CN117143200A - Cyclic peptides with excellent performance and application thereof - Google Patents
Cyclic peptides with excellent performance and application thereof Download PDFInfo
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- CN117143200A CN117143200A CN202311089774.1A CN202311089774A CN117143200A CN 117143200 A CN117143200 A CN 117143200A CN 202311089774 A CN202311089774 A CN 202311089774A CN 117143200 A CN117143200 A CN 117143200A
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- cyclic peptide
- pentapeptide
- cyclic
- palmitoyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0815—Tripeptides with the first amino acid being basic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
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- Genetics & Genomics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Dermatology (AREA)
- Birds (AREA)
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- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Cosmetics (AREA)
Abstract
The application provides a cyclic peptide with excellent performance and application thereof, wherein the cyclic peptide comprises hexapeptide-9 cyclic peptide, palmitoyl pentapeptide-4 cyclic peptide, myristoyl pentapeptide-4 cyclic peptide and palmitoyl tripeptide-5 cyclic peptide which are mainly prepared through cyclization of an amide bond/ester bond, and are subjected to structure identification and efficacy research, and compared with the original linear structure, the cyclic peptide has higher stability and affinity, also has the effects of promoting the expression of Collagen Collagen I, FLG and TGM1, improving the skin water content and the like, and particularly has stronger application potential in the anti-aging field and wide application prospect.
Description
The application is a division application of the parent application 202211550526.8, the application day 2022, 12 and 5.
The application claims a prior application in China, application number: 202210087176.X, priority of day 2022, month 1, 25; all of which are included as part of the present application.
Technical Field
The application belongs to the technical field of skin care product raw materials, relates to a group of functional cyclic peptides with excellent performance and application thereof, and particularly relates to a group of functional cyclic peptides with high bioavailability and stability and obvious efficacy, which are mainly applied to the aspects of cosmetics, skin care and beauty, and skin care.
Background
The polypeptide is a core anti-aging component for repeatedly acquiring Nobel prize, the basic constituent unit is amino acid, and the amino acid is formed by dehydration condensation according to a specific sequence, and the essence is the same as protein. The common cosmetic peptide is generally a short peptide consisting of 2-10 amino acids, has a clear mechanism which is generally acted on a certain microscopic receptor (commonly called a target point) of skin, and has different effects of resisting wrinkle, whitening, moisturizing, resisting oxidation, repairing and the like. The polypeptide has higher biological activity, and the polypeptide can have obvious effect by adding a few to hundreds of ppm. However, the linear structure of the polypeptide determines that it is more hydrophilic and not easily absorbed transdermally on the skin. Meanwhile, polypeptide molecules are substrates for hydrolysis of many proteases, most of the polypeptides are degraded and inactivated by proteases in blood and tissues, and the efficacy is lost, so that the bioavailability of the polypeptide raw materials is low, so that the application of the polypeptide raw materials is greatly limited. Meanwhile, the polypeptide on the efficacy of the common cosmetic peptides in the market at present is generally single, namely the effect obtained by the skin is single and the effect is slow. For example, the classical anti-wrinkle (dynamic texture) raw material acetyl hexapeptide-8 can inhibit dynamic texture, and the action mechanism is mainly to inhibit the release of acetylcholine, but there is no report on promotion of collagen expression; collagen-promoting peptides such as palmitoyl pentapeptide-4 have no related report on other effects such as whitening, relieving and resisting dynamic wrinkles, and the utilization rate of the collagen-promoting peptides is greatly limited.
Currently, the main methods for enhancing the metabolic stability of polypeptide molecules include unnatural amino acid modification, inverse peptide strategy, cyclization strategy, higher fatty acid modification, polyethylene glycol modification, and the like. Among them, the superiority of cyclization strategy is represented by conformational change limitation caused by cyclic structure, cyclic peptide compounds generally have larger surface area, so that they have high affinity and recognition specificity with target proteins. The restriction of the conformational flexibility of the macrocyclic structure also reduces the entropy value of the combination of the drug and the target spot, and improves the combination stability. Second, the amino acid composition characteristics determine that cyclic peptides tend to have very low, or even no, cytotoxicity. However, not all polypeptide structures can form stable ring structures, whether the structures exist stably or not is determined according to the ring tension of the ring structures after ring formation, for example, structures which are too short or too long cannot form stable structures, short chain tension is large, ring formation is not easy, and ring opening is easy after ring formation; in addition, the ring bond angle characteristics determine that the stability of the six-membered ring structure is greater than that of ten-membered rings, seven-membered rings, five-membered rings and the like, while the oligopeptides and derivatives of various polymer peptides have little ring formation meaning, and the extremely large ring formation tension of dipeptide and the like after ring formation leads to an unsteady structure, thereby limiting the application thereof.
Therefore, developing a technology which has strong stability, can improve the comprehensiveness of the polypeptide effect, increase new targets of the polypeptide and verify the effect is a direction with potential for realizing high-energy polypeptide, greatly improving the utilization rate of raw materials and improving the effect.
Meanwhile, classical anti-wrinkle peptides (procollagen mechanisms) such as (1) palmitoyl pentapeptide-4 are known on the market as accurate mimics of matrikins (messenger peptides), which are hydrolysates of procollagen α1 chain. Promoting the production of collagen types I and III and IV, glycosaminoglycans, fibronectin by activating certain genes involved in extracellular matrix turnover and cell proliferation processes, thereby increasing skin thickness and reducing wrinkles; (2) myristoyl pentapeptide-4: isopalmitoyl pentapeptide-4; (3) palmitoyl tripeptide-5: is a small peptide with unique sequence, can imitate the mechanism of human body for stimulating fibroblast to produce collagen by activating TGF-beta, thereby achieving the effect of improving wrinkles; (4) hexapeptide-9 is a collagen peptide with obvious anti-wrinkle repair effect, and the main mechanism path is to promote the synthesis of collagen by dermis fibroblast and supplement the content of collagen I, IV and XVII types. The hexapeptide-9, palmitoyl pentapeptide-4, myristoyl pentapeptide-4 and palmitoyl tripeptide-5 are taken as small molecule linear peptides, and have the problems of low stability, easiness in degradation and inactivation, poor transdermal absorption, single mechanism path on anti-wrinkle efficacy and the like.
The space structure complexity of the polypeptide can be improved, the specific surface area is increased, and more contact possibility with target spots is provided, so that the effects are more diversified, the utilization rate of the polypeptide raw material is higher, and the application prospect of the anti-wrinkle peptide in the field of beauty and skin care is enlarged. There are no relevant reports of palmitoyl pentapeptide-4 cyclic peptide, palmitoyl tripeptide-5 cyclic peptide, myristoylpentapeptide-4 cyclic peptide and hexapeptide-9 cyclic peptide.
Disclosure of Invention
In order to solve the problems, the invention aims to provide an anti-aging cyclic peptide with excellent performance, which is mainly applied to the field of beauty and skin care, including palmitoyl pentapeptide-4 cyclic peptide, palmitoyl tripeptide-5 cyclic peptide, myristoyl pentapeptide-4 cyclic peptide and hexapeptide-9 cyclic peptide, and is mainly prepared through cyclization of an amide bond or an ester bond, and structure identification and efficacy research are carried out on the cyclic peptide, and the cyclic peptide has larger surface area, high affinity with a target point, identification specificity and excellent stability, is not easy to degrade, has strong skin permeability, has stability and affinity compared with the original linear structure, and has stronger application potential in the fields of beauty and aging prevention.
The cyclic peptide is prepared by carrying out amide bond cyclization reaction on linear peptide, and the prepared cyclic structure has amide bonds, and a few membered rings represent the cyclic structure to have a plurality of amide bonds, for example, six membered rings represent the cyclic structure to have six amide bonds.
In one aspect, the invention provides a cyclic peptide, wherein the cyclic peptide contains 1-6 amide bonds in the ring, and the cyclic peptide is prepared by performing amide bond cyclization on hexapeptide-9, palmitoyl pentapeptide-4, myristoyl pentapeptide-4 or palmitoyl tripeptide-5.
In some embodiments, the cyclic peptide has 3 to 6 cyclic amide bonds.
In some embodiments, the cyclic peptide further comprises an ester linkage.
In some embodiments, the amide bond cyclizing method of the cyclic peptide is head-to-tail cyclizing or intermediate cyclizing or end cyclizing, preferably head-to-tail cyclizing.
The head-to-tail cyclization refers to head-to-tail interlinking of a linear peptide; intermediate cyclization refers to cyclization of certain peptide fragments in a linear peptide, some of which remain linear; by terminal cyclization is meant partial cyclization of the head or tail of a linear peptide with a smaller loop.
In some embodiments, the cyclic peptide has a general structural formula as shown in formula (a), formula (b), or formula (c), or an enantiomer thereof:
wherein R is selected from H, (CH) 2 )nCH 3 、(CH 2 )mNH 2 、(CH 2 ) X COOA1、(CH 2 ) m Any one of CONA 2; wherein n, m, x are independently selected from 0 or natural numbers; a1 and A2 are independently selected from H 2 、OH、NH 2 Any one or more of COOH, C1-18 alkyl, phenyl, heteroaryl.
Further, R in the formulas (a) and (b) is (CH) 2 ) 3 CONH 2 。
Further, the cyclic peptide is prepared by performing amide bond cyclization on hexapeptide-9, and the structural formula of the hexapeptide-9 is shown as formula (1):
in some embodiments, the cyclic peptide has a general structural formula as shown in formula (d), formula (e), formula (f), or formula (g), or an enantiomer thereof:
wherein R, R and R2 are independently selected from H and (CH) 2 )nCH 3 、(CH 2 )mNH 2 、(CH 2 ) X COOA1、(CH 2 ) m Any one of CONA 2; wherein n, m, x are independently selected from 0 or natural numbers; a1 and A2 are independently selected from H 2 、OH、NH 2 Any one or more of COOH, C1-18 alkyl, phenyl, heteroaryl.
Further, R1 and R2 in formula (e) are NH 2 (CH 2 ) 13 CH 3 、(CH 2 ) 4 NH 2 One of, or NH 2 (CH 2 ) 11 CH 3 、(CH 2 ) 4 NH 2 R1 and R2 are different; r in the formulas (f) and (g) is
Further, the cyclic peptide is prepared by performing amide bond cyclization on palmitoyl pentapeptide-4 or myristoyl pentapeptide-4, wherein the structural formula of palmitoyl pentapeptide-4 is shown in a formula (5), and the structural formula of myristoyl pentapeptide-4 is shown in a formula (10):
in some embodiments, the cyclic peptide has a general structural formula as shown in formula (h) or formula (i):
wherein R, R and R4 are independently selected from H and (CH) 2 )nCH 3 、(CH 2 )mNH 2 、(CH 2 ) X COOA1、(CH 2 ) m Any one of CONA 2; wherein n, m, x are independently selected from 0 or natural numbers; a1 and A2 are independently selected from H 2 、OH、NH 2 Any one or more of COOH, C1-18 alkyl, phenyl, heteroaryl.
Further, R3 and R4 in the formula (h) are each (CH) 2 ) 3 NH 2 Or (b)And R3 and R4 are different; r in formula (i) is +.>
Further, the cyclic peptide is prepared by cyclizing an amide bond or an ester bond of palmitoyl tripeptide-5, and the palmitoyl tripeptide-5 has a structural formula shown in formula (15):
in another aspect, the invention provides a use of a hexapeptide-9 cyclic peptide for preparing a preparation for promoting expression of Collagen Collagen I, FLG or TGM1 or improving skin water content, wherein the structural formula of the cyclic hexapeptide compound is shown as formula (2), (3) and (4):
in still another aspect, the invention provides a use of a hexapeptide-9 cyclic peptide for preparing a whitening preparation, wherein the structural formula of the cyclic hexapeptide compound is shown as formula (2).
Compared with hexapeptide-9 linear peptide, the cyclized hexapeptide-9 cyclic peptide formula (2) has the effect of obviously improving the content of the melanocyte inhibition, thereby playing a better role in whitening.
In still another aspect, the present invention provides a use of a palmitoyl pentapeptide-4 cyclic peptide for preparing a preparation for promoting expression of Collagen type i, FLG or TGM1, or increasing skin moisture content, wherein the structural formula of the cyclic pentapeptide compound is shown in formulas (6), (7), (8), (9):
in still another aspect, the invention provides a use of palmitoyl pentapeptide-4 cyclic peptide for preparing a soothing preparation, wherein the structural formula of the cyclic pentapeptide compound is shown in a formula (6).
Compared with palmitoyl pentapeptide-4 linear peptide, the cyclized palmitoyl pentapeptide-4 cyclic peptide (6) has the effect of obviously improving the expression of multiple inflammatory factors (IL-6, IL-8 and TNF-alpha), thereby playing a better relieving role.
In still another aspect, the present invention provides a use of myristoyl pentapeptide-4 cyclic peptide for preparing a preparation for promoting expression of Collagen type i, FLG or TGM1, or increasing skin moisture content, wherein the structural formula of the cyclic pentapeptide compound is shown in formulas (11), (12), (13), (14):
in still another aspect, the present invention provides a use of a palmitoyl tripeptide-5 cyclic peptide for preparing a preparation for promoting expression of Collagen type i, FLG or TGM1, or for increasing skin moisture content, wherein the structural formula of the cyclic pentapeptide is shown in formulas (16), (17):
in still another aspect, the present invention provides a hexapeptide-9 cyclic peptide, which is prepared by subjecting hexapeptide-9 to amide bond cyclization, wherein the hexapeptide-9 cyclic peptide has a structural formula as shown in formula (2), formula (3) or formula (4), or an enantiomer thereof.
In yet another aspect, the present invention provides a palmitoyl pentapeptide-4 cyclic peptide, wherein the palmitoyl pentapeptide-4 cyclic peptide is prepared by performing amide bond cyclization on palmitoyl pentapeptide-4, and the palmitoyl pentapeptide-4 cyclic peptide has a structural formula shown as formula (6), formula (7), formula (8) or formula (9), or an enantiomer shown as formula (6), formula (7), formula (8) or formula (9).
In still another aspect, the present invention provides a myristoyl pentapeptide-4 cyclic peptide, wherein the myristoyl pentapeptide-4 cyclic peptide is prepared by performing amide bond cyclization on myristoyl pentapeptide-4, and the myristoyl pentapeptide-4 cyclic peptide has a structural formula shown in formula (11), formula (12), formula (13) or formula (14), or an enantiomer shown in formula (11), formula (12), formula (13) or formula (14).
In yet another aspect, the present invention provides a palmitoyl tripeptide-5 cyclic peptide, wherein the palmitoyl tripeptide-5 cyclic peptide is prepared by performing amide bond or ester bond cyclization on palmitoyl tripeptide-5, and the structural formula of the palmitoyl tripeptide-5 cyclic peptide is shown as formula (16) or formula (17), or an enantiomer of formula (16) or formula (17).
The beneficial effects of the invention are as follows:
1) A group of cyclic peptides with superior properties including hexapeptide-9 cyclic peptide, palmitoyl pentapeptide-4 cyclic peptide, myristoyl pentapeptide-4 cyclic peptide, palmitoyl tripeptide-5 cyclic peptide were found;
2) It was found that hexapeptide-9 cyclic peptide, palmitoyl pentapeptide-4 cyclic peptide, myristoyl pentapeptide-4 cyclic peptide, palmitoyl tripeptide-5 cyclic peptide can be prepared by an amide/esterification method, and a series of cyclic peptide structures with better efficacy can be selected from the above;
3) The hexapeptide-9 cyclic peptide, palmitoyl pentapeptide-4 cyclic peptide, myristoyl pentapeptide-4 cyclic peptide and palmitoyl tripeptide-5 cyclic peptide are found to have higher stability and affinity and stronger application potential in the anti-aging field compared with the original linear structure;
4) The hexapeptide-9 cyclic peptide, palmitoyl pentapeptide-4 cyclic peptide, myristoyl pentapeptide-4 cyclic peptide and palmitoyl tripeptide-5 cyclic peptide are superior to other cyclic structures in stability, efficacy and the like compared with cyclic peptides with intermediate cyclization and end cyclization, and meanwhile, the hexapeptide-9 cyclic peptide has the effects of promoting the expression of Collagen Collagen I, FLG or TGM1 and improving the skin moisture content;
5) The head-tail cyclized hexapeptide-9 cyclic peptide also has better whitening application, and the head-tail cyclized palmitoyl pentapeptide-4 cyclic peptide also has better relieving effect;
6) The development of a technology capable of improving the comprehensiveness of the polypeptide, increasing new targets of the polypeptide and verifying the efficacy is a direction with potential for realizing high-energy polypeptide, greatly improving the utilization rate of raw materials and improving the efficacy.
Drawings
FIG. 1 is a schematic diagram showing the promotion of the expression of the Collagen I gene by hexapeptide-9 linear peptide and cyclic peptide of example 5;
FIG. 2 is a schematic diagram showing promotion of Collagen I gene expression by palmitoyl pentapeptide-4 linear peptide and cyclic peptide of example 5;
FIG. 3 is a schematic representation of myristoylpentapeptide-4 linear peptide and cyclic peptide promotion of Collagen I gene expression in example 5;
FIG. 4 is a schematic diagram showing promotion of Collagen I gene expression by palmitoyl tripeptide-5 linear peptide and cyclic peptide of example 5;
FIG. 5 is a graph showing the FLG and TGM1 promotion rates of hexapeptide-9 linear and cyclic peptides of example 6;
FIG. 6 is a graph showing the FLG and TGM1 promotion rates of palmitoyl pentapeptide-4 linear peptide and cyclic peptide of example 6;
FIG. 7 is a graph showing the FLG and TGM1 promotion rates of myristoylpentapeptide-4 linear peptide and cyclic peptide of example 6;
FIG. 8 is a graph showing the FLG and TGM1 promotion rates of palmitoyl tripeptide-5 linear and cyclic peptides of example 6;
FIG. 9 is a graph showing the effect of hexapeptide-9 linear and cyclic peptides on melanin content in example 8;
FIG. 10 is a graph showing the results of inhibition of IL-6 expression by palmitoyl pentapeptide-4 linear peptide and cyclic peptide of example 9;
FIG. 11 is a graph showing the results of inhibition of IL-8 expression by palmitoyl pentapeptide-4 linear peptide and cyclic peptide of example 9;
FIG. 12 is a graph showing the result of inhibiting TNF- α expression by palmitoyl pentapeptide-4 linear peptide and cyclic peptide of example 9.
Detailed Description
The following description of the preferred embodiments of the present invention in further detail with reference to the accompanying drawings, it should be noted that the following embodiments are intended to facilitate an understanding of the present invention, and are not intended to limit the invention in any way, and all of the features disclosed in the embodiments of the present invention, or all of the steps in the methods or processes disclosed, can be combined in any way, except mutually exclusive features and/or steps.
In the following examples, the experimental methods, unless otherwise specified, were all conventional. Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
Example 1: preparation of hexapeptide-9 cyclic peptides
The hexapeptide-9 cyclic peptide is prepared by an amide bond cyclization method, and two hexapeptide-9 cyclic peptides with structural formulas are prepared in the embodiment, wherein the two hexapeptide-9 cyclic peptides are shown as formula (2), formula (3) and formula (4):
the preparation process comprises the following steps:
step 1: fmoc-Gly-OH (4.46 g,15 mmol) and HOBt (2.03 g,15 mmol) were taken in a 100mL beaker, cooled to 4 ℃, 25mL of DMF solution was added, DIC (2.3 mL,15 mmol) was allowed to stand still for reaction for 20 minutes, and the 100mL beaker solution was added to a 125mL solid phase synthesis reactor, and the reaction was stirred for 1.5 hours and completed; the resin was washed three times with 65mL of DMF solution each time; after the washing is finished, 65mL of 20% pip/DMF solution is added, the mixture is stirred and reacts for 30min, suction filtration is carried out, the protective solution is removed, then the mixture is washed for 6 times by 65mL of DMF solution, and suction drying is carried out for standby;
step 2: fmoc-Pro-OH (5.06 g,15 mmol) and HOBt (2.03 g,15 mmol) were taken in a 100mL beaker, cooled to 4 ℃, 25mL of DMF solution was added, DIC (2.3 mL,15 mmol) was allowed to stand still for reaction for 20 minutes, and the solution in the 100mL beaker was added to a 125mL solid phase synthesis reactor, and the reaction was stirred for 1.5 hours and completed; the resin was washed three times with 65mL of DMF solution each time; after the washing is completed, 65mL of 20% pip/DMF solution is added, the reaction is stirred for 30min, suction filtration is carried out, the protection solution is removed, then the reaction product is washed 6 times with 65mL of DMF solution, 2 times with 65mL of methanol, 2 times with 65mL of DCM solution and 2 times with 65mL of methanol;
Step 3: fmoc-Gln (Trt) -OH and HOBt (2.03 g,15 mmol) were taken in a 100mL beaker, cooled to 4 ℃, 25mL of DMF solution was added, DIC (2.3 mL,15 mmol) was allowed to stand still for reaction for 20 minutes, and the solution in the 100mL beaker was added to a 125mL solid phase synthesis reactor, and the reaction was stirred for 1.5 hours and completed; the resin was washed three times with 65mL of DMF solution each time; after the washing is finished, carrying out the next reaction; adding 65mL of 20% pip/DMF solution, stirring and reacting for 30min, filtering, removing the protective solution, washing 6 times with 65mL of DMF solution, and drying in a pumping way to be carried out in the next step;
step 4: vacuum drying, adding 200mL of 1% TFA/DCM solution, stirring at 30 ℃ for reaction for 30 minutes, filtering, and removing resin to obtain filtrate; pumping the filtrate to obtain full-protection polypeptide H-Gly-Pro-Gln (Trt) -Gly-Pro-Gln (Trt) -OH;
step 5: the fully protected polypeptide was dissolved in 1.4L of Dichloromethane (DCM), DIC (1.54 mL,10 mmol), HOBt (1.35 g,10 mmol), DIEA (1.74 mL,10 mmol) was added and reacted with stirring at 30℃for 14 hours to form Cyclo (Gly-Pro-Gln (Trt) -Gly-Pro-Gln (Trt)), and DCM was concentrated to remove DCM for the next step;
step 6: cyclo (Gly-Pro-Gln (Trt) -Gly-Pro-Gln (Trt)) was treated with TFA/TIS/H 2 O=90/5/5 (70 mL) for 2.5 hours, adding the cutting solution into 700mL of tert-butyl methyl ether (4 ℃) solution, separating out white solid, and centrifuging to obtain white solid crude peptide; drying the white solid crude peptide under vacuum drying to obtain crude peptide powder Cyclo (Gly-Pro-Gln-Gly-Pro-Gln); purifying by reversed phase C18 preparative chromatography, and lyophilizing to obtain refined Cyclo (Gly-Pro-Gln-Gly-Pro-Gln) with chemical structure shown in formula (2). 1 HNMR(400MHz,D 2 O),δppm:8.65(s,4H),δ7.03(s,4H),δ4.40-4.44(m,4H),δ4.08-4.10(d,4H),δ3.41-3.51(m,4H),δ1.92-2.33(m,16H).C 24 H 36 N 8 O 8 ,[M+H]+＝565.20.
The starting material used, the preparation method, and the structure of the catalyst were substantially the same as in example 1, except that after obtaining the linear peptide, fmoc was first selectively protected with free-NH at both ends of the linear chain 2 And performing chromatographic purification, amidating the linear free carboxyl group and the residual unprotected amino group through amidation to obtain a product, and performing deprotection to obtain the formula (3). 1 H NMR(400 MHz,D 2 O)δppm 10.0(s,1H),δ8.70(s,2H),δ8.32(d,1H),δ7.50(t,2H),δ7.03(s,2H),δ4.40-4.44(m,4H),δ4.08-4.10(m,2H),δ3.54-3.41(m,6H),δ1.92-2.21(m,16H).C 24 H 36 N 8 O 8 ,[M+H]+＝565.27.
The starting materials used in the structure of formula (4) and the preparation method are basically the same as those in example 1, except that Gln added at the end of step 3 selectively protects one free carboxyl group, then the purification of the free carboxyl group is performed, HOBt coupling is performed, the rest refers to formula (2), and deprotection is performed to obtain the formula (4). 1 HNMR(400 MHz,D 2 O)δppm 11.06(d,1H),δ9.04(s,1H),δ8.70(s,2H),δ8.32(d,2H),δ7.03(s,2H),δ4.40-4.44(m,3H),δ4.09(s,2H),δ3.99(t,1H),δ3.41-3.51(m,6H),δ1.92-2.21(m,16H).C 24 H 36 N 8 O 8 ,[M+H]+＝565.27.
Example 2: preparation of palmitoyl pentapeptide-4 cyclic peptide
In this example, palmitoyl pentapeptide-4 cyclic peptide is prepared by an amide bond cyclization method, and 4 palmitoyl pentapeptide-4 cyclic peptides with structural formulas shown in formula (6), formula (7), formula (8) or formula (9) are prepared in total:
The preparation process comprises the following steps:
step 1. Preparation of Fmoc-Ser (tBu) -Wangresin 1.71g Wangresin was put into a reaction column, washed once with DMF and drained; swelling with appropriate amount of dry dichloromethane at normal temperature, N 2 Stirring for 30min until the resin is fully swelled, and pumping the liquid; washing once by DMF and pumping; the DMF is distilled again and washed once and dried. 5ml of a solution of 3.07g Fmoc-Gly-OH, 1.30g HOBt, 1.49ml DIC in DMF/DCM (1:1) was added. After 5min of reaction, 0.10g of DMAP was added and the reaction was continued for 4h. After the reaction, the reaction solution was drained, washed three times with DMF and drained, and a small amount of resin was taken out for substitution detection. 200ml of blocking reagent (AC 2O/pyridine (7:6, V: V)) were then added, reacted for 8-16h, and washed 2 times with DMF; washing twice (10 min/time) with absolute methanol, and drying under reduced pressure to constant weight. The degree of substitution of Fmoc-Ser (tBu) -Wang Resin was determined to be 0.71mmol/g. Preparation of matrixyl-Wang Resin 1) in Fmoc-Ser (tBu) -Wang Resin reaction column, DCM was added to swell for 20-30min and pumped off. Deprotection was performed 2 times (5+10 min) with addition of DBLK solution (piperidine/DMF (V/V) =1:4), and washing with DMF for 1min was required between the two deprotection steps, and the solution was removed. After the two deprotection pumps are removed, DMF, methanol, DCM and DMF are used for washing 1 time each for charging.
Step 2. In the deprotection process, 0.93g Fmoc-lys (palmitoyl) -OH and 0.81g HOBt are weighed into a beaker, 2ml of refined DMF is added for dissolution, after complete dissolution, the beaker is placed into an ice bath for cooling for 2min, then 0.93ml DIC is added for activation in the solution for 8min, if white appearsThe color flocculent foam shows that the activation is complete, the white solid small particles in the activation liquid are filtered out by using a Buchner funnel, the obtained clear filtrate is poured into a reaction column, and DMF is added into the reaction column to regulate N 2 The resin is uniformly blown up, a drying pipe is sleeved, no wall hanging occurs in the reaction process, and if wall hanging occurs, a little of refined DMF is used for flushing the resin on the wall into the reaction liquid. And (3) reacting for 2 hours at room temperature, and after the indene is qualified, pumping out the reaction solution to continue to connect with the next amino acid.
Cleavage of matrixyl-Wang Resin Matrixyl Wang Resin 0.10.10 g dried to constant weight was placed in a glass flask, 4ml of TFA-benzylsulfide-anisole-EDT (volume ratio 95:5:3:2) was added with stirring in an ice bath, reacted for 30min, gradually warmed to room temperature, and reacted at room temperature for 2h. The resin was washed with a little TFA, the filtrate was poured into 40ml of dry glacial ethyl ether, a white solid was precipitated, centrifuged at 4000rpm for 4min, the supernatant was discarded, and the reaction was repeated 2 times, and dried under vacuum to give the crude peptide.
Step 4, adding 50ml of water and 50ml,MatrixylWang Resin of tetrahydrofuran into a 250ml three-necked flask with a thermometer and a stirrer under stirring, adjusting the pH to be 8.5 with 30% sodium hydroxide solution, concentrating under reduced pressure after reacting for 2 hours, adjusting the pH to be 2 with 6M hydrochloric acid, extracting 50ml of 1 with ethyl acetate, washing 15ml of 3 with brine, concentrating under reduced pressure to obtain white solid, and feeding; in a 250ml three-necked flask equipped with a thermometer and a stirrer, 30ml of tetrahydrofuran is added under stirring, after stirring for 2 hours at room temperature, the material is dripped into glacial ethyl ether, the qualified product is obtained by filtration, and the filter cake is dried in vacuum to obtain a white solid formula 6. 1 H NMR(400 MHz,D 2 O)δppm 8.30(s,1H),7.49(s,4H),5.36(d,2H),4.94(d,1H),4.62(m,2H),4.44(d,4H),3.96-4.16(2,2H),3.17-3.20(t,2H),2.68(m,2H),2.06(t,2H),1.16-1.90(m.50H),1.14(d,1H),0.88(s,3H).C 39 H 73 N 7 O 9 [M+H]+＝784.55.
The raw materials and the preparation method used in the structure shown in the formula (7) are basically the same as those in the formula (6), except that Fmoc-Ser (tBu) -Wangresin input in the step 1 is esterified, the rest refers to the formula (6), and deprotection is finally carried out to obtain the formula (7). 1 H NMR(400 MHz,D 2 O)δppm 8.31(s,4H),7.50(s,1H),5.36(d,2H),4.93(t,1H),4.62(d,2H),4.43-4.54(t,5H),3.91-4.16(m,2H),3.17-3.20(m,2H),2.71(t,2H),2.06(t,2H),1.20-1.17(m,47H),0.88(s,3H).C 39 H 73 N 7 O 9 [M+H]+＝784.55.
The structure is basically the same as that of the formula (8), except that after the linear peptide is obtained, one of free hydroxyl groups of the linear peptide is selectively protected, amino groups are subjected to chromatographic purification, and then amidation is performed on the free carboxyl groups of the linear peptide and the remaining unprotected amino groups to obtain a product, and deprotection is performed to obtain the formula (8). 1 H NMR(400 MHz,D 2 O)δppm 8.32(s,2H),7.51(s,3H),5.68(m,1H),5.36(d,1H),5.03(t,1H),4.62(m,1H),4.43(m,4H),4.01-4.26(m,2H),2.68(t,2H),2.06(t,2H),1.77(t,4H),1.5-1.53(m,10H),1.16-1.35(m,37H),0.88(s,3H).C 39 H 73 N 7 O 9 [M+H]+＝784.55.
The structure is basically the same as that of the formula (9), except that after the linear peptide is obtained, the other free hydroxyl group of the linear peptide is selectively protected, amino group is purified by chromatography, and then the free carboxyl group of the linear peptide and the residual unprotected amino group are amidated by amidation to obtain a product, and deprotection is carried out to obtain the formula (9). 1 H NMR(400MHz,D 2 O)δppm8.32(s,3H),7.51(s,2H),5.69(m,1H),5.36(d,1H),5.03(t,1H),4.61(m,1H),4.44(m,4H),4.014.25(m,2H),2.68(t,4H),2.04(t,2H),1.76(t,4H),1.5-1.54(m,10H),1.16-1.35(m,35H),0.89(s,3H).C 39 H 73 N 7 O 9 [M+H]+＝784.55.
Example 3: preparation of myristoyl pentapeptide-4 cyclic peptides
In this example, myristoyl pentapeptide-4 cyclic peptides were prepared by an amide bond cyclization method, and a total of 4 myristoyl pentapeptide-4 cyclic peptides of formula (11), formula (12), formula (13) or formula (14) were prepared:
the preparation process comprises the following steps:
the preparation method of formula (11) was as described in example 2, except that Fmoc-lys (palmitoyl) -OH was used as the starting material and Fmoc-lys (myristoyl) -OH was used as the starting material, and the preparation method was substantially the same as that of formula (6), to obtain formula (11) having nuclear magnetic data of: 1 H NMR(400 MHz,D 2 O)δppm 8.32(s,1H),7.50(s,4H),5.37(m,2H),4.94(m,1H),4.54-4.62(m,3H),4.44(m,4H),3.91-4.16(m,2H),3.17-3.20(t,2H),2.69(m.2H),1.16-2.05(m,45H)0.88(t,3H).C 37 H 69 N 7 O 9 [M+H]+＝756.52.
the starting material used for the formula (12) and the preparation method are substantially the same as those for the formula (7) in example 2, except that Fmoc-lys (palmitoyl) -OH used is changed to Fmoc-lys (myristoyl) -OH, to obtain the formula (12), whose nuclear magnetic data are: 1 H NMR(400 MHz,D 2 O)δppm 8.32(s,4H),7.5(s,1H),5.37(s.2H),4.94(s.1H),4.54-4.62(t,3H),4.44(t,4H),3.61-4.16(dt,2H),3.17(m.2H),2.69(t.2H),2.05(t.2H),1.16-2.05(m,33H)0.88(s,3H)C 37 H 69 N 7 O 9 [M+H]+＝756.52.
the starting material and the preparation method used in the formula (13) were substantially the same as those used in the preparation of the formula (8) in example 2, except that Fmoc-lys (palmitoyl) -OH was used instead of Fmoc-lys (myristoyl) -OH, to obtain the formula (13). 1 H NMR(400 MHz,D 2 O)δppm 8.30(s.2H),7.50(s.3H),5.63(m,1H),5.37(m,1H),5.03(m,1H),4.94(t,1H),4.62(m,1H),4.43(m,4H),4.01-4.26(m,2H),2.69(t,4H),2.05(t,2H),1.77(m,4H),1.16-1.53(m,40H),0.88(s,3H).C 37 H 69 N 7 O 9 [M+H]+＝756.52.
Or formula (14) is prepared by substantially the same starting material and preparation method as in example 2 for formula (9), except that Fmoc-lys (palmitoyl) -OH is used instead of Fmoc-lys (myristoyl) -OH. 1 H NMR(400 MHz,D 2 O)δppm 8.31(s.3H),7.51(s.2H),5.63(m,1H),5.36(m,1H),5.02(m,1H),4.94(t,1H),4.61(m,1H),4.43(m,4H),4.01-4.26(m,2H),2.70(t,4H),2.01(t,2H),1.76(m,4H),1.16-1.53(m,40H),0.88(s,3H).C 37 H 69 N 7 O 9 [M+H]+＝756.52.
Example 4: preparation of palmitoyl tripeptide-5 cyclic peptides
In the embodiment, palmitoyl tripeptide-5 cyclic peptides are prepared by an amide bond cyclization method, and two palmitoyl tripeptide-5 cyclic peptides with structural formulas are prepared together, wherein the palmitoyl tripeptide-5 cyclic peptides are shown in a formula (16) or a formula (17):
the preparation process comprises the following steps:
step 1; synthesis of Pal-Lys (Boc) -OH. 200ml of water, 21.51g (87.31 mmol) of NE- (tert-butoxycarbonyl) -L-lysine, were added with stirring to a 500ml three-necked flask equipped with a thermometer and a stirrer, the pH value was adjusted to 10 with 30% sodium hydroxide solution, 20g (72.76 mmol) of palmitoyl chloride was added dropwise with stirring, the pH value was adjusted to 10 with 30% sodium hydroxide solution, the reaction was completed for 3 hours at room temperature, a large amount of solid was precipitated with 6M hydrochloric acid to adjust the pH value to 2, and the solid was filtered, and the filter cake was dried in vacuo to give a white solid;
step 2: synthesis of Pal-Lys (Boc) -OSu. In a 250ml three-necked flask equipped with a thermometer and a stirrer, 60ml of tetrahydrofuran and 10g (20.63 mmol) of pal-Lys (Boc) -OH are added under stirring, the temperature is reduced to 0 to 5 ℃, 2.62g (22.69 mmol) of N-hydroxysuccinimide is added, 4.75g (24.76 mmol) of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride is added in portions for reaction at room temperature for 16 hours, the mixture is filtered, the mixture is concentrated under reduced pressure to obtain a white solid, the filter cake is pulped with 20ml of isopropanol and then filtered, and the filter cake is dried in vacuum to obtain a white solid;
Synthesis of Val-NCA. 100ml of tetrahydrofuran, 10g (85.36 mmol) of valine and 12.67g (42.68 mmol) of triphosgene are added into a 250ml three-necked flask provided with a thermometer and a stirrer under stirring, the mixture is reacted for 2 hours at 50 ℃, the mixture is concentrated under reduced pressure, 100ml of petroleum ether is added after the concentration, the mixture is pulped for half an hour, the mixture is filtered, and a filter cake is dried in vacuum to obtain a white solid;
step 4.H Synthesis of Val-Lys (Boc) -OH. In a 250ml three-necked flask equipped with a thermometer and a stirrer, 50ml of water, 40ml of tetrahydrofuran and 2.51g (62.87 mmol) of sodium hydroxide are added under stirring, 13.77g (55.89 mmol) of NE- (tert-butoxycarbonyl) -L-lysine is stirred and dissolved, a cold trap is cooled to 0-5 ℃ and 10g (69.86 mmol) of Val-NCA is added while controlling pH to 10 by 30% sodium hydroxide solution, the temperature of the material is controlled to 0-5 ℃, the mixture is heated to 25 ℃ after the dropwise addition is completed and reacted for 2 hours, then 6M hydrochloric acid is used for adjusting pH to = 2, 20ml x 3 is extracted by n-butanol, 20ml x 3 is washed by brine, 5g of magnesium sulfate is added, the mixture is stirred for half an hour and filtered, and the mixture is concentrated under reduced pressure to obtain oily substance;
synthesis of pal-Lys (Boc) -Val-Lys (Boc) -OH. In a 250ml three-necked flask equipped with a thermometer and a stirrer, 50ml of water, 50ml of tetrahydrofuran, 10g (17.19 mmol) of pal-Lys (Boc) -OSu, H-Val-Lys (Boc) -oh7.12g (20.63 mmol) were added under stirring, the pH was adjusted to 8.5 with 30% sodium hydroxide solution, after 2 hours of reaction, the mixture was concentrated under reduced pressure, the pH was adjusted to 2 with 6M hydrochloric acid, 50ml of 1 was extracted with ethyl acetate, 15ml of 3 was washed with brine, and the mixture was concentrated under reduced pressure to give a white solid;
Step 6, adding 30ml of tetrahydrofuran, pal-Lys (Boc) -Val-Lys (Boc) -OH 10g (12.53 mmol) and stirring H-Lys (Boc) -OH for 2 hours at room temperature in a 250ml three-necked flask with a thermometer and a stirrer, dripping the material into glacial ethyl ether, filtering to obtain a qualified product, and vacuum drying a filter cake to obtain a white solid type 16, wherein the nuclear magnetic data are as follows: 1 H NMR(400MHz,D 2 O)δppm 8.30(s,3H),7.49(s,1H),4.43(m,2H),4.34(d.1H),3.17-3.20(dt,2H),2.73(m,1H),2.68(m,2H),2.04(t,2H),1.26-1.90(m,43H),0.96(d,6H),0.88(t,3H).C 33 H 63 N 5 O 4 [M+H]+＝594.49.
the raw material used in the structure shown in the formula (17) and the preparation method are basically the same as those in the formula (16), except that Fmoc-Lys (Boc) -OH raw material finally input in the step 5 is subjected to ester bond cyclization, chromatographic purification, HOBt coupling, the rest of the raw material is referred to in the formula (16), and deprotection is performed to obtain the formula (17). 1 H NMR(400MHz,D 2 O)δppm 8.31(s,1H),7.49(s,3H),4.43-4.44(m,3H),3.17-3.20(dt,2H),2.74(m,1H),2.69(m,2H),2.04(t,2H),1.26-1.90(m,41H),0.96(d,6H),0.88(t,3H).C 33 H 63 N 5 O 4 [M+H]+＝594.49.
Example 5: polypeptide application in vitro anti-wrinkle efficacy test
Collagen is mainly produced by fibroblasts existing in the dermis layer of the skin and is an important element for supporting the skin, wherein Collagen I is the specific gravity of Collagen I accounting for about 80% of the dermis layer of the skin, so that the skin is full, the increase of the content of the Collagen I is promoted, and the effect of resisting the generation of wrinkles can be achieved to a certain extent. The reduction of Collagen I is evident from the UV-irradiated ex-vivo skin, and thus the anti-photoaging and anti-wrinkle efficacy of the actives to be tested can be assessed by examining the changes in Collagen I described above. In the embodiment, based on UVA irradiation of fibroblasts, the anti-wrinkle effect of a sample to be tested is evaluated by detecting the expression condition of the Collagen I gene after the sample acts.
The cells used in the test used in this example are fibroblasts, all commercially available. The main reagent comprises: DMEM broth (Gibco), PBS (Soxhausto), MTT (Sigma), DMSO (Sigma), RNAisoPlus (Takara), reverse transcription kit (PrimeScript) TM RTreagentKit)(Takara)、SYBRPremixExTaq TM II fluorescent dye (Takara), sterile ddH 2 O (Takara), TGF-. Beta.1 (Peprotech). Main plant CO 2 Incubator (Thermo, 150I), ultra clean bench (Sujingtai, SW-CJ-1F), incubator (Teste), general PCR instrument (Bori), fluorescent quantitative PCR instrument (BioRad, CFX-96), inverted microscope (Olympus, CKX 41), UVA irradiator (Philips).
The experimental process comprises the following steps: uniformly distributing the sample on the surface of the model, and placing the model on CO 2 Incubator (37 ℃,5% CO) 2 ) And incubated for 24h. After the incubation, the sample remained on the surface of the model was washed with sterile PBS solution, and the inner and outer residual liquids of the model were wiped off with sterile cotton swabs.
The procedure for anti-wrinkle efficacy test was as follows:
1) Cell inoculation: according to 4X 10 4 Seed density of cells/well fibroblasts were seeded into 24 well plates, incubator (37 ℃,5% co) 2 ) Incubate overnight. 2) Preparing liquid: test object working solutions were prepared according to the test protocols (table 1), respectively. 3) Administration: according to the test scheme, when the cell plating rate in the 24-hole plate reaches 40% -60%, grouping drug administration is carried out, and 3 compound holes are arranged in each group. After the completion of the administration, the 6-well plate was placed in an incubator (37 ℃,5% CO) 2 ) Is cultured for 24 hours. Samples 1-17 correspond to: formulas 1-17.
Table 1, experimental design
4) UVA irradiation: according to the test scheme, UVA irradiation is carried out on the groups needing to be irradiated, and the irradiation dose is 30J/cm 2 . After the irradiation, the mixture was placed in an incubator (37 ℃ C., 5% CO) 2 ) The culture was continued for 24 hours. 5) Collecting cells: after 24h incubation, cell supernatants were collected, washed twice with 1 mL/well PBS, 1mLRNAisoPlus was added to each well, and after lysis of cells by blowing, samples were collected. 6) And (3) gene expression detection: RNA was extracted, reverse transcribed to cDNA, and then subjected to fluorescent quantitative PCR detection, and the result was calculated by a 2-DeltaCT method.
The experimental results are shown in figures 1-4 and table 2, and figure 1 is a column diagram of hexapeptide-9 linear peptide and cyclic peptide for promoting the expression of Collagen I gene; FIG. 2 is a bar graph of palmitoyl pentapeptide-4 linear peptide and cyclic peptide promoting the expression of the Collagen I gene; FIG. 3 is a bar graph of myristoyl pentapeptide-4 linear peptide and cyclic peptide promoting expression of the Collagen I gene; FIG. 4 is a histogram of palmitoyl tripeptide-5 linear and cyclic peptides promoting the expression of the Collagen I gene.
TABLE 2 Collagen I promotion rate (%)
| Sequence number | Group of | Collagen I promotion Rate (%) |
| 1 (1) | Sample 1 (straight chain 1-1) | 99 |
| 2, 2 | Sample 2 (Ring 1-1) | 150 |
| 3 | Sample 3 (Ring-shaped 1-2) | 105 |
| 4. The method is to | Sample 4 (Ring shape 1-3) | 90 |
| 5. The method is to | Sample 5 (straight chain 2-1) | 70 |
| 6. The method is to | Sample 6 (Ring-shaped 2-1) | 110 |
| 7. The method of the invention | Sample 7 (Ring-shaped 2-2) | 95 |
| 8. The method is used for preparing the product | Sample 8 (Ring-shaped 2-3) | 90 |
| 9. The invention is applicable to | Sample 9 (Ring-shaped 2-4) | 85 |
| 10. The method of the invention | Sample 10 (straight chain 3-1) | 71 |
| 11. The method of the invention | Sample 11 (Ring 3-1) | 112 |
| 12. Fig. | Sample 12 (Ring 3-2) | 68 |
| 13 of the group | Sample 13 (Ring 3-3) | 89 |
| 14, of the order of magnitude | Sample 14 (Ring 3-4) | 90 |
| 15 of the formula | Sample 15 (straight chain 4-1) | 65 |
| 16, respectively | Sample 16 (Ring-shaped 4-1) | 100 |
| 17 (17) | Sample 17 (Ring-shaped 4-2) | 70 |
As can be seen from Table 2 and FIGS. 1 to 4, the samples differed in the promotion rate (%) of Collagen I expression.
As can be seen from FIG. 1, compared with the sample hexapeptide-9 linear peptide, 1-1 and 1-2 after cyclization have corresponding promotion in promoting the expression of the Collagen I gene, and the modification of the hexapeptide-9 linear peptide proves to be advantageous, while 1-3 does not obviously promote the expression of the Collagen I gene, but also has a descending trend; the different structures obtained after cyclization are different in effect of improving the expression of the Collagen I gene, and the hexapeptide-9 cyclic peptide (2) has the best effect, probably because the formula (2) is an amide bond six-membered ring, the 6 amide bonds are the most stable, the effects are the most obvious after the amide bonds on the ring are stable, and 1-3 are linear terminal cyclization, and only 1 amide bond is on the ring, so that the six-membered peptide has no advantage in promoting the expression of Collagen Collagen I compared with the linear peptide.
As can be seen from FIG. 2, compared with the palmitoyl pentapeptide-4 linear peptide, the cyclized 2-1, 2-2, 2-3 and 2-4 have corresponding promotion on the gene expression of Collagen I, and the modification of the palmitoyl pentapeptide-4 linear peptide proves to be advantageous; meanwhile, the different structures obtained after cyclization are different in effect of improving the expression of the Collagen I gene, and palmitoyl pentapeptide-4 cyclopeptide 2-1 (formula (6)) has better effect than other annular structures, probably because compared with 2-2, 2-3 and 2-4, the palmitoyl pentapeptide-4 cyclopeptide has five-membered rings and 5 amide bonds on the rings, and the other three-membered rings, and meanwhile, the more amide bonds on the rings are indicated to have better effect.
As can be seen from FIG. 3, compared with the myristoyl pentapeptide-4 linear peptide, 3-1, 3-3 and 3-4 after cyclization have corresponding promotion on the expression of the Collagen I gene, and the modification of the myristoyl pentapeptide-4 linear peptide proves to be advantageous, while 3-2 does not obviously promote the expression of the Collagen I gene, but also has a descending trend; the different structures obtained after cyclization can be distinguished from each other in terms of the effect of improving the expression of the Collagen I gene, and myristoyl pentapeptide-4 cyclic peptide 3-1 (formula (11)) has the best effect compared with other cyclic structures, probably because the formula (11) is five-membered ring, most stable, 5 amide bonds are all on the ring, meanwhile, the more the effect of the amide bonds on the ring is better, 3-2 is straight-chain terminal cyclization, only 2 amide bonds are on the ring, and the effect is not superior to the effect of promoting the expression of Collagen Collagen I compared with the straight-chain peptide.
As can be seen from FIG. 4, compared with the palmitoyl tripeptide-5 linear peptide, the 4-1 and 4-2 after cyclization have corresponding promotion on the expression of the Collagen I gene, and the modification of the palmitoyl tripeptide-5 linear peptide proves to be advantageous; meanwhile, the different structures obtained after cyclization are different in effect of improving the expression of the Collagen I gene, and the palmitoyl tripeptide-5 cyclic peptide (17) has the best effect compared with other cyclic structures, probably because the formula (17) is a three (amido bond) membered ring and is more stable, the formula (16) is a linear end cyclization, and only 1 amido bond is on the ring, so that the palmitoyl tripeptide-5 cyclic peptide has no advantage in promoting the expression of Collagen Collagen I compared with the linear peptide.
Example 6: polypeptide application in vitro repair efficacy test
Some substances to be tested with stronger skin contact irritation or ultraviolet rays and the like can cause clinical acute damage to skin barriers, dry skin and erythema. The anionic surfactant SLS has amphiphilic (hydrophilic and lipophilic) character and is capable of damaging the skin barrier, especially the lipid components of the barrier and the cell membrane, after contact with the skin at large concentrations. Filaggrin (FLG) is a key component in the CE assembly process, and FLG, in addition to being a structural component of the skin barrier, can be hydrolyzed by Caspase-14 to form natural moisturizing factors. Transglutaminase 1 (TGM 1) is the major subtype of three TGMs expressed in the epidermis, TGM1 encodes a membrane-associated calcium-dependent thiol enzyme with the ability to transfer amino acids to glutamate residues of proteins to form isopeptidic bonds, involved in the formation of epsilon- (gamma glutamyl) lysine crosslinks during the formation of the cuticle. The cross-linking is very stable, can resist the hydrolysis of protease, is a key step of the terminal differentiation of keratinocytes to form a keratinocyte envelope, and is a material basis of skin barrier function. The reduction of TGM1 protein content is another key indicator of impaired skin barrier function. Therefore, the repair efficacy of the test substance can be evaluated by detecting changes in the content of silk-polymer protein (FLG) and the content of TGM1 protein after administration.
And (3) a testing system: the model used in this test is a 3D epidermis skin modelCommercially available.
The main reagent comprises: epiGrow broth (Boxi organism), WY14643 (Sigma), FLG antibody (Abcam), TGM1 antibody (Abcam) SLS (Sigma) DMEM broth (Gibco). The main equipment comprises: CO 2 Incubator (Thermo, 150I), ultra clean bench (Suzhou Antai, SW-CJ-1)F) Microplate reader (BioTek, epoch), fluorescence microscope (Leica, DM 2500).
The operation steps are as follows: 1. and (3) preparing a working solution: 1) 0.2% SLS working solution configuration: 1mL of 0.4% SLS solution was aspirated, and 1mL of PBS was added to prepare 0.2% SLS working solution; 2) Positive control (50 μm WY 14643) working fluid configuration: mu.L of WY14643 mother liquor (30 mM) was added to 6mL of the model culture broth to prepare a 50. Mu.M working solution.
Model drug administration: 1) According to the test packets of table 2, the model was transferred to 6-well plates (0.9 mL of EpiGrowth broth added in advance), and test group numbers were noted on the 6-well plates; 2) Adding 12.5 mu L of 0.4% SLS solution and 12.5 mu L of sample working solution with corresponding concentration on the surface of a sample group, distributing the sample on the surface of a model, and placing the model on CO 2 Incubator (37 ℃,5% CO) 2 ) Incubating for 24 hours; 3) After the incubation, the sample remained on the surface of the model was washed with sterile PBS solution, and the inner and outer residual liquids of the model were wiped off with sterile cotton swabs. Samples 1-17 correspond to: formulas 1-17.
Table 2, test packet
Immunofluorescence test: taking a model for detection, performing fixation treatment by using 4% paraformaldehyde, performing immunofluorescence detection of silk-Fibroin (FLG) content after 24 hours of fixation, photographing and observing under a microscope, and collecting and analyzing pictures. The Integrated Optical Density (IOD) values between groups are indirectly related to the results, and all group number results are counted in table 3. The results are shown in Table 3 and FIGS. 5-8.
TABLE 3 FLG, TGM1 promotion rates of the respective structures
As can be seen from Table 3 and FIGS. 5 and 6, the respective samples differed in the promotion rate (%) of FLG and TGM1 expression.
Compared with the hexapeptide-9 linear peptide, the promotion rate of FLG and TGM1 expression can be obviously improved by 1-1 and 1-2 after cyclization, but 1-3 is not obviously different from that of the linear peptide, and the promotion rate of FLG and TGM1 expression by different hexapeptide-9 cyclic peptides obtained after cyclization is completely different, wherein the most preferable hexapeptide-9 cyclic peptide 1-1 (formula 2) is that the formula (2) is a six (amide bond) membered ring, the most stable is that 6 amide bonds are all on the ring, the more and better effects of the amide bonds on the ring are also indicated, and the 1-3 is that the linear terminal cyclization is that only 1 amide bond is on the ring, and the promotion of FLG and TGM1 expression is not advantageous compared with the linear peptide.
Compared with the palmitoyl pentapeptide-4 linear peptide, the promotion rate of FLG and TGM1 expression can be obviously improved by all 2-1, 2-2 and 2-3 after cyclization, but 2-4 is not obviously different from that of the linear peptide, and the promotion rate of FLG and TGM1 expression by different palmitoyl pentapeptide-4 cyclic peptides obtained after cyclization is completely different, wherein the most preferred palmitoyl pentapeptide-4 cyclic peptide 2-1 (formula 6) is probably because the formula (6) is a five-membered ring, 5 amide bonds are arranged on the ring, and the other three-membered rings are all three-membered rings, and meanwhile, the more amide bonds on the ring are better.
Compared with the myristoylpentapeptide-4 linear peptide, 3-1, 3-3 and 3-4 after cyclization can significantly improve the promotion rate of FLG and TGM1 expression, but 3-2 cannot be improved, and there is a downward trend, so that the promotion rate of FLG and TGM1 expression is completely different by different myristoylpentapeptide-4 cyclic peptides obtained after cyclization, wherein myristoylpentapeptide-4 cyclic peptide 3-1 (formula 11) is most preferred, the reason is probably that the formula (11) is a five-membered ring, 5 amide bonds are arranged on the ring, the effect is better when the amide bonds on the ring are more, and 3-2 is in the linear terminal cyclization, and only 2 amide bonds are arranged on the ring, so that the promotion of FLG and TGM1 expression is not advantageous compared with the linear peptide.
The 4-2 after cyclization significantly increased the rate of promotion of FLG and TGM1 expression compared to the palmitoyl tripeptide-5 linear peptide, while 4-1 did not significantly differ from the linear peptide, and it was seen that the different palmitoyl tripeptide-5 cyclic peptides obtained after cyclization also showed completely different rates of promotion of FLG and TGM1 expression, with palmitoyl tripeptide-5 cyclic peptide 4-2 (formula 17) being most preferred, probably because formula (17) is a three (amide bond) membered ring, more stable, and formula (16) is a linear terminal cyclization, with only 1 amide bond on the ring, and not advantageous in promoting FLG and TGM1 expression compared to the linear peptide.
Example 7: polypeptide application in vitro moisturizing efficacy test
When skin contacts with irritant factors, clinical acute damage to the skin barrier can occur, leading to dry skin and erythema. The moisture content of the skin is a main index for determining the health state of the skin, and is also an important parameter for evaluating the skin state related to moisture loss, and the moisturizing skin care agent can keep the moisture on the surface of the skin, moisten the surface of the skin and increase the capacitance on the surface of the skin. The higher its capacitance value indicates a higher moisture content of the stratum corneum.
The test uses a 3D epidermis skin modelFor the test tool, the moisturizing efficacy of the sample to be tested was evaluated by observing the change in skin moisture content of the epidermal skin model after administration by means of surface administration.
And (3) a testing system: 3D epidermal skin model for this testCommercially available.
The main reagent comprises: epiGrow broth (Boxi organism), PBS (Boshide). The main equipment comprises: CO 2 Incubator (Thermo, 150I), ultra clean bench (Suzhou Antai, SW-CJ-1F),CM 825 skin moisture tester (courage+khazakaelectronic).
The test protocol is shown in Table 4:
table 4, test protocol
The method comprises the following specific steps:
1. preparing a working solution: positive control group (glycerol) working solution preparation: is formulated into 20% glycerol.
2. Model drug administration: 1) The model was transferred to 6-well plates (0.9 mL of EpiGrowth broth added in advance) according to the test protocol of table 4, and test group numbers were noted on the 6-well plates; 2) The PC group and the sample group are added with working solution with corresponding concentration, the samples are uniformly distributed on the surface of the model and placed in CO 2 Incubator (37 ℃,5% CO) 2 ) And incubated for 24h.
3. Skin moisture content test: 1) Cleaning: and cleaning the sample on the surface of the model, lightly wiping the water remained on the surface by using a cotton swab, preparing 24 pore plates according to the number of the model after the completion of the cleaning, and marking correspondingly. 0.3mL of EpiGrow broth was added to each well. The 24-well plate with the model is placed in an ultra-clean workbench, the cover of the 24-well plate is opened, and the 24-well plate is kept stand for 30min for measurement. 2) And (3) instrument debugging: will be The CM 825 skin moisture test probe was connected to the MPA6 adapter, instrument measurement software was turned on, the measurement parameters were selected for moisture content, the measurement mode was selected for single point measurement, and the probe was then cleaned with 75% alcohol. 3) Measurement: the water at the bottom of the model was wiped dry, the model was cut out from the cell chamber bottom ring with a surgical blade, the model was placed on the probe of the tester with forceps, and then the probe was pressed for measurement, and each model was measured three times, 9 data were obtained, and an average value was taken.
4. Results statistical analysis: the test results are shown in Table 5.
TABLE 5 influence of different structures on skin moisture content
| Sample of | Group of | Skin moisture content (%) |
| Blank control | 55.3 | |
| 1 (1) | Sample 1 (straight chain 1-1) | 73 |
| 2, 2 | Sample 2 (Ring-shaped 1-1) | 167 |
| 3 | Sample 3 (Ring-shaped 1-2) | 96 |
| 4. The method is to | Sample 4 (Ring shape 1-3) | 82 |
| 5. The method is to | Sample 5 (straight chain 2-1) | 65 |
| 6. The method is to | Sample 6 (Ring-shaped 2-1) | 139 |
| 7. The method of the invention | Sample 7 (Ring-shaped 2-2) | 115 |
| 8. The method is used for preparing the product | Sample 8 (Ring-shaped 2-3) | 107 |
| 9. The invention is applicable to | Sample 9 (Ring-shaped 2-4) | 83 |
| 10. The method of the invention | Sample 10 (straight chain 3-1) | 61 |
| 11. The method of the invention | Sample 11 (Ring 3-1) | 104 |
| 12. Fig. | Sample 12 (Ring 3-2) | 69 |
| 13 of the group | Sample 13 (Ring 3-3) | 86 |
| 14, of the order of magnitude | Sample 14 (Ring 3-4) | 83 |
| 15 of the formula | Sample 15 (straight chain 4-1) | 57 |
| 16, respectively | Sample 16 (Ring-shaped 4-1) | 88 |
| 17 (17) | Sample 17 (Ring-shaped 4-2) | 62 |
As can be seen from Table 5, the effect of each structural sample on skin moisture (%). The cyclized 1-1, 1-2, 1-3 can all raise the skin moisture content compared to the hexapeptide-9 linear peptide, but the different hexapeptide-9 cyclic peptides obtained after cyclizing have a distinct difference in effect on raising the skin moisture content, with hexapeptide-9 cyclic peptide 1-1 (formula 2) being most preferred, followed by cyclic peptide 1-2 (formula 3) being seen to be more effective as more amide bonds on the hexapeptide-9 cyclic peptide. The cyclized 2-1, 2-2, 2-3, 2-4 can significantly increase the skin moisture content compared to the palmitoyl pentapeptide-4 linear peptide, but the different palmitoyl pentapeptide-4 cyclic peptides obtained after cyclizing have a significant difference in effect on increasing the skin moisture content, wherein the palmitoyl pentapeptide-4 cyclic peptide 2-1 (formula 6) is most preferred, probably because the formula (6) is a five-membered ring, 5 amide bonds are on the ring, and the other are all three-membered rings, and the more amide bonds on the ring are also indicated to have better effect. The effect of the different myristoylpentapeptide-4 cyclic peptides obtained after cyclization on the skin moisture content was clearly different compared with the myristoylpentapeptide-4 linear peptide, 3-1, 3-2, 3-3, 3-4 after cyclization was seen, and the most preferred myristoylpentapeptide-4 cyclic peptide 3-1 (formula 11) was that the effect was slightly worse than that of other cyclic peptides, because formula (11) was five-membered ring with 5 amide bonds on the ring, and it was also demonstrated that the more effect of amide bonds on the ring was better, 3-2 was a linear terminal cyclization, and only 2 amide bonds were on the ring. Compared with the palmitoyl tripeptide-5 linear peptide, the cyclized 4-1 and 4-2 can significantly improve the skin moisture content, and the different palmitoyl tripeptide-5 cyclic peptides obtained after cyclizing can be obviously different in effect of improving the skin moisture content, wherein the palmitoyl tripeptide-5 cyclic peptide 4-2 (formula 17) is most preferred, and the reason is probably that the formula (17) is a three-membered ring, so that the palmitoyl tripeptide-5 cyclic peptide is more stable and can effectively improve the skin moisture content.
Example 8: hexapeptide-9 cyclic peptide in vitro whitening efficacy test
The test provided in this example is based on melanocytes, and the detection of melanin content is performed to evaluate the whitening efficacy of the sample to be tested.
And (3) a testing system: the cells used in this test are melanocytes and are commercially available.
The main reagent comprises: m-254 broth (Boxi organism), MTT (Sigma), DMSO (Sigma), PBS (Boshide), fetal bovine serum (FBS, bright Rong, lanzhou). The main equipment comprises: CO 2 Incubator (Thermo, HF151 UV), ultra clean bench (Sujingtai, SW-CJ-1F), microplate reader (BioTek, epoch).
1. The testing method comprises the following steps: 1) Inoculating: according to 2X 10 5 Cell/well seeding density cells were seeded into 6-well plates and incubated overnight in incubator (37 ℃, 5% co 2); 2) Preparing liquid: preparing a test object working solution according to a specific test scheme (table 6); wherein the samples 1-2 are respectively shown in the formula 1 and the formula 2; 3) Administration: according to the test scheme of Table 6, when the cell plating rate in the 6-hole plate reaches 40% -60%, group administration is carried out, the administration amount of each hole is 2mL, 3 compound holes are arranged in each group, the culture solution is abandoned after incubation for 72 hours in an incubator (37 ℃ and 5% CO 2), and PBS is washed for 1 time; 4) Cell digestion: melanocytes (700 μl/well) were digested with 0.25% pancreatin, and when 80% of the cells were observed under a microscope to retract into a sphere without detachment from the attached surface at 37 ℃ for 1-2min, DMEM containing 10% fbs was added to terminate the reaction, and the cells were collected in 1.5mL EP tube and centrifuged at 10000r/min for 10min; 5) Preparing a mixed solution of distilled water, absolute ethyl alcohol and diethyl ether according to the ratio of 2:5:5, adding the mixed solution into an EP tube according to 1.2 mL/tube after uniformly mixing, standing for 30min at room temperature, and centrifuging for 10min at 10000 r/min; 6) 1mL of 1mol/L NaOH aqueous solution containing 10% DMSO is added, and sealing is carried out, and sealing tightness is ensured; 7) Placing the sample and the melanin standard substance solutions with different concentrations in a water bath at 80 ℃ for heating for 40min; 8) After room temperature, adding 200 mu L/hole of the solution into a 96-well plate in sequence, setting 2 compound holes for each EP pipe, and measuring absorbance value on an enzyme-labeled instrument by selecting 405nm wavelength; 9) And (3) taking OD values measured by standard substance solutions with different concentrations as an abscissa and the melanin content as an ordinate, obtaining a regression equation, and calculating the melanin content of the sample group.
TABLE 6 test protocol
2. Statistical analysis of results
GraphPad Prism was used to map and the results were expressed as mean±sd. Comparisons between groups were performed using t-test statistical analysis. All statistical analyses were double tailed. The results are shown in FIG. 9.
The results showed that compared with the BC group, the melanin content of the sample hexapeptide-9 linear peptide sample 1 and the cyclic sample 2 is significantly reduced, and the inhibition rates are respectively 15.23% and 32.72%. It is shown that the sample 1 and the annular sample 2 can achieve the whitening effect by reducing the melanin content at the concentration. The cyclic sample 2 has significantly reduced melanin content compared to the hexapeptide-9 linear peptide. The cyclization of hexapeptide-9 has remarkable effect on whitening compared with the linear peptide, can better inhibit the expression of melanin in melanocytes, can achieve the whitening effect, and proves that the cyclization is beneficial.
Example 9: palmitoyl pentapeptide-4 in vitro soothing efficacy test
In the embodiment, 1 mug/mL of LPS is adopted to stimulate macrophages, and the relief efficacy of a sample to be tested is evaluated by detecting the change condition of the content of inflammatory factors (IL-6, IL-8 and TNF-alpha) after the sample acts.
And (3) a testing system: macrophages used in this test were obtained commercially.
The main reagent comprises: high glucose DMEM (Gibco), dexamethasone (Sigma), lipopolysaccharide LPS (e.coli.sigma), PBS (solebao), IL-6 ELISA kit (Abcam), IL-8 ELISA kit (Abcam), TNF-alpha ELISA kit (Abcam). The main equipment comprises: CO 2 Incubator (Thermo, 150I), ultra clean bench (Suzhou Antai, SW-CJ-1F), inverted microscope (Olympus, CKX 41), incubator (Test), microplate reader (BioTek, epoch).
The testing method comprises the following steps:
1. the test protocol is shown in Table 6, where samples 5, 6 are palmitoyl pentapeptide-4 linear and cyclic peptides 2-1 (formula 6), respectively.
TABLE 6 test protocol
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And (3) preparing a working solution: 1) Positive control (dexamethasone) working solution preparation: 0.01% dexamethasone was formulated. 2) Preparation of working solution containing 1. Mu.g/mL LPS: 2mg/mL LPS stock solution was diluted to 1. Mu.g/mL with the test substance working solution, negative control working solution and positive control working solution remaining after the administration, respectively.
2. The operation steps are as follows: 1) Cell inoculation: at 2.2X10 5 Cell was inoculated into 6-well plates, 2mL of cell suspension was added to each well, and the cell culture plates were placed in an incubator for continuous culture for 24 hours (5% CO) 2 37 ℃); 2) 1.8mL of culture solution containing the test substance with corresponding concentration is added into each hole of the sample group; 1.8mL of solvent control culture solution is added to each hole of the negative control group; adding 1.8mL of positive control culture solution into each hole of the positive control group; adding 1.8mL of normal culture solution into each hole of the blank control group; 3) After the completion of the administration, the 6-well plate was placed in a cell incubator (5% CO 2 Culturing at 37 ℃ for 2 hours. 4) LPS stimulation: after 2h of administration, 200. Mu.L of the prepared working solution containing LPS was added to each well of each group, and the mixture was placed in a cell incubator (5% CO) 2 Culturing was continued at 37℃for 22 hours. 5) IL-6, IL-8, TNF- α assay: cell culture supernatants were collected and assayed according to ELISA kit instructions.
3. Statistical analysis of results
GraphPad Prism was used to map and the results were expressed as mean±sd. Comparisons between groups were performed using t-test statistical analysis. P <0.05 was considered to have significant differences and P <0.01 was considered to have very significant differences. The results are shown in FIGS. 10-12, wherein FIG. 10 is a histogram of IL-6 content, FIG. 11 is a histogram of IL-8 content, and FIG. 12 is a histogram of TNF- α content.
Compared with NC groups, the IL-6 content of the palmitoyl pentapeptide-4 linear peptide-1% (v/v) and palmitoyl pentapeptide-4 cyclic peptide-1% (v/v) of the samples is obviously reduced, and the inhibition rate is 5.01% and 43.08%. Compared with NC groups, the IL-8 content of the palmitoyl pentapeptide-4 linear peptide-1% (v/v) and palmitoyl pentapeptide-4 cyclic peptide-1% (v/v) of the samples is obviously reduced, and the inhibition rates are 2.50% and 32.53%. Compared with NC groups, the content of TNF-alpha of the palmitoyl pentapeptide-4 linear peptide-1% (v/v) and palmitoyl pentapeptide-4 cyclic peptide-1% (v/v) of the samples is obviously reduced, and the inhibition rate is 3.05% and 39.74%.
The cyclized palmitoyl pentapeptide-4 cyclic peptide has obvious effect of inhibiting the expression of multiple inflammatory factors (IL-6, IL-8 and TNF-alpha) and can achieve a relieving effect, and the cyclized palmitoyl pentapeptide-4 cyclic peptide is obviously superior to the original palmitoyl pentapeptide-4 linear peptide in inhibiting the expression of IL-6, IL-8 and TNF-alpha genes, thus proving that cyclizing is beneficial.
While the foregoing embodiments have been described in connection with the exemplary embodiments of the invention, it should be understood that the foregoing embodiments are merely illustrative of the invention, and that any modifications, additions, substitutions and the like made without departing from the scope of the invention.
Claims (12)
1. A cyclic peptide comprising 1 to 6 amide bonds in the ring, wherein the cyclic peptide is prepared by cyclizing an amide bond/ester bond of hexapeptide-9, palmitoyl pentapeptide-4, myristoyl pentapeptide-4 or palmitoyl tripeptide-5, respectively.
2. The cyclic peptide of claim 1, having a general structural formula as shown in formula (a), formula (b) or formula (c), or an enantiomer thereof:
wherein R is selected from H, (CH) 2 )nCH 3 、(CH 2 )mNH 2 、(CH 2 ) X COOA1、(CH 2 ) m Any one of CONA 2; wherein n, m, x are independently selected from 0 or natural numbers; a1 and A2 are independently selected from H 2 、OH、NH 2 Any one or more of COOH, C1-18 alkyl, phenyl, heteroaryl.
3. The cyclic peptide of claim 2, wherein R in formulas (a) and (b) is (CH) 2 ) 3 CONH 2 The method comprises the steps of carrying out a first treatment on the surface of the The cyclic peptide is prepared by performing amide bond cyclization on hexapeptide-9, and the structural formula of the hexapeptide-9 is shown as a formula (1):
4. the cyclic peptide of claim 1, having a general structural formula as shown in formula (d), formula (e), formula (f) or formula (g), or an enantiomer thereof:
wherein R, R and R2 are independently selected from H and (CH) 2 )nCH 3 、(CH 2 )mNH 2 、(CH 2 ) X COOA1、(CH 2 ) m Any one of CONA 2; wherein n, m, x are independently selected from 0 or natural numbers; a1 and A2 are independently selected from H 2 、OH、NH 2 Any one or more of COOH, C1-18 alkyl, phenyl, heteroaryl.
5. The cyclic peptide of claim 4, wherein R1 and R2 in formula (e) are NH 2 (CH 2 ) 13 CH 3 、(CH 2 ) 4 NH 2 One of, or NH 2 (CH 2 ) 11 CH 3 、(CH 2 ) 4 NH 2 R1 and R2 are different; r in the formulas (f) and (g) is
The cyclic peptide is prepared by performing amide bond cyclization on palmitoyl pentapeptide-4 or myristoyl pentapeptide-4, wherein the structural formula of palmitoyl pentapeptide-4 is shown in a formula (5), and the structural formula of myristoyl pentapeptide-4 is shown in a formula (10):
6. The cyclic peptide of claim 1, having a general structural formula as shown in formula (h) or formula (i):
wherein R, R and R4 are independently selected from H and (CH) 2 )nCH 3 、(CH 2 )mNH 2 、(CH 2 ) X COOA1、(CH 2 ) m Any one of CONA 2; wherein n, m, x are independently selected from 0 or natural numbers; a1 and A2 are independently selected from H 2 、OH、NH 2 Any one or more of COOH, C1-18 alkyl, phenyl, heteroaryl.
7. The cyclic peptide of claim 6, wherein R3 and R4 in formula (h) are each (CH) 2 ) 3 NH 2 Or (b)And R3 and R4 are different; r in formula (i) is +.>
The cyclic peptide is prepared by cyclizing palmitoyl tripeptide-5 through an amide bond or an ester bond, and the structural formula of the palmitoyl tripeptide-5 is shown as a formula (15):
8. use of a hexapeptide-9 cyclic peptide for preparing a preparation for promoting expression of Collagen i, FLG or TGM1, or for increasing skin moisture content, wherein the structural formula of the cyclic hexapeptide is shown as formula (2), (3), (4):
9. use of a palmitoyl pentapeptide-4 cyclic peptide for preparing a preparation for promoting expression of Collagen i, FLG or TGM1, or for increasing skin moisture content, wherein the structural formula of the cyclic pentapeptide compound is shown as formula (6), (7), (8), (9):
10. Use of a palmitoyl pentapeptide-4 cyclic peptide for preparing a soothing formulation, wherein the structural formula of the cyclic pentapeptide compound is shown in formula (6):
11. use of a myristoyl pentapeptide-4 cyclic peptide for preparing a formulation for promoting expression of Collagen i, FLG or TGM1, or for increasing skin moisture content, characterized in that the structural formula of the cyclic pentapeptide compound is shown in formula (11), (12), (13), (14):
12. use of a palmitoyl tripeptide-5 cyclic peptide for preparing a formulation for promoting expression of Collagen i, FLG or TGM1, or for increasing skin moisture content, wherein the structural formula of the cyclic pentapeptide is shown as formulas (16), (17):
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