CN116731110A - Polypeptide with melanocyte stimulating receptor antagonism and related application thereof - Google Patents
Polypeptide with melanocyte stimulating receptor antagonism and related application thereof Download PDFInfo
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- CN116731110A CN116731110A CN202310769031.2A CN202310769031A CN116731110A CN 116731110 A CN116731110 A CN 116731110A CN 202310769031 A CN202310769031 A CN 202310769031A CN 116731110 A CN116731110 A CN 116731110A
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- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 72
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- 230000004936 stimulating effect Effects 0.000 title description 4
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Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Toxicology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Birds (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cosmetics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
The application discloses a polypeptide with a melanocyte stimulating hormone receptor antagonism effect and related application thereof, and relates to the fields of cosmetics and functional peptides. The application provides two polypeptides, the amino acid sequences of which are GPFHPPN and SLDWRAK respectively, and the two polypeptides have the characteristics of good stability, small cytotoxicity, easy absorption and the like, have the effect of promoting antagonism of a melanin receptor, reduce melanin generation through an alpha-MSH/MC 1R signal path, play a role in whitening, and have high market value when applied to the fields of cosmetics or medical science.
Description
Technical Field
The application relates to the field of cosmetics and functional peptides, in particular to a polypeptide with a melanocyte-stimulating receptor antagonism and related application thereof.
Background
It is known that melanin can protect skin from environmental pollution factors such as ultraviolet radiation, oxidative pressure, etc., but excessive accumulation of melanin also causes many skin diseases such as freckle, senile plaque, melanoma, etc. Therefore, effective control of pigmentation and reduction of melanin generation are the main ways of whitening and removing spots. There are now five major signaling pathways for the melanin synthesis pathway, including the α -MSH/MC1R signaling pathway, the PI3K/Akt signaling pathway, the MAPK signaling pathway, the Wnt- β -catenin signaling pathway, and the NO signaling pathway. Most of the whitening agents on the market are regulated based on both melanin generation and transport, with the aim of reducing melanin generation or transfer. Some whitening agents have been demonstrated to have whitening efficacy, which can reduce melanin production or block melanin transport, but the specific whitening mechanism is not very clear and may be limited in application value.
In recent years, polypeptides are gradually introduced into the public as novel whitening agents, and have very high market prospects, and related polypeptide products have been reported. The polypeptide is a compound formed by connecting alpha-amino acids together through peptide bonds, is a proteolytic intermediate product, has small molecular weight, is easy to be absorbed through skin, and has good stability in a formula. At present, there are few reports on skin active peptides obtained from fresh water pearls, so that the pearl-derived active peptides need to be further mined.
In view of this, the present application has been made.
Disclosure of Invention
The present application aims to provide polypeptides having a melanocyte stimulating receptor antagonism and related uses thereof.
The application is realized in the following way:
in a first aspect, embodiments of the present application provide a polypeptide having an amino acid sequence as set forth in SEQ ID NO. 1.
In a second aspect, embodiments of the present application provide a polypeptide having an amino acid sequence as set forth in SEQ ID NO. 2.
In a third aspect, embodiments of the present application provide a composition comprising a polypeptide according to the previous embodiments and a polypeptide according to the previous embodiments.
In a fourth aspect, the present application provides the use of the polypeptide according to the previous embodiment or the composition according to the previous embodiment for the preparation of a product with whitening effect.
In a fifth aspect, embodiments of the present application provide a dermatological article comprising: a substrate and an active peptide of a dermatological article; the active peptide comprises the polypeptide or the composition of the previous embodiment.
In a sixth aspect, embodiments of the present application provide the use of a polypeptide as described in the preceding embodiments or a composition as described in the preceding embodiments for the preparation of a product having melanin inhibiting activity or for inhibiting melanin activity.
In a seventh aspect, embodiments of the present application provide the use of a polypeptide as described in the previous embodiments or a composition as described in the previous embodiments for the preparation of a product having tyrosinase inhibitory activity or for inhibiting tyrosinase activity.
The application has the following beneficial effects:
the application provides two polypeptides, the amino acid sequences of which are GPFHPPN and SLDWRAK respectively, and the two polypeptides have the characteristics of good stability, small cytotoxicity, easy absorption and the like, have the effect of promoting antagonism of a melanin receptor, reduce melanin generation through an alpha-MSH/MC 1R signal path, play a role in whitening, and have high market value when applied to the fields of cosmetics or medical science.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present application and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 shows the measurement results of melanin inhibiting activity;
FIG. 2 is an α -MSH/MC1R melanin synthesis-signaling pathway;
FIG. 3 shows the measurement results of MC1R protein content;
FIG. 4 shows the CREB protein content measurement results;
FIG. 5 shows MITF protein content measurement results;
FIG. 6 shows the results of TYR protein content detection;
in FIGS. 3 to 5, X1, X2 and X3 each represent arbutin (1/6400) (1/25600) (1/102400) g/mL; s1, S2, S3 represent polypeptide or polypeptide mixture (1/6400) (1/25600) (1/102400) g/mL, respectively; NT represents a blank group without any sample;
in FIG. 6, X1, X2, X3, X4 respectively represent arbutin (1/1600) (1/6400) (1/25600) (1/102400); s1, S2, S3, S4 represent, respectively, an S polypeptide or polypeptide mixture (1/1600) (1/6400) (1/25600) (1/102400); NT is a blank group, without any sample.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present application more clear, the technical solutions of the embodiments of the present application will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The inventor of the application carries out enzymolysis, ultrafiltration and other processes on pearl powder of the freshwater pearl, carries out polypeptide identification and sequencing on the pearl powder by combining high-resolution mass spectrum, and then obtains two whitening polypeptides (SEQ ID NO:1 and SEQ ID NO: 2) with definite amino acid sequences through computer simulation and cell experiment screening. Both polypeptides have the effect of promoting antagonism of a melanin receptor, reduce melanin generation through an alpha-MSH/MC 1R signal pathway, and play a role in whitening.
The two polypeptides are natural active peptides, have the characteristics of whitening efficacy, good stability, small cytotoxicity, easy absorption and the like, and have high market value when applied to the fields of cosmetics or medical science.
In one aspect, the embodiment of the application provides a polypeptide, the amino acid sequence of which is shown as SEQ ID NO. 1 (GPFHPPN).
In another aspect, the embodiment of the application provides a polypeptide, the amino acid sequence of which is shown as SEQ ID NO. 2 (SLDWRAK).
In another aspect, embodiments of the present application provide a composition comprising the polypeptide of the preceding embodiment (SEQ ID NO: 1) and the polypeptide of the preceding embodiment (SEQ ID NO: 2).
In some embodiments, the composition is a polypeptide composition, and may further include other polypeptides having whitening efficacy.
In another aspect, the present application provides an application of the polypeptide of the previous embodiment or the composition of the previous embodiment in preparing a product with whitening effect.
In some embodiments, the product comprises: any one or more of cosmetics, skin care products, medical products, medicines and health care products.
In some embodiments, the skin care product comprises: any one or more of facial cleanser, lotion, toner, moisturizing lotion, eye essence, moisturizing cream, essence, skin bottom, sunscreen cream and facial mask.
In some embodiments, the cosmetic comprises: any one or more of the foundation solution and the barrier cream.
In some embodiments, the medical product comprises: any one or more of medical mask, microneedle and hydro-optical needle.
In some embodiments, the dosage form of the pharmaceutical product is selected from the group consisting of: any one or more of injection, tablet, capsule, granule, ointment, controlled release agent and aerosol.
In another aspect, embodiments of the present application provide a dermatological article comprising: a substrate and an active peptide of a dermatological article; the active peptide comprises the polypeptide of any of the preceding embodiments or the composition of any of the preceding embodiments.
In some embodiments, the substrate of the dermatological article includes any one of a skin care product, a cosmetic product, and a medical product. The skin care product, the cosmetic and the medical product are the same as those in any of the previous embodiments, and will not be described again.
In another aspect, the embodiments of the present application further provide the use of the polypeptide of any of the preceding embodiments or the composition of any of the preceding embodiments for the preparation of a product having melanin inhibiting activity or for inhibiting melanin activity.
In some embodiments, the product having melanin inhibiting activity comprises a product having an efficacy of inhibiting melanin production.
In some embodiments, the inhibiting melanin activity comprises inhibiting melanin production.
In some embodiments, the inhibiting melanin production comprises inhibiting melanin production by a cell or animal. The cells may be mammalian cells and cell lines. Mammalian cells include cells from any member of a mammal, such as human cells, mouse cells, rat cells, monkey cells, hamster cells, and the like. Alternatively, the cell is a B16 cell. The animals include mammals and humans, including in particular but not limited to mice, rats, monkeys, rabbits, sheep and humans.
In some embodiments, the product comprises any one of a skin care product, a cosmetic product, and a medical product. The substrate of the dermatological product is specifically a conventional or existing dermatological product itself, specifically a conventional dermatological product which is used as a substrate, and the polypeptide or the composition of any of the previous embodiments is contained on the basis of the conventional dermatological product. The skin care product, the cosmetic and the medical product are the same as those in any of the previous embodiments, and will not be described again.
In addition, the embodiment of the application also provides application of the polypeptide of any embodiment or the composition of any embodiment in preparing a product with tyrosinase inhibitory activity or inhibiting tyrosinase activity.
In some embodiments, the inhibiting tyrosinase activity comprises inhibiting tyrosinase activity in a cell and/or animal. The cells and the animals are as described in any of the preceding examples.
In some embodiments, the product comprises any one of a skin care product, a cosmetic product, and a medical product. The skin care product, the cosmetic and the medical product are the same as those in any of the previous embodiments, and will not be described again.
In some embodiments, the product having tyrosinase inhibitory activity is the same as a tyrosinase inhibitor.
The features and capabilities of the present application are described in further detail below in connection with the examples.
Example 1: molecular docking of polypeptide with Mushroom tyrosinase (2Y 9X)
The small molecule peptides were screened for whitening activity using molecular docking software Discovery studio 2019. The receptor protein (2Y 9X) is downloaded from a PDB database, and is pretreated after being opened by using a Discovery studio 2019, and the treatment process comprises removing water molecules, hydrogenating the protein and the like, so that 66 sites are totally obtained in the new protein after treatment. Polypeptide structure was mapped using Chemdraw 20.0, then opened with Discovery studio 2019 and ligand prepared, and a rigid docking (LibDock) protocol was selected for docking, with successful docking assuming the polypeptide has tyrosinase inhibitory activity.
The simulation result shows that the two polypeptides with the amino acid sequence of GPFHPPN, SLDWRAK have high tyrosinase inhibitory activity.
Example 2: synthesis of two Polypeptides (GPFHPPN, SLDWRAK)
(1) 0.3mmol of MBHA amino resin was weighed into a reaction tube, the resin was swelled with Dichloromethane (DCM) for 40min, the resin was washed with N, N-Dimethylformamide (DMF) and pumped dry for a total of 5 washes.
(2) The Fmoc protecting group was removed with 20% piperidine (in DMF) for 3min, drained, washed with DMF and drained, and the Fmoc protecting group was removed again with 20% piperidine for 7min, drained, the resin was washed with DMF and drained and a total of 5 washes.
(3) To the reaction tube were added 0.9mmol Fmoc-Asn-OH, 0.85mmol HBTU, 0.85mmol HOBT and 1.8mmol Dipea, reacted at room temperature for 45min, drained, the resin was washed with DMF and drained, and washed 5 times total.
(4) A small amount of resin was taken and washed 2 times with DMF and MeOH each, about 0.3mL of 2% ninhydrin indicator was added, and after 5 minutes of heating, the resin was observed for a color change, no blue coloration indicated complete reaction, and blue coloration indicated incomplete reaction, requiring continued reaction.
(5) And (3) replacing Fmoc-Asn-OH in the step (3) with Fmoc-Pro-OH, fmoc-His-OH, fmoc-Phe-OH, fmoc-Pro-OH and Fmoc-Gly-OH in sequence, and repeating the operation of the steps 2-4 until the amino acid connection on the polypeptide sequence is complete.
(6) After Fmoc protection of the last attached amino acid Fmoc-Gly-OH, the resin was washed 5 times with DMF and 5 times with DCM.
(7) To the reaction tube was added 5mL of TFA: h 2 O: TIPS (95:2.5:2.5), reacted at room temperature for 2h, filtered, rinsed with small amount of TFA and the liquid collected into a centrifuge tube. Slowly dripping diethyl ether into the liquid to generate light yellow solid, placing the centrifuge tube in a refrigerator at-20 ℃ for 2 hours, centrifuging to remove the supernatant, adding diethyl ether again, and centrifuging to remove the supernatant.
(8) The resulting solid was dried in a fume hood, then dissolved in water and passed through a 0.22 μm PES filter, and purified by SemiPrep RP-HPLC, wherein the mobile phase was water containing 0.1% TFA (Buffer A) and acetonitrile containing 0.1% TFA (Buffer B), and the detection wavelength was set to 214nm. And (3) carrying out characterization and confirmation on the collected polypeptide by using Analytical RP-HPLC and MALDI-TOF-MS, and then freeze-drying by using a freeze dryer to obtain the target polypeptide VPGF.
Another polypeptide was also synthesized according to this method, except that the corresponding amino acid with Fmoc protecting group was replaced.
Example 3: measurement of melanin inhibiting Activity
(1) Inoculating B16 melanocyte grown in logarithmic phase in 10% FBS-containing high sugar DMEM medium to 100mm cell culture dish at (10-15) ×104 cells/well, adding 10mL culture solution per well, and standing at 37deg.C and 5% CO 2 Incubate in carbon dioxide incubator at concentration for 24h.
(2) The dissolved polypeptide GPFHPPN, SLDWRAK was diluted with PBS to a final concentration of 100ppm, 3 duplicate wells were provided for each polypeptide, the positive control was supplemented with arbutin at final concentrations of 100ppm and 1000ppm, respectively, and the blank control was supplemented with equal volumes of PBS and incubation was continued for 24h.
(3) Cells were collected by pancreatin digestion, the supernatant was discarded, washed 2 times with PBS, and 300. Mu.L of 1N NaOH containing 10% DMSO was added to each tube to dissolve melanin particles, and the mixture was subjected to water bath at 80℃for 40 minutes. 100. Mu.L was added to a 96-well plate, and absorbance was measured at 405nm using an enzyme-labeled instrument.
The specific experimental results show that the 1,2 polypeptides have good melanin generation inhibiting effect. At a concentration of 100ppm, the inhibition rate of GPFHPPN melanin production was 65.63% and the inhibition rate of SLDWRAK melanin production was 50.21%.
Example 4: whitening mechanism of polypeptide
(1) B16 melanocytes grown in logarithmic growth phase in high-sugar DMEM medium containing 10% fbs, at (10-15) ×10 4 The number of cells per well was inoculated into 100mm cell culture dishes, 10mL of culture medium was added to each well, and the mixture was placed at 37℃with 5% CO 2 Incubate in carbon dioxide incubator at concentration for 24h.
(2) Diluting and dissolving polypeptide or polypeptide mixture with PBS, diluting at a ratio of 3 to 4, each polypeptide has 3 multiple holes, positive control contains arbutin, diluting at a ratio of 3 to 4, blank control contains equal volume of PBS, and culturing for 24 hr.
(3) After 24h, the cells were harvested, total protein was extracted according to RIPA and protein extraction kit instructions, and protein concentration was determined by BCA method. SDS-PAGE electrophoresis, membrane transfer, 5% skim milk powder blocking for 1h, primary antibody incubation at 4deg.C overnight, secondary antibody incubation at 37deg.C for 1h, ECL chemiluminescence development, and band scanning analysis results using an imaging analysis system. And (3) taking beta-action as an internal reference, carrying out band gray level analysis by using Image J software, obtaining the gray level ratio between the target protein and the corresponding internal reference protein, and carrying out group comparison.
Specific experimental results are shown in fig. 3-6, and MC1R, CREB, MITF, TYR was down-regulated after addition of the polypeptide or mixture of polypeptides. According to FIG. 2, the polypeptide or mixture of polypeptides has a melanocyte stimulating receptor antagonizing effect derived from the alpha-MSH/MC 1R melanin synthesis signaling pathway on the KEGG website, regulated melanin production by the alpha-MSH/MC 1R pathway.
The above description is only of the preferred embodiments of the present application and is not intended to limit the present application, but various modifications and variations can be made to the present application by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (10)
1. A polypeptide is characterized in that the amino acid sequence is shown as SEQ ID NO. 1.
2. A polypeptide is characterized in that the amino acid sequence is shown as SEQ ID NO. 2.
3. A composition comprising the polypeptide of claim 1 and the polypeptide of claim 2.
4. Use of the polypeptide of claim 1 or 2 or the composition of claim 3 for the preparation of a product having whitening efficacy.
5. The use according to claim 4, wherein the product comprises: cosmetic, skin care product, medical product, medicine and health product.
6. The use according to claim 5, wherein the skin care product comprises: any one of facial cleanser, lotion, toner, moisturizing lotion, eye essence, moisturizing cream, essence, skin bottom, sunscreen cream and facial mask;
optionally, the cosmetic comprises: any one of the foundation solution and the barrier cream;
optionally, the medical product comprises: any one of medical facial masks, microneedles and hydro-optical needles;
optionally, the dosage form of the pharmaceutical product is selected from: any one of injection, tablet, capsule, granule, ointment, controlled release agent and aerosol.
7. A dermatological article, comprising: a substrate and an active peptide of a dermatological article; the active peptide comprising the polypeptide of claim 1 or 2 or the composition of claim 3;
optionally, the skin product comprises any one of a skin care product, a cosmetic product and a medical product;
optionally, the base of the cosmetic comprises any one of a foundation solution and a barrier cream;
optionally, the substrate of the skin care product comprises any one of facial cleanser, lotion, toner, moisturizing lotion, eye essence, moisturizing cream, essence, skin bottom, sun cream and facial mask;
optionally, the medical product comprises: any one of medical facial mask, micro needle and water light needle.
8. Use of the polypeptide of claim 1 or 2 or the composition of claim 3 for the preparation of a product having melanin inhibiting activity or for inhibiting melanin activity.
9. The use according to claim 8, wherein the product having melanin inhibiting activity comprises a product having an efficacy of inhibiting melanin production;
optionally, the inhibiting melanin activity comprises inhibiting melanin production;
optionally, the product comprises any one of a skin care product, a cosmetic product, and a medical product.
10. Use of the polypeptide of claim 1 or 2 or the composition of claim 3 for the preparation of a product having b inhibitory activity or for inhibiting tyrosinase activity;
optionally, the product comprises any one of a skin care product, a cosmetic product, and a medical product.
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