)), 1,4-Bis-(3-aminopropyl)piperazine), Diethylamine, 4-Dimethylaminopyridine ) and inorganic bases such as lithium hydroxide, sodium hydroxide, calcium hydroxide, and potassium hydroxide.
단계 3)에 있어서, 보호화된 아미노산이 결합할 때 사용하는 시약으로는 DCC (N,N-Dicyclohexylcarbodiimide), DIC (N,N-Diisopropylcarbodiimide), BOP (Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate), PyBOP (Benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate), PyBrOP (Bromo-tripyrrolidino-phosphonium hexafluorophosphate), PyAOP (7-Aza-benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate), PyOxim (Ethyl cyano(hydooxyimino)acetato-O2)-tri-(1-pyrrolidinyl)-phosphonium hexafluorophosphate), HBTU (O-Benzotriazole-N,N,N',N'-tetramethyluroniumhexafluorophosphate), HCTU (2-(6-Chloro-1H-benzotriazol-1-yl)-N,N,N’,N’,-tetramethylaminium hexafluorophosphate), HDMC (N-[(5-chloro-1H-benzotriazol-1-yl)-dimethylamino-morpholino]-uronium hexafluorophosphate N-oxide), TBTU (O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate), HATU (2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphatemethanaminium), TATU (2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroboratemethanaminium), CDI (carbonyldiimidazole), COMU (1-[1-(Cyano-2-ethoxy-2-oxoethylidene-aminooxy)-dimethylamino-morpholino]-uronium hexafluorophosphate), TOTT (2-(1-Oxy-pyridin-2-yl)-1,1,3,3-tetramethyl-isothiouronium tetrafluoroborate), EDC·HCl (N-(3-dimethylaminopropyl)-N`-ethylcarbodiimide hydrochloride), TFFH (Tetramethylfluoroformamidinium hexafluorophosphate), EEDQ (N-Ethoxycarbony-2-ethoxy-1,2-dihydro-quinoline), T3P (2-Propanephosphonic acid anhydride), DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one), Oxyma (Ethyl cyanohydroxyiminoacetate), HOBt (1-Hydroxybenzotriazole), HOOBt(HODhbt, Hydroxy-3,4-dihydro-4-ox-1,2,3-benzo-triazine), BTC (bis-Trichloromethylcarbonate or Triphosgene), CDI (1,1’-Carbonyldiimidazole), 6-ClHOBt (1-Hydroxy-6-chloro-benzotriazole), HOAt (1-Hydroxyazabenzotriazole) HOSu (N-Hydroxysuccinimide) 등으로 구성된 군에서 선택되는 1 이상의 것을 들 수 있다.In step 3), reagents used to bind protected amino acids include DCC (N,N-Dicyclohexylcarbodiimide), DIC (N,N-Diisopropylcarbodiimide), and BOP (Benzotriazole-1-yl-oxy-tris-( dimethylamino)-phosphonium hexafluorophosphate), PyBOP (Benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate), PyBrOP (Bromo-tripyrrolidino-phosphonium hexafluorophosphate), PyAOP (7-Aza-benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate), PyOxim (Ethyl cyanophosphate) (hydooxyimino)acetato-O2)-tri-(1-pyrrolidinyl)-phosphonium hexafluorophosphate), HBTU (O-Benzotriazole-N,N,N',N'-tetramethyluroniumhexafluorophosphate), HCTU (2-(6-Chloro-1H- benzotriazol-1-yl)-N,N,N',N',-tetramethylaminium hexafluorophosphate), HDMC (N-[(5-chloro-1H-benzotriazol-1-yl)-dimethylamino-morpholino]-uronium hexafluorophosphate N- oxide), TBTU (O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate), HATU (2-(1H-7-Azabenzotriazol-1-yl)-1,1,3, 3-tetramethyluroniumhexafluorophosphatemethanaminium), TATU (2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroboratemethanaminium), CDI (carbonyldiimidazole), COMU (1-[1-(Cyano-2-ethoxy -2-oxoethylidene-aminooxy)-dimethylamino-morpholino]-uronium hexafluorophosphate), TOTT (2-(1-Oxy-pyridin-2-yl)-1,1,3,3-tetramethyl-isothiouronium tetrafluoroborate), EDC·HCl (N-(3-dimethylaminopropyl)-N`-ethylcarbodiimide hydrochloride), TFFH (Tetramethylfluoroformamidinium hexafluorophosphate), EEDQ (N-Ethoxycarbony-2-ethoxy-1,2-dihydro-quinoline), T3P (2-Propanephosphonic acid anhydride), DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one), Oxyma (Ethyl cyanohydroxyiminoacetate), HOBt (1-Hydroxybenzotriazole), HOOBt(HODHbt, Hydroxy-3,4-dihydro-4 -ox-1,2,3-benzo-triazine), BTC (bis-Trichloromethylcarbonate or Triphosgene), CDI (1,1'-Carbonyldiimidazole), 6-ClHOBt (1-Hydroxy-6-chloro-benzotriazole), HOAt ( One or more selected from the group consisting of 1-Hydroxyazbenzotriazole) HOSu (N-Hydroxysuccinimide), etc. may be mentioned.
단계 5)에 있어서, 레진 및 아미노산의 보호기를 동시에 제거하는 과정은 산성 용액의 존재 하에서 수행한다. 상기 산성 용액은 TFA/phenol/water/TIPS (88/5/5/2), TFA/phenol/water/thioanisole/EDT (82.5/5/5/5/2.5), TFA/phenol/water/thioanisole/1-decanethiol (82.5/5/5/5/2.5), TFA/DTT/water/TIPS (88/5/5/2), TFA-DODT-TIS-anisole-water (183:5:2:5:5, v/v), TFA/phenol (95/5), TFA/phenol/Methanesulfonic acid (95/2.5/2.5), TFA/thioanisole/EDT/anisole (90/5/3/2), TFA/TES (95/5), TFA/water (95/5), TFA/DCM/indole (70/28/2), TFA/TIPS/water (95/2.5/2.5), TFA/TIS/water (95/2.5/2.5) 등의 용액을 예시할 수 있다.In step 5), the process of simultaneously removing the protective groups of the resin and the amino acid is performed in the presence of an acidic solution. The acidic solution is TFA/phenol/water/TIPS (88/5/5/2), TFA/phenol/water/thioanisole/EDT (82.5/5/5/5/2.5), TFA/phenol/water/thioanisole/ 1-decanethiol (82.5/5/5/5/2.5), TFA/DTT/water/TIPS (88/5/5/2), TFA-DODT-TIS-anisole-water (183:5:2:5: 5, v/v), TFA/phenol (95/5), TFA/phenol/Methanesulfonic acid (95/2.5/2.5), TFA/thioanisole/EDT/anisole (90/5/3/2), TFA/TES (95/5), TFA/water (95/5), TFA/DCM/indole (70/28/2), TFA/TIPS/water (95/2.5/2.5), TFA/TIS/water (95/2.5 /2.5) solutions can be exemplified.
단계 6)에 있어서, Crude 펩타이드를 정제할 때 사용하는 용매로는 메탄올 (Methanol), 에탄올 (Ethanol), 이소프로판올 (Isopropanol), 아세토니트릴 (Acetonitrile) 및 정제수의 혼합용액이며, 이때 사용하는 산으로는 삼불화아세트산 (Trifluoroacetic acid), 아세트산 (Acetic acid), 포름산 (Formic acid)를 0.1% 내지 5% 이내로 사용하여 정제할 수 있다. In step 6), the solvent used to purify the crude peptide is a mixed solution of methanol, ethanol, isopropanol, acetonitrile, and purified water, and the acid used at this time is It can be purified using trifluoroacetic acid, acetic acid, and formic acid within 0.1% to 5%.
상기 작용기에 대한 보호기는 “Protecting Groups in Organic Synthesis (Greene and Wuts, John Wiley & Sons, 1991)”에 상세히 기재되어 있다.Protecting groups for the above functional groups are described in detail in “Protecting Groups in Organic Synthesis (Greene and Wuts, John Wiley & Sons, 1991).”
본 명세서에서 용어 “펩타이드”는 펩타이드 결합에 의해 아미노산 잔기들이 서로 결합되어 형성된 선형의 분자를 의미한다.As used herein, the term “peptide” refers to a linear molecule formed by linking amino acid residues together through peptide bonds.
본 발명에 따른 신규한 펩타이드는 Control 보다 우수한 프로콜라겐 생성 활성(도 4)이 있었다.The novel peptide according to the present invention had better procollagen production activity than Control (Figure 4).
따라서, 또 다른 관점에서, 본 발명은 상기 신규한 펩타이드를 포함하는 피부 주름개선용 조성물에 관한 것이다. 본 발명의 신규한 펩타이드를 유효성분으로 함유하는 주름개선 조성물은 약학용, 화장용 또는 건강기능식품용으로 활용 가능하다.Accordingly, from another perspective, the present invention relates to a composition for improving skin wrinkles containing the novel peptide. The wrinkle improvement composition containing the novel peptide of the present invention as an active ingredient can be used for pharmaceutical, cosmetic or health functional food purposes.
상기 펩타이드를 포함하는 약학용 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있으나, 이에 제한되지 않는다.The pharmaceutical composition containing the peptide is formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions according to conventional methods. It may be used, but is not limited to this.
본 발명의 펩타이드를 함유하는 약학용 조성물에 함유될 수 있는 담체, 부형제 및 희석제로는 락토오즈, 덱스트로즈, 수크로스, 덱스트린, 말토덱스트린, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들수 있으나, 이에 제한되지 않는다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제되나, 이에 제한되지 않는다.Carriers, excipients, and diluents that may be contained in the pharmaceutical composition containing the peptide of the present invention include lactose, dextrose, sucrose, dextrin, maltodextrin, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, and acacia. Examples include rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. However, it is not limited to this. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants, but is not limited thereto.
상기 펩타이드를 포함하는 화장용 조성물은 피부 등에 사용할 수 있고, 피부 미백 효과를 위하여 사용할 수 있다.The cosmetic composition containing the peptide can be used on the skin, etc., and can be used for skin whitening effect.
본 발명의 화장용 조성물에 포함되는 펩타이드의 함량은 용도, 적용 형태, 사용 목적 및 소망하는 효과에 따라서 적절히 조절 가능하며, 함량 대비 효과를 고려하여, 예컨대 전체 조성물 중량에 대하여 0.0001 내지 99.9 중량% 이내에서 사용할 수 있다.The content of the peptide included in the cosmetic composition of the present invention can be appropriately adjusted depending on the use, application form, purpose of use, and desired effect, and considering the effect compared to the content, for example, within 0.0001 to 99.9% by weight based on the total weight of the composition. It can be used in
상기 화장용 조성물은 피부 및 두피에 경피적으로 적용되고, 기초 화장품, 가슴 및 둔부 전용 크림, 메이크업 화장품, 바디 제품, 면도용 제품, 모발 제품 등을 포함한 모든 화장품 제품의 제조에 사용 가능한 조성물을 의미하는 것으로, 경구제, 스프레이, 현탁액, 유액, 크림, 젤, 폼 등의 형태로 제제화된 것일 수 있으나 그 형태에 특별한 제한이 없다.The cosmetic composition refers to a composition that is applied percutaneously to the skin and scalp and can be used for the manufacture of all cosmetic products, including basic cosmetics, creams for chest and buttocks, makeup cosmetics, body products, shaving products, hair products, etc. It may be formulated in the form of an oral agent, spray, suspension, emulsion, cream, gel, foam, etc., but there is no particular limitation on the form.
또한, 상기 화장용 조성물은 유연 화장수, 수렴화장수, 영양화장수, 영양 크림, 마사지크림, 아이크림, 아이 에센스, 에센스, 클렌징크림, 클렌징로션, 클렌징폼, 클렌징 워터, 팩, 파우더, 보디로션, 보디 크림, 보디 에센스, 보디 세정제, 자외선 차단 크림, 염모제, 샴푸, 린스, 치약, 구강 청정제, 로션, 연고, 젤, 크림, 패치 및 분무제로 이루어진 군으로부터 선택되는 제형을 가지는 것을 포함한다.In addition, the cosmetic composition includes softening lotion, astringent lotion, nourishing lotion, nourishing cream, massage cream, eye cream, eye essence, essence, cleansing cream, cleansing lotion, cleansing foam, cleansing water, pack, powder, body lotion, body and those having a formulation selected from the group consisting of creams, body essences, body cleansers, sunscreen creams, hair dyes, shampoos, rinses, toothpastes, mouthwashes, lotions, ointments, gels, creams, patches and sprays.
상기 펩타이드를 포함하는 건강기능식품용 조성물은 정제, 캅셀, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공할 수 있다. Compositions for health functional foods containing the above peptides can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc.
본 발명의 건강기능식품이라 함은, 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 말하며, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.Health functional food of the present invention refers to food manufactured and processed using raw materials or ingredients with functionality useful to the human body in accordance with Act No. 6727 on Health Functional Food, and provides nutrients for the structure and function of the human body. It means ingestion for the purpose of obtaining useful effects for health purposes such as regulation or physiological action.
본 발명의 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 식품 첨가물로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.The health functional food of the present invention may contain common food additives, and its suitability as a food additive is determined in accordance with the general provisions and general test methods of the food additive code approved by the Food and Drug Administration, unless otherwise specified. Judgment is made according to specifications and standards.
상기 식품 첨가물 공전에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼슘, 니코틴산, 계피산 등의 화학적 합성물; 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물; L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류 등을 포함하나, 이에 제한되지 않는다.Items listed in the Food Additives Code include, for example, chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; Natural additives such as dark pigment, licorice extract, crystalline cellulose, kaoliang pigment, and guar gum; It includes, but is not limited to, mixed preparations such as sodium L-glutamate preparations, noodle additive alkaline preparations, preservative preparations, and tar coloring preparations.
또한, 상기 본 발명의 피부 주름개선용 조성물은 상기 유효성분 이외에 통상의 제품화 및 제제화에 사용 가능한 모든 종류의 성분, 예컨대 향료, 색소, 살균제, 산화 방지제, 방부제, 보습제, 점증제, 부형제, 희석제, 무기염류 및 합성 고분자 물질 등을 추가로 포함할 수 있으며, 그 종류와 함량은 최종 산물의 용도 및 사용 목적에 따라 적절하게 조절할 수 있다.In addition, the composition for improving skin wrinkles of the present invention contains, in addition to the active ingredients, all kinds of ingredients that can be used in general commercialization and formulation, such as fragrances, pigments, disinfectants, antioxidants, preservatives, moisturizers, thickeners, excipients, diluents, Inorganic salts and synthetic polymer materials may be additionally included, and their type and content can be appropriately adjusted depending on the use and purpose of the final product.
본 발명에 따른 펩타이드는 하기 화학식 I의 구조를 갖는다.The peptide according to the present invention has the structure of formula (I) below.
[화학식 I][Formula I]
본 발명의 신규한 펩타이드는 프로콜라겐 생성 활성 효과가 뛰어나므로, 인체 적용시 본래의 기능을 효과적으로 발휘할 수 있어, 의약, 화장품, 기능성 식품 분야에서 유용하게 이용될 수 있다.Since the novel peptide of the present invention has an excellent procollagen production activity effect, it can effectively exert its original function when applied to the human body, and can be usefully used in the fields of medicine, cosmetics, and functional foods.
[실시예][Example]
본 명세서 전체에 거쳐, 특정 물질의 농도를 나타내기 위하여 사용되는 “%”는 별도의 언급이 없는 한 고체/고체는 (중량/중량) %, 고체/액체는 (중량/부피) %, 그리고 액체/액체는 (부피/부피) %이다.Throughout this specification, “%” used to indicate the concentration of a specific substance means (weight/weight) % for solid/solid, (weight/volume) % for solid/liquid, and liquid (weight/volume) %, unless otherwise specified. /Liquid is (volume/volume) %.
실시 예. 화학식 I로 표시되는 펩타이드의 제조Example. Preparation of peptides represented by formula I
본 명세서 전체에 거쳐, 특정 물질의 농도를 나타내기 위하여 사용되는 “%“는 별도의 언급이 없는 한 고체/고체는 (중량/중량) %, 고체/액체는 (중량/부피) %, 그리고 액체/액체는 (부피/부피) %이다.Throughout this specification, “%” used to indicate the concentration of a specific substance means (weight/weight) % for solid/solid, (weight/volume) % for solid/liquid, and liquid (weight/volume) %, unless otherwise specified. /Liquid is (volume/volume) %.
실시 예 1 : H-Lys(Boc)-O-Resin(2-Chlorotrityl)의 제조Example 1: Preparation of H-Lys(Boc)-O-Resin(2-Chlorotrityl)
[화학식 1][Formula 1]
2-Chlorotrityl chloride 레진 141.84g (치환율 = 1.41, 100 mmole)이 들어있는 반응기에 Fmoc-Lys(Boc)-OH (분자량 = 468.5 g/mol, 93.7 g, 200 mmole)과 DIPEA (N,N-Diisopropylethylamine, 분자량 = 129.25 g/mol, 51.7 g, 400 mmole)을 DCM 1000 ml에 용해한 다음 투입하고 상온에서 12시간 동안 교반하였다. Fmoc-Lys(Boc)-OH (molecular weight = 468.5 g/mol, 93.7 g, 200 mmole) and DIPEA (N,N-Diisopropylethylamine) were added to a reactor containing 141.84g of 2-chlorotrityl chloride resin (ratio of substitution = 1.41, 100 mmole). , molecular weight = 129.25 g/mol, 51.7 g, 400 mmole) was dissolved in 1000 ml of DCM and then added and stirred at room temperature for 12 hours.
반응액을 배출한 다음 DCM/MeOH/DIPEA(17/2/1) 용액 1000mL를 투입하고 10분 동안 교반하였다. 반응액을 배출하고 1회 더 DCM/MeOH/DIPEA(17/2/1) 용액 1000mL를 투입하고 10분 동안 교반하였다.After discharging the reaction solution, 1000 mL of DCM/MeOH/DIPEA (17/2/1) solution was added and stirred for 10 minutes. The reaction solution was discharged, and 1000 mL of DCM/MeOH/DIPEA (17/2/1) solution was added once more and stirred for 10 minutes.
레진을 DMF 1000 ml으로 2회 세척한 후, 20% 피페리딘/DMF 용액 1000 ml를 더하고 15분 동안 교반하였다. After washing the resin twice with 1000 ml of DMF, 1000 ml of 20% piperidine/DMF solution was added and stirred for 15 minutes.
감압 여과하여 반응액을 제거하고, 레진을 동일하게 1회 더 처리하였다. DMF 1000 ml으로 총 6회 레진을 세척한 후 화학식 1로 표시되는 H-Lys(Boc)-O-Resin(2-Chlorotrityl)을 수득하였다 (수율 >99%).The reaction solution was removed by filtration under reduced pressure, and the resin was treated one more time in the same manner. After washing the resin a total of 6 times with 1000 ml of DMF, H-Lys(Boc)-O-Resin(2-Chlorotrityl) represented by Chemical Formula 1 was obtained (yield >99%).
실시 예 2 : H-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl)의 제조Example 2: Preparation of H-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl)
[화학식 2][Formula 2]
H-Lys(Boc)-O-Resin(2-Chlorotrityl) (100 mmole)이 들어있는 반응기에 Fmoc-His(Trt)-OH (분자량 = 619.7 g/mol, 185.91 g, 300 mmole)과 Oxyma (Ethyl cyanohydroxyiminoacetate, 분자량 = 142.11 g/mol, 46.9 g, 330 mmole)을 DMF 1000 ml에 용해한 다음 투입하였다. 혼합된 반응액에 DIC (분자량 = 126.2 g/mol, 41.64 g, 330 mmole)을 서서히 적가한 다음 상온에서 4시간 동안 서서히 교반하였다. 레진을 DMF 1000 ml으로 2회 세척한 후, 20% 피페리딘/DMF 용액 1000 ml를 더하고 15분 동안 교반하였다. 감압 여과하여 반응액을 제거하고, 레진을 동일하게 1회 더 처리하였다. DMF 1000 ml으로 총 6회 레진을 세척한 후 화학식 2로 표시되는 H-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl)을 수득하였다 (수율 >99%).Fmoc-His(Trt)-OH (molecular weight = 619.7 g/mol, 185.91 g, 300 mmole) and Oxyma (Ethyl) were added to a reactor containing H-Lys(Boc)-O-Resin(2-Chlorotrityl) (100 mmole). cyanohydroxyiminoacetate (molecular weight = 142.11 g/mol, 46.9 g, 330 mmole) was dissolved in 1000 ml of DMF and then added. DIC (molecular weight = 126.2 g/mol, 41.64 g, 330 mmole) was slowly added dropwise to the mixed reaction solution and then slowly stirred at room temperature for 4 hours. After washing the resin twice with 1000 ml of DMF, 1000 ml of 20% piperidine/DMF solution was added and stirred for 15 minutes. The reaction solution was removed by filtration under reduced pressure, and the resin was treated one more time in the same manner. After washing the resin a total of 6 times with 1000 ml of DMF, H-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl) represented by Chemical Formula 2 was obtained (yield >99%).
실시 예 3 : H-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl)의 제조Example 3: Preparation of H-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl)
[화학식 3][Formula 3]
H-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl) (100 mmole)이 들어있는 반응기에 Fmoc-Gly-OH (분자량 = 297.3 g/mol, 89.19 g, 300 mmole)과 Oxyma (Ethyl cyanohydroxyiminoacetate, 분자량 = 142.11 g/mol, 46.9 g, 330 mmole)을 DMF 1000 ml에 용해한 다음 투입하였다. 혼합된 반응액에 DIC (분자량 = 126.2 g/mol, 41.64 g, 330 mmole)을 서서히 적가한 다음 상온에서 4시간 동안 서서히 교반하였다. 레진을 DMF 1000 ml으로 2회 세척한 후, 20% 피페리딘/DMF 용액 1000 ml를 더하고 15분 동안 교반하였다. 감압 여과하여 반응액을 제거하고, 레진을 동일하게 1회 더 처리하였다. DMF 1000 ml으로 총 6회 레진을 세척한 후 화학식 3으로 표시되는 H-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl)을 수득하였다 (수율 >99%).Fmoc-Gly-OH (molecular weight = 297.3 g/mol, 89.19 g, 300 mmole) and Oxyma were added to a reactor containing H-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl) (100 mmole). (Ethyl cyanohydroxyiminoacetate, molecular weight = 142.11 g/mol, 46.9 g, 330 mmole) was dissolved in 1000 ml of DMF and then added. DIC (molecular weight = 126.2 g/mol, 41.64 g, 330 mmole) was slowly added dropwise to the mixed reaction solution and then slowly stirred at room temperature for 4 hours. After washing the resin twice with 1000 ml of DMF, 1000 ml of 20% piperidine/DMF solution was added and stirred for 15 minutes. The reaction solution was removed by filtration under reduced pressure, and the resin was treated one more time in the same manner. After washing the resin a total of 6 times with 1000 ml of DMF, H-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl) represented by Chemical Formula 3 was obtained (yield >99%).
실시 예 4 : H-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl)의 제조Example 4: Preparation of H-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl)
[화학식 4][Formula 4]
H-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl) (100 mmole)이 들어있는 반응기에 Fmoc-His(Trt)-OH (분자량 = 619.7 g/mol, 185.91 g, 300 mmole)과 Oxyma (Ethyl cyanohydroxyiminoacetate, 분자량 = 142.11 g/mol, 46.9 g, 330 mmole)을 DMF 1000 ml에 용해한 다음 투입하였다. 혼합된 반응액에 DIC (분자량 = 126.2 g/mol, 41.64 g, 330 mmole)을 서서히 적가한 다음 상온에서 4시간 동안 서서히 교반하였다. 레진을 DMF 1000 ml으로 2회 세척한 후, 20% 피페리딘/DMF 용액 1000 ml를 더하고 15분 동안 교반하였다. 감압 여과하여 반응액을 제거하고, 레진을 동일하게 1회 더 처리하였다. DMF 1000 ml으로 총 6회 레진을 세척한 후 화학식 4로 표시되는 H-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl)을 수득하였다 (수율 >99%).Fmoc-His(Trt)-OH (molecular weight = 619.7 g/mol, 185.91 g, 300 mmole) and Oxyma (Ethyl cyanohydroxyiminoacetate, molecular weight = 142.11 g/mol, 46.9 g, 330 mmole) were dissolved in 1000 ml of DMF and then added. DIC (molecular weight = 126.2 g/mol, 41.64 g, 330 mmole) was slowly added dropwise to the mixed reaction solution and then slowly stirred at room temperature for 4 hours. After washing the resin twice with 1000 ml of DMF, 1000 ml of 20% piperidine/DMF solution was added and stirred for 15 minutes. The reaction solution was removed by filtration under reduced pressure, and the resin was treated one more time in the same manner. After washing the resin a total of 6 times with 1000 ml of DMF, H-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl) represented by Chemical Formula 4 was obtained (yield > 99%).
실시 예 5 : H-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin (2-Chlorotrityl)의 제조Example 5: Preparation of H-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin (2-Chlorotrityl)
[화학식 5][Formula 5]
H-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl) (100 mmole)이 들어있는 반응기에 Fmoc-Arg(Pbf)-OH (분자량 = 648.8 g/mol, 194.64 g, 300 mmole)과 Oxyma (Ethyl cyanohydroxyiminoacetate, 분자량 = 142.11 g/mol, 46.9 g, 330 mmole)을 DMF 1000 ml에 용해한 다음 투입하였다. 혼합된 반응액에 DIC (분자량 = 126.2 g/mol, 41.64 g, 330 mmole)을 서서히 적가한 다음 상온에서 4시간 동안 서서히 교반하였다. 레진을 DMF 1000 ml으로 2회 세척한 후, 20% 피페리딘/DMF 용액 1000 ml를 더하고 15분 동안 교반하였다. 감압 여과하여 반응액을 제거하고, 레진을 동일하게 1회 더 처리하였다. DMF 1000 ml으로 총 6회 레진을 세척한 후 화학식 5로 표시되는 H-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl)을 수득하였다 (수율 >99%).Fmoc-Arg(Pbf)-OH (molecular weight = 648.8 g/ mol, 194.64 g, 300 mmole) and Oxyma (Ethyl cyanohydroxyiminoacetate, molecular weight = 142.11 g/mol, 46.9 g, 330 mmole) were dissolved in 1000 ml of DMF and then added. DIC (molecular weight = 126.2 g/mol, 41.64 g, 330 mmole) was slowly added dropwise to the mixed reaction solution and then slowly stirred at room temperature for 4 hours. After washing the resin twice with 1000 ml of DMF, 1000 ml of 20% piperidine/DMF solution was added and stirred for 15 minutes. The reaction solution was removed by filtration under reduced pressure, and the resin was treated one more time in the same manner. After washing the resin a total of 6 times with 1000 ml of DMF, H-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl) represented by Chemical Formula 5 Obtained (yield >99%).
실시 예 6 : H-Trp(Boc)-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin (2-Chlorotrityl)의 제조Example 6: Preparation of H-Trp(Boc)-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin (2-Chlorotrityl)
[화학식 6][Formula 6]
H-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl) (100 mmole)이 들어있는 반응기에 Fmoc-Trp(Boc)-OH (분자량 = 526.6 g/mol, 157.98 g, 300 mmole)과 Oxyma (Ethyl cyanohydroxyiminoacetate, 분자량 = 142.11 g/mol, 46.9 g, 330 mmole)을 DMF 1000 ml에 용해한 다음 투입하였다. 혼합된 반응액에 DIC (분자량 = 126.2 g/mol, 41.64 g, 330 mmole)을 서서히 적가한 다음 상온에서 4시간 동안 서서히 교반하였다. 레진을 DMF 1000 ml으로 2회 세척한 후, 20% 피페리딘/DMF 용액 1000 ml를 더하고 15분 동안 교반하였다. 감압 여과하여 반응액을 제거하고, 레진을 동일하게 1회 더 처리하였다. DMF 1000 ml으로 총 6회 레진을 세척한 후 화학식 6으로 표시되는 H-Trp(Boc)-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl)을 수득하였다 (수율 >99%).Fmoc-Trp(Boc)-OH ( Molecular weight = 526.6 g/mol, 157.98 g, 300 mmole) and Oxyma (Ethyl cyanohydroxyiminoacetate, molecular weight = 142.11 g/mol, 46.9 g, 330 mmole) were dissolved in 1000 ml of DMF and then added. DIC (molecular weight = 126.2 g/mol, 41.64 g, 330 mmole) was slowly added dropwise to the mixed reaction solution and then slowly stirred at room temperature for 4 hours. After washing the resin twice with 1000 ml of DMF, 1000 ml of 20% piperidine/DMF solution was added and stirred for 15 minutes. The reaction solution was removed by filtration under reduced pressure, and the resin was treated one more time in the same manner. After washing the resin a total of 6 times with 1000 ml of DMF, H-Trp(Boc)-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin ( 2-Chlorotrityl) was obtained (yield >99%).
실시 예 7 : H-Arg(Pbf)-Trp(Boc)-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc) -O-Resin(2-Chlorotrityl)의 제조Example 7: Preparation of H-Arg(Pbf)-Trp(Boc)-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl)
[화학식 7][Formula 7]
H-Trp(Boc)-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl) (100 mmole)이 들어있는 반응기에 Fmoc-Arg(Pbf)-OH (분자량 = 648.8 g/mol, 194.64 g, 300 mmole)과 Oxyma (Ethyl cyanohydroxyiminoacetate, 분자량 = 142.11 g/mol, 46.9 g, 330 mmole)을 DMF 1000 ml에 용해한 다음 투입하였다. 혼합된 반응액에 DIC (분자량 = 126.2 g/mol, 41.64 g, 330 mmole)을 서서히 적가한 다음 상온에서 4시간 동안 서서히 교반하였다. 레진을 DMF 1000 ml으로 2회 세척한 후, 20% 피페리딘/DMF 용액 1000 ml를 더하고 15분 동안 교반하였다. 감압 여과하여 반응액을 제거하고, 레진을 동일하게 1회 더 처리하였다. DMF 1000 ml으로 총 6회 레진을 세척한 후 화학식 7로 표시되는 H-Arg(Pbf)-Trp(Boc)-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl)을 수득하였다 (수율 >99%).Fmoc-Arg ( Pbf)-OH (molecular weight = 648.8 g/mol, 194.64 g, 300 mmole) and Oxyma (Ethyl cyanohydroxyiminoacetate, molecular weight = 142.11 g/mol, 46.9 g, 330 mmole) were dissolved in 1000 ml of DMF and then added. DIC (molecular weight = 126.2 g/mol, 41.64 g, 330 mmole) was slowly added dropwise to the mixed reaction solution and then slowly stirred at room temperature for 4 hours. After washing the resin twice with 1000 ml of DMF, 1000 ml of 20% piperidine/DMF solution was added and stirred for 15 minutes. The reaction solution was removed by filtration under reduced pressure, and the resin was treated one more time in the same manner. After washing the resin a total of 6 times with 1000 ml of DMF, H-Arg(Pbf)-Trp(Boc)-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc) represented by Chemical Formula 7 -O-Resin(2-Chlorotrityl) was obtained (yield >99%).
실시 예 8 : H-His(Trt)-Arg(Pbf)-Trp(Boc)-Arg(Pbf)-His(Trt)-Gly-His(Trt) -Lys(Boc)-O-Resin(2-Chlorotrityl)의 제조Example 8: H-His(Trt)-Arg(Pbf)-Trp(Boc)-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl )Manufacture of
[화학식 8][Formula 8]
H-Arg(Pbf)-Trp(Boc)-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl) (100 mmole)이 들어있는 반응기에 Fmoc-His(Trt)-OH (분자량 = 619.7 g/mol, 185.91 g, 300 mmole)과 Oxyma (Ethyl cyanohydroxyiminoacetate, 분자량 = 142.11 g/mol, 46.9 g, 330 mmole)을 DMF 1000 ml에 용해한 다음 투입하였다. 혼합된 반응액에 DIC (분자량 = 126.2 g/mol, 41.64 g, 330 mmole)을 서서히 적가한 다음 상온에서 4시간 동안 서서히 교반하였다. 레진을 DMF 1000 ml으로 2회 세척한 후, 20% 피페리딘/DMF 용액 1000 ml를 더하고 15분 동안 교반하였다. 감압 여과하여 반응액을 제거하고, 레진을 동일하게 1회 더 처리하였다. DMF 1000 ml으로 총 6회 레진을 세척한 후 화학식 8로 표시되는 H-His(Trt)-Arg(Pbf)-Trp(Boc)-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl)을 수득하였다 (수율 >99%).Reactor containing H-Arg(Pbf)-Trp(Boc)-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl) (100 mmole) Fmoc-His(Trt)-OH (molecular weight = 619.7 g/mol, 185.91 g, 300 mmole) and Oxyma (Ethyl cyanohydroxyiminoacetate, molecular weight = 142.11 g/mol, 46.9 g, 330 mmole) were dissolved in 1000 ml of DMF and then added. did. DIC (molecular weight = 126.2 g/mol, 41.64 g, 330 mmole) was slowly added dropwise to the mixed reaction solution and then slowly stirred at room temperature for 4 hours. After washing the resin twice with 1000 ml of DMF, 1000 ml of 20% piperidine/DMF solution was added and stirred for 15 minutes. The reaction solution was removed by filtration under reduced pressure, and the resin was treated one more time in the same manner. After washing the resin a total of 6 times with 1000 ml of DMF, H-His(Trt)-Arg(Pbf)-Trp(Boc)-Arg(Pbf)-His(Trt)-Gly-His(Trt) represented by Chemical Formula 8 -Lys(Boc)-O-Resin(2-Chlorotrityl) was obtained (yield >99%).
실시 예 9 : Crude H-His-Arg-Trp-Arg-His-Gly-His-Lys-OH의 제조Example 9: Preparation of Crude H-His-Arg-Trp-Arg-His-Gly-His-Lys-OH
[화학식 9][Formula 9]
H-His(Trt)-Arg(Pbf)-Trp(Boc)-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl)을 반응기에 투입하고 냉각된 TFA/TIS/water (95/2.5/2.5) 용액 3 L를 서서히 부어 넣은 다음 상온에서 3시간 동안 교반하였다. 반응액을 받아낸 다음 냉각된 디에틸에테르 9 L에 반응액을 서서히 적가하여 펩타이드를 석출시켰다. 실온에서 30분 동안 교반한 다음 여과하여 펩타이드를 회수하였다. 최대한 용매를 감압 제거한 다음 진공 건조기에서 7시간 동안 건조 시켰다. 거의 백색의 화학식 9로 표시되는 Crude peptide 108.87 g을 수득하였다. (분자량 1113.24g/mol, Crude peptide 순도 63.8%, 수율 97.8%)H-His(Trt)-Arg(Pbf)-Trp(Boc)-Arg(Pbf)-His(Trt)-Gly-His(Trt)-Lys(Boc)-O-Resin(2-Chlorotrityl) into the reactor. 3 L of the cooled TFA/TIS/water (95/2.5/2.5) solution was slowly poured into the solution and stirred at room temperature for 3 hours. After collecting the reaction solution, the reaction solution was slowly added dropwise to 9 L of cooled diethyl ether to precipitate the peptide. After stirring at room temperature for 30 minutes, the peptide was recovered by filtration. The solvent was removed under reduced pressure as much as possible and then dried in a vacuum dryer for 7 hours. 108.87 g of almost white crude peptide represented by Chemical Formula 9 was obtained. (Molecular weight 1113.24g/mol, crude peptide purity 63.8%, yield 97.8%)
실시 예 10 : H-His-Arg-Trp-Arg-His-Gly-His-Lys-OH의 제조Example 10: Preparation of H-His-Arg-Trp-Arg-His-Gly-His-Lys-OH
[화학식 I][Formula I]
실시 예 9에서 수득한 Crude 펩타이드 108.87 g을 정제수에 용해한 다음 0.46μm membrane으로 여과하였다. 여과액을 산업용 HPLC (230 nm, 500 ml/분, 10 미크론 C18 컬럼에서 30분 내에 0.1% TFA 내 아세토니트릴 초기농도 5%에서 65%로 증가)로 반복 주입한 후 분리 정제하여 화학식 I로 표시되는 펩타이드, 51.50 g (수율: 47.3%, 순도: 98.87%)을 수득하였다.(도 1 및 도 2 참조)108.87 g of the crude peptide obtained in Example 9 was dissolved in purified water and then filtered through a 0.46μm membrane. The filtrate was repeatedly injected into industrial HPLC (230 nm, 500 ml/min, 10 micron C18 column, initial concentration of acetonitrile in 0.1% TFA increased from 5% to 65% within 30 minutes), and then separated and purified to obtain formula (I). 51.50 g (yield: 47.3%, purity: 98.87%) of the peptide was obtained (see Figures 1 and 2).
참고로, 상기 화학식 I로 표시되는 펩타이드는 서열번호 1로 표시되는 아미노산 서열을 포함한다.For reference, the peptide represented by Formula I includes the amino acid sequence represented by SEQ ID NO: 1.
실험 예 1: 세포독성 시험 및 프로콜라겐 생성량 측정Experimental Example 1: Cytotoxicity test and measurement of procollagen production
1) HS68 세포 배양1) HS68 cell culture
실험에 사용한 세포주 HS68은 한국세포주은행 (KCLB, Seoul, Korea)에서 분양받아 사용하였다. 배지는 10% Feral Bovine Serum (FBS)를 함유한 DMEM High glucose 성장배지를 사용하였다. 세포주는 습도 95%, 5% CO₂, 37℃로 조절된 배양기에서 배양하였으며, 이 때 미생물의 오염이나 증식을 억제하기 위해 배지용 항생제 (Penicillin streptomycin, Gibco, CA, USA)를 사용하였다.The cell line HS68 used in the experiment was purchased from the Korea Cell Line Bank (KCLB, Seoul, Korea). The medium used was DMEM high glucose growth medium containing 10% Feral Bovine Serum (FBS). Cell lines were cultured in an incubator controlled at 95% humidity, 5% CO₂, and 37°C, and medium antibiotics (Penicillin streptomycin, Gibco, CA, USA) were used to prevent contamination or growth of microorganisms.
2) HS68 세포 독성시험2) HS68 cytotoxicity test
세포주의 생존율을 측정은 MTS (CellTiter 96® AQueous One Solution Cell Proliferation Assay, Promega, USA) 시약을 이용하여 세포의 생존율을 측정하였다. 96 well plate에 세포를 1×10⁴cells/well의 농도로 분주 후 습도 95%, 5% CO₂, 37℃로 조절된 배양기에서 24시간 안정화하였다. 이후 시료를 농도별로 처리하여 습도 95%, 5% CO₂, 37℃로 조절된 배양기에서 24시간 배양하였다. 배지를 제거한 후 MTS 시약을 배지 (DMEM high glucose, free FBS)로 10배 희석한 후 well 당 100 ㎕씩 처리하였다. 37℃에서 60 분간 반응 후 microplate reader (Molecular Devices, Versa Max ELISA Microplate Reader, USA)로 490 nm에서 흡광도를 측정하였다. 세포의 생존율은 시료를 처리하지 않은 대조군에 대비한 시료 처리군의 흡광도로 도 3에 표시하였다. 도 3에 도시된 바와 같이, 화학식 I로 표시되는 펩타이드(WP-CPP21-011)는 세포독성이 없다는 것을 확인할 수 있었다.The survival rate of cell lines was measured using MTS (CellTiter 96 ® AQueous One Solution Cell Proliferation Assay, Promega, USA) reagent. Cells were distributed in a 96 well plate at a concentration of 1 Afterwards, the samples were treated according to concentration and cultured for 24 hours in an incubator controlled at 95% humidity, 5% CO₂, and 37°C. After removing the medium, the MTS reagent was diluted 10 times with medium (DMEM high glucose, free FBS) and then treated at 100 ㎕ per well. After reaction at 37°C for 60 minutes, absorbance was measured at 490 nm using a microplate reader (Molecular Devices, Versa Max ELISA Microplate Reader, USA). The survival rate of cells is shown in Figure 3 as the absorbance of the sample treated group compared to the control group that did not treat the sample. As shown in Figure 3, it was confirmed that the peptide represented by Formula I (WP-CPP21-011) was not cytotoxic.
3) HS68 세포 Procollagen 함량 측정3) Measurement of HS68 cell Procollagen content
Procollagen 함량은 Procollagen Type ⅠC-peptide (PIP) EIA kit(TaKaRa, MK101)을 사용하여 측정하였다.Procollagen content was measured using the Procollagen Type ⅠC-peptide (PIP) EIA kit (TaKaRa, MK101).
섬유아세포주 HS68을 24 well plate에 2×105 cells/well의 농도로 1 ml 씩 분주하고 24 시간 동안 37℃, 습도 95%, 5% CO₂로 조절된 CO₂배양기에서 세포 안정화하였다. 각 시료를 세포독성이 나타나지 않는 농도범위로 희석한 후 세포에 처리하여 24 시간 동안 배양하였다.The fibroblast cell line HS68 was dispensed at a concentration of 2×10 5 cells/well in 1 ml each in a 24 well plate, and the cells were stabilized in a CO₂ incubator controlled at 37°C, 95% humidity, and 5% CO₂ for 24 hours. Each sample was diluted to a concentration range that does not cause cytotoxicity, then treated with cells and cultured for 24 hours.
세포상등액을 취하여 Procollagen Type ⅠC-peptide (PIP) EIA kit (TaKaRa, MK101)의 시료로 사용하였으며 Procollagen 함량을 측정하였다.The cell supernatant was taken and used as a sample for the Procollagen Type ⅠC-peptide (PIP) EIA kit (TaKaRa, MK101), and the Procollagen content was measured.
4) 통계처리4) Statistical processing
모든 실험의 데이터 통계처리는 3회 반복하였으며, 실험값의 통계는 Excel 2020 (Microsoft Office, Redmond, WA, USA) 프로그램을 사용하였다. 대응표본 t-검정 (paired T-Test)로 실시하여 95% 신뢰구간에서 유의확률 p<0.05 일 때 통계적으로 유의한 차이가 있는 것으로 판정하였다.Statistical processing of data from all experiments was repeated three times, and statistics on experimental values were performed using the Excel 2020 (Microsoft Office, Redmond, WA, USA) program. A paired T-Test was used to determine that there was a statistically significant difference when the probability of significance was p<0.05 in the 95% confidence interval.
도 4에 도시된 바와 같이, 본 발명에 따른 펩타이드(WP-CPP21-011으로 표시)는 농도에 따라 프로콜라겐 생성량이 우수하며, 주름 개선에 효과가 있음을 알 수 있었다.As shown in Figure 4, it was found that the peptide according to the present invention (expressed as WP-CPP21-011) has an excellent amount of procollagen production depending on the concentration and is effective in improving wrinkles.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적 기술은 단지 바람직한 실시 양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.As the specific parts of the present invention have been described in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. will be. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
서열목록 전자파일 첨부Sequence list electronic file attached
Claims (5)
[화학식 I]
A peptide having the structure of formula (I) below;
[Formula I]
The peptide according to claim 1, wherein the peptide has procollagen producing activity.
A composition for improving skin wrinkles comprising a peptide having the structure of formula (I) of claim 1.
The composition for improving skin wrinkles according to claim 3, wherein the composition has procollagen production activity.
The composition for improving skin wrinkles according to claim 3, wherein the composition is a pharmaceutical, cosmetic or health functional food composition.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100753472B1 (en) | 2002-03-15 | 2007-08-31 | 주식회사 엘지생활건강 | Fusion peptide comprising tat peptide and human type-? collagen derived peptide, its preparation method, and anti-aging cosmetic composition comprising the same |
| KR101173412B1 (en) | 2011-11-08 | 2012-08-10 | 주식회사 코리아나화장품 | Cosmetic composition for prevention of skin-wrinkle containing microbial fermented extract of Helichrysum Italicum flower |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100753472B1 (en) | 2002-03-15 | 2007-08-31 | 주식회사 엘지생활건강 | Fusion peptide comprising tat peptide and human type-? collagen derived peptide, its preparation method, and anti-aging cosmetic composition comprising the same |
| KR101173412B1 (en) | 2011-11-08 | 2012-08-10 | 주식회사 코리아나화장품 | Cosmetic composition for prevention of skin-wrinkle containing microbial fermented extract of Helichrysum Italicum flower |
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