CN116172894A - Hexapeptide-9 cyclic peptide for resisting dynamic skin wrinkles and composition thereof - Google Patents
Hexapeptide-9 cyclic peptide for resisting dynamic skin wrinkles and composition thereof Download PDFInfo
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- CN116172894A CN116172894A CN202211550129.0A CN202211550129A CN116172894A CN 116172894 A CN116172894 A CN 116172894A CN 202211550129 A CN202211550129 A CN 202211550129A CN 116172894 A CN116172894 A CN 116172894A
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- hexapeptide
- cyclic peptide
- acetylcholine
- peptide
- inhibiting
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Abstract
The invention provides a hexapeptide-9 cyclic peptide for resisting skin wrinkle (namely resisting dynamic wrinkles) and a composition thereof, which are characterized in that hexapeptide-9 cyclic peptide (CHP-9) with a brand new structure is synthesized by cyclizing hexapeptide-9 linear peptide (HEX-9), and structural identification and efficacy research are carried out on the hexapeptide-9 cyclic peptide, so that the hexapeptide-9 cyclic peptide has unique efficacy on the aspect of resisting dynamic wrinkles of skin, can remarkably inhibit the activation of acetylcholine receptors, can effectively inhibit the synthesis of acetylcholine, and HEX-9 has no effect on the hexapeptide-9; further, the composition of the CHP-9 and the snake venom peptide has obvious synergistic effect in inhibiting the activation of an acetylcholine receptor, and the composition of the CHP-9 and the acetyl hexapeptide-8 has great application prospect in the fields of cosmetics, beauty, skin care, wrinkle resistance, aging resistance and medical science.
Description
The present application claims a chinese prior application, application number: 202210087176.X, priority of day 2022, month 1, 25; all of which are included as part of the present invention.
Technical Field
The invention belongs to the technical field of skin care product raw materials, and relates to hexapeptide-9 cyclic peptide for resisting dynamic wrinkles of skin and a composition thereof.
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, the mechanism of the common cosmetic peptide is clear and generally acts on a certain microscopic receptor (commonly called a target point) of skin, the common cosmetic peptide 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 remarkable effect by only adding a few ppm to hundreds 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.
In order to reduce or avoid degradation of the polypeptide molecule by proteases, the polypeptide molecule must be modified chemically or otherwise to increase the metabolic stability of the polypeptide. Currently, the main methods for enhancing the metabolic stability of polypeptide molecules include unnatural amino acid modification, pseudo-peptide strategy, inverse peptide strategy, cyclization strategy, higher fatty acid modification, protein fusion strategy, polyethylene glycol modification, and the like. Among them, cyclic peptide compounds generally have a large surface area due to conformational change limitation caused by cyclic structures, thereby having 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. The cyclic peptide compound is easy to realize production through an automatic chemical synthesis flow, is convenient to modify, process and monitor, and is very beneficial to the drug development process.
On the other hand, the polypeptides on the efficacy of the cosmetic peptides commonly found in the market at present are generally relatively single, for example, anti-wrinkle (dynamic wrinkles) mainly comprises the following mechanisms according to inhibition of expression lines: (1) inhibit synthesis of neurotransmitters such as acetylcholine; (2) inhibiting the binding of acetylcholine to receptors; (3) inhibiting voltage-gated channel opening-Na + Classification such as influx, for example, classical polypeptide acetyl hexapeptide-8 is known to be capable of inhibiting dynamic wrinkles, and targets at inhibiting release of acetylcholine, but there is no report on antagonism of acetylcholine receptor or aspects; the mechanism of the snake venom peptide for inhibiting dynamic vein is that the snake venom peptide can selectively antagonize the postsynaptic membrane acetylcholine receptor, but has no report on the aspect of inhibiting the release of acetylcholine. Therefore, the development of the anti-dynamic-pattern passage which can simultaneously have two or more than two anti-dynamic-pattern passages can greatly improve the utilization rate of raw materials and the efficacy.
The hexapeptide-9 is a collagen peptide consisting of six amino acids, is simultaneously present in the structures of human collagen IV and XVII (two key basement membrane collagens), and has remarkable anti-wrinkle repair effects. The main mechanism path of the collagen is to promote the synthesis of collagen by fibroblast of dermis layer and supplement the content of collagen of dermis layer. However, hexapeptide-9 has the problems of low stability, easy degradation, inactivation, poor transdermal absorption and the like as a small molecule linear peptide. At present, no report related to wrinkle resistance (dynamic wrinkles) exists.
There is no report on hexapeptide-9 cyclic peptide. Whether to synthesize hexapeptide-9 cyclic peptide to further improve the efficacy, increase the diversity of the efficacy and enrich the raw material sources of the cosmetic skin care health care product industry is an urgent problem to be solved.
Disclosure of Invention
In order to solve the above problems, an object of the present invention is to provide a hexapeptide-9 cyclic peptide for skin anti-dynamic wrinkles and a composition thereof, which synthesizes a hexapeptide-9 cyclic peptide (CHP-9) of a completely new structure by cyclizing a hexapeptide-9 linear peptide, and performs structural identification and efficacy study thereof, and has a unique efficacy in skin anti-dynamic wrinkles, which can significantly inhibit the activation of acetylcholine receptors, but the hexapeptide-9 linear peptide (HEX-9) has no effect thereon; further, the composition of CHP-9 and acetyl hexapeptide-8 has obvious synergistic effect in inhibiting the content of acetylcholine, and has great application prospect in the field of cosmetics.
The invention prepares a hexapeptide-9 cyclic peptide (CHP-9) by cyclizing a hexapeptide-9 linear peptide, wherein the hexapeptide-9 cyclic peptide has a structural formula shown as a formula (1):
chinese name: 3,3' - (5,8,11,16,19,22-hexaoxoacetylsalicylic acid-1H, 5H-dipyrrole [1,2-a:1',2' -j ] [1,4,7,10,13,16] hexaazacyclooctadecene-9, 20-diacyl) dipropylamide;
english name:
3,3'-(5,8,11,16,19,22-hexaoxoicosahydro-1H,5H-dipyrrolo[1,2-a:1',2'
j][1,4,7,10,13,16]hexaazacyclooctadecine-9,20-diyl)dipropanamide
the molecular formula: c (C) 24 H 36 N 8 O 8
The hexapeptide-9 cyclic peptide (CHP-9) is prepared by cyclizing an amide bond on hexapeptide-9, and the structural formula of the hexapeptide-9 linear peptide (HEX-9) is shown as a formula (2):
the preparation method of the hexapeptide-9 cyclic peptide (CHP-9) comprises the following steps: the hexapeptide-9 cyclic peptide is prepared by synthesizing chain hexapeptide-9 linear peptide (HEX-9) and then carrying out a cyclization reaction.
According to the invention, a great deal of researches prove that the cyclized hexapeptide-9 cyclic peptide has higher stability and affinity compared with the hexapeptide-9 linear peptide with the original linear structure, has stronger application potential in the anti-aging field, has unique efficacy in the aspect of skin anti-dynamic lines, can be better applied to the fields of cosmetic skin care products or medical and aesthetic fields, can be used for preparing skin care toner, mask, essence, emulsion, cream, freeze-dried powder and the like, and has wide prospect.
Related studies have shown that when a person conveys facial expressions, facial muscles move, and expression lines are caused by repeated movements of facial muscles. Expression lines are precisely distributed in several common parts of the face, which are perpendicular to the direction of contraction of the subcutaneous muscles of the face. Repeated contractions of subcutaneous muscles produce tension and cause expression lines, and these wrinkles due to facial expression are called dynamic lines, also called false wrinkles, expression lines. With the continuous tension and long-term overshrinking state, dynamic lines gradually deepen and become irreversible static wrinkles, which seriously influences the pursuit of people on beauty and cannot be ignored.
Neurotransmitter acetylcholine is equivalent to WIFI signal, and muscle is just like terminal equipment, and once "signal" is cut off, the muscle just can not receive the instruction from nerve, and local muscle that originally contracts along with facial expression can be released gradually to reach nature, wrinkle effect. Specific blocking of acetylcholine release at neuromuscular junctions can lead to temporary chemical denervation of muscles, relaxing muscles that cause dynamic wrinkles, presenting younger appearance. Meanwhile, the wrinkles can be gradually reduced, and the formation of new dynamic wrinkles can be prevented, so that the effect of clinically improving the wrinkles is achieved.
After the acetylcholine receptor and the acetylcholine molecule are combined, the neuromuscular impulse is transferred, which causes the muscle to contract. Acetylcholine receptor M1 is a G protein-coupled receptor, mainly coupled to Gq protein, activating Gq pathway; when the receptor is activated by the ligand, the receptor conformation changes, triggering activation of the intracellular G-protein. The activated G protein has the ability to induce various intracellular messengers (including calcium) cascades. Voltage gate channel open-Na + The inflow is limited, and the opposite endplate membranes depolarize to form a weakening of endplate potential, thereby inhibiting conduction of action potential among neuron cells and finally inhibiting formation of dynamic patterns. Therefore, the activation of the acetylcholine receptor M1 is inhibited, the generation of dynamic lines can be effectively prevented, the wrinkles are remarkably improved, the effects of resisting wrinkles and dynamic lines (expression lines) are achieved, even the wrinkles can be immediately prevented, and the effect of inhibiting the expression lines is achieved.
In one aspect, the present invention provides a use of a hexapeptide-9 cyclic peptide for preparing an anti-dynamic skin texture agent, the hexapeptide-9 cyclic peptide having a structural formula as shown in formula (1):
further, the hexapeptide-9 cyclic peptide promotes skin anti-dynamic wrinkles by inhibiting acetylcholine receptor activation.
Further, the hexapeptide-9 cyclic peptide is used in an amount of 0.1% -20.0%.
In another aspect, the present invention provides the use of a hexapeptide-9 cyclic peptide for the preparation of a formulation for inhibiting activation of acetylcholine receptors, or inhibiting the synthesis of acetylcholine, said formulation having the structural formula shown in formula (1):
further, the hexapeptide-9 cyclic peptide is used in an amount of 0.1% -20.0%.
In yet another aspect, the invention provides a skin care composition comprising a hexapeptide-9 cyclic peptide and an acetyl hexapeptide-8, or a hexapeptide-9 cyclic peptide and a snake venom-like peptide.
Further, the hexapeptide-9 cyclic peptide has a structural formula as shown in formula (1):
further, the specific gravity of the hexapeptide-9 cyclic peptide and the acetyl hexapeptide-8 is (0.1-20): (0.1-20); the specific weight of hexapeptide-9 cyclic peptide and snake venom-like peptide is (0.1-20): (0.1-20).
In a further aspect, the present invention provides the use of a composition as described above for the preparation of an anti-dynamic skin texture formulation.
In a further aspect, the invention provides the use of a composition as described above for the preparation of a formulation for inhibiting activation of an acetylcholine receptor, or for inhibiting synthesis of acetylcholine.
In yet another aspect, the present invention provides the use of hexapeptide-9 cyclic peptide in the preparation of a toner, mask, essence, emulsion, cream, lyophilized powder for skin care.
In addition, the hexapeptide-9 cyclic peptide provided by the invention can be compounded with other active ingredients with skin care effects (such as anti-aging, anti-wrinkle, moisturizing and the like), and all products adopting the hexapeptide-9 cyclic peptide provided by the invention to be compounded with other active ingredients are also within the protection scope of the invention.
The beneficial effects of the invention are as follows:
1) The hexapeptide-9 cyclic peptide (CHP-9) with a brand new structure is successfully synthesized, and the CHP-9 has obvious effects of inhibiting the activation of an acetylcholine receptor and inhibiting the synthesis of acetylcholine, so that the effect of multi-channel inhibition of dynamic lines is realized, and the linear peptide HEX-9 is ineffective for inhibiting the activation of the acetylcholine receptor or inhibiting the synthesis of acetylcholine;
2) Compared with the linear hexapeptide-9, the CHP-9 has lower cytotoxicity, can realize high-concentration application, and better plays the anti-wrinkle effect and has high efficacy. In addition, compared with the snake venom peptide with the same concentration, the CHP-9 has higher cell tolerance, high concentration and high efficiency in the field of inhibiting the activation of the acetylcholine receptor, and compared with the acetyl hexapeptide-8 with the same concentration, the CHP-9 has higher cell tolerance and high concentration and high efficiency in the field of inhibiting the content of the acetylcholine;
3) The composition of CHP-9 and acetyl hexapeptide-8 has obvious synergistic effect in inhibiting the synthesis of acetylcholine;
4) Can be applied to the field of skin care and anti-aging, and can effectively improve the dynamic skin lines.
Drawings
FIG. 1 is a high performance liquid chromatogram of the hexapeptide-9 cyclic peptide prepared in example 1;
FIG. 2 is an infrared absorption spectrum of the sample in example 2;
FIG. 3 is a hydrogen nuclear magnetic resonance spectrum of the sample in example 2;
FIG. 4 is a nuclear magnetic resonance spectrum of the sample in example 2;
FIG. 5 is a mass spectrum of the sample in example 2;
FIG. 6 is a graph showing the trend of cell viability of acetyl hexapeptide-8 of example 3 at various concentrations;
FIG. 7 is a graph showing the trend of cell viability of the snake venom peptides of example 3 at various concentrations;
FIG. 8 is a graph showing the trend of cell viability of hexapeptide-9 cyclic peptide (CHP-9) of example 3 at various concentrations;
FIG. 9 is a graph showing the trend of cell viability of linear hexapeptide-9 (HEX-9) of example 3 at various concentrations;
FIG. 10 is a graph showing the results of inhibiting the antagonism of acetylcholine receptor in the samples of example 4, wherein the left graph shows the results of antagonism of acetylcholine receptor in the samples at 2.0% concentration, and the right graph shows the results of antagonism of acetylcholine receptor in the samples at 5.0% concentration;
FIG. 11 is a graph showing the results of inhibition of acetylcholine receptor antagonism by various samples or compositions of example 4;
FIG. 12 is a graph showing the results of inhibition of acetylcholine synthesis by various samples or compositions of example 5.
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.
Example 1: preparation of hexapeptide-9 cyclic peptides
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.
The preparation process comprises the following steps:
in the embodiment, amino acid raw materials Fmoc-Pro-OH, fmoc-Gly-OH, fmoc-Gln (Trt) -OH, fmoc-Pro-OH, fmoc-Gly-OH and Fmoc-Gln (Trt) -OH are sequentially adopted for connection of linear peptides, then all-protection cutting is carried out to obtain linear peptides H-Gln (Trt) -Gly-Pro-Gln (Trt) -Gly-Pro-OH, then the linear peptides H-Gln (Trt) -Gly-Pro-Gln (Trt) -Gly-Pro-OH are cyclized to obtain a closed ring product Cyclo (Gln (Trt) -Gly-Pro-Gln (Trt) -Gly-Pro), and finally the crude peptide Cyclo (Gln-Gly-Pro-Gln-Gly-Pro) is obtained after cutting again.
After cleavage to obtain crude product, the crude product is purified and freeze-dried to obtain the finished product Cyclo (Gln-Gly-Pro-Gln-Gly-Pro), namely hexapeptide-9 cyclic peptide (CHP-9), with the purity of 99.2 percent.
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) (high performance liquid chromatography shown in figure 1), with chemical structure shown in formula (1).
Example 2: structural identification of hexapeptide-9 cyclic peptides
In this example, the hexapeptide-9 cyclic peptide prepared in example 1 was subjected to compound structure confirmation, and specific analysis procedures and results are as follows:
chemical structure confirmation was performed by a variety of analytical characterization methods (elemental analysis, infrared absorption spectroscopy, nuclear magnetic resonance spectroscopy, mass spectrometry) on the structure of the samples (prepared according to the method provided in example 1).
1. Elemental analysis
Instrument model: vario MICRO cube elemental analyzer (Elementar Analysensysteme GmbH Germany); test conditions: combustion temperature: 1000 ℃, helium flow: 140mL/min; test data, analysis: elemental analysis test results for samples:
TABLE 1 elemental analysis data sheet for samples
Analysis and conclusion: through calculation, the test value is consistent with the theoretical value, and the molecular formula of the sample is C 24 H 36 N 8 O 8 。
2. Infrared absorption spectrum
Instrument model: NICOLET iS50 FT-IR fourier infrared spectrometer; the infrared spectrogram of the sample is shown in the figure (figure 2), and the infrared spectrum absorption peak data and attribution of the sample are shown in the table 2.
Table 2, infrared Spectrometry absorption Peak data and assignment of samples
| Absorption peak (cm) -1 ) | Strength of | Type of vibration | Radicals (C) | Remarks |
| 3357 | Strong strength | υ N-H | -NH-,-NH 2 | Amino group |
| 2881,2928,2950,2976 | Strong strength | υ C-H | -CH 2 -,-CH- | Methylene, |
| 1655 | Strong strength | υ C＝O | -NH-C＝O | Amide absorption band I |
| 1522 | Strong strength | δ N-H | -NH-C＝O | Amide absorption band II |
| 1243 | Strong strength | υ C-N | -NH-C＝O | Amide absorption band III |
Analysis and conclusion:
1)3357cm -1 the telescopic vibration of the amino group indicates that the amino group exists in the molecule;
2)2881cm -1 、2928cm -1 、2950cm -1 、2976cm -1 stretching vibration of alkyl (methylene, methine) indicates the presence of alkyl in the molecule;
3)1655cm -1 is an amide carbonyl stretching vibration of 1522cm -1 Is deformed and vibrated by amide amine group, 1243cm -1 The amide carbon nitrogen stretching vibration indicates that amide exists in the molecule;
the infrared spectrum analysis result shows that the amino, alkyl (methylene, methine), amide and other groups exist in the sample, which accords with the structure of the sample.
3. Nuclear magnetic resonance spectrum (NMR)
3.1 nuclear magnetic resonance hydrogen spectrum @ 1 H NMR)
Instrument model: bruker DMX-500 nuclear magnetic resonance apparatus; measurement conditions: solvent: d (D) 2 O (deuterated water); the nuclear magnetic resonance hydrogen spectrum of the sample is shown in figure 3 1 The H NMR spectrum data and assignment are shown in Table 3.
TABLE 3 sample 1 H NMR spectrum data and attribution
3.2 nuclear magnetic resonance carbon spectrum @ 13 C NMR)
Instrument model: bruker DMX-500 nuclear magnetic resonance apparatus; measurement conditions: solvent: d (D) 2 O (deuterated water); the nuclear magnetic resonance carbon spectrum of the sample is shown in figure 4, and the sampleA kind of electronic device 13 The C NMR data and assignment are shown in Table 4.
TABLE 4 sample 13 C NMR data and assignment
4. Mass spectrometry
Instrument model: agilent 6460; test conditions: an ESI source; test pattern: the mass spectrum of the sample is shown in the attached figure (figure 5). Test data and analysis: the molecular formula: c (C) 24 H 36 N 8 O 8 Molecular weight: 12.01x24+1.008 x 36+14.01x8+16.00 x 8= 564.60; analysis and conclusion: m/z= 565.20 is [ m+h ] of the sample] +- Ion peaks. Mass spectrometry analysis showed that the ion peaks were consistent with the molecular weight of the sample.
5. Comprehensive analysis
The molecular composition of the sample is C through elemental analysis and mass spectrum confirmation 24 H 36 N 8 O 8 Molecular weight 564.60, unsaturation of 10. Infrared spectrum shows that amino, alkyl (methylene, methine), amide and other groups exist in the sample; 1 h NMR 13 C NMR spectra indicated that the relevant carbons and hydrogens were assigned. Mass spectrometry analysis showed that the ion peaks were consistent with the molecular weight of the sample. The structure of the sample is as follows, by combining the above information: (1)
Example 3: cytotoxicity test of hexapeptide-9 cyclic peptide and the like
The testing method comprises the following steps:
1) Cell inoculation: according to 9E 3 Seed density of cells/well neuronal cells were seeded into 96-well plates, incubator (37 ℃,5% co) 2 ) Incubating overnight;
2) Test grouping: the test set was zeroed, solvent control, positive control and sample. In the sample group, each sample is provided with a concentration gradient, and 3 repeated holes are arranged under each concentration gradient; the experimental design is shown in table 4.
Table 4, test packet and group design of experiments
3) Administration: administration was performed when the cell plating rate in 96 well plates reached 40% -60%. 200. Mu.L of culture solution was added to each well of the solvent control group; 200. Mu.L of culture medium containing 10% DMSO was added to each well of the positive control group; 200 mu L of culture solution containing samples with corresponding concentrations is added into each hole of the sample group; the zeroed group was inoculated without cells and only 200. Mu.L of cell culture medium was added. After completion of the administration, the 96-well plate was placed in an incubator (37 ℃ C., 5% CO) 2 ) Is cultured for 24 hours.
4) And (3) detection: after incubation of the cells for 24h, the supernatant was discarded, MTT working solution (0.5 mg/mL) was added, incubated at 37℃for 4h in the absence of light, after incubation, the supernatant was discarded, 150. Mu.L of DMSO was added per well, and the OD was read at 490 nm.
5) Cell relative viability calculation: according to the formula, cell relative viability (%) = sample well OD-zerowell OD solvent control well OD-zerowell OD 100%.
The test result samples are set to be the drug administration concentration, cytotoxicity detection tests are carried out on neuron cells, MTT detection results and cell viability change trend results are shown as follows:
the MTT assay results are shown in FIGS. 6-9, wherein FIG. 6 is a graph of cell viability of acetyl hexapeptide-8, FIG. 7 is a graph of cell viability of snake venom peptide, FIG. 8 is a graph of cell viability of CHP-9, and FIG. 9 is a graph of cell viability of HEX-9.
From the MTT results of fig. 6, it is believed that the sample acetyl hexapeptide-8 does not exhibit significant cytotoxicity over a concentration range of 1.25% based on neuronal cells; from the MTT results of fig. 7, it was thought that the sample snake venom peptides were neuronal cell based and did not exhibit significant cytotoxicity in the 0.625% concentration range; according to the MTT results of FIG. 8, no significant cytotoxicity was exhibited in the concentration range of 3.0% considering that the sample CHP-9 was based on neuronal cells. From the MTT results of fig. 9, it was considered that sample HEX-9 did not exhibit significant cytotoxicity in the concentration range of 2.5% based on neuronal cells.
Thus, the high safety concentration of CHP-9 relative to linear HEX-9 after cyclization was obtained, which proved to be beneficial.
On the other hand, compared with acetyl hexapeptide-8 and snake venom peptide, the neuron toxicity of the cyclized CHP-9 is lower, the CHP-9 is obtained to have high safety concentration compared with the nerve inhibition polypeptide (anti-dynamic vein) known in the market, and the CHP-9 is safer, thereby providing a new application prospect for obviously improving the dynamic vein in the cosmetic field.
In addition, the hexapeptide-9 cyclopeptide CHP-9 provided by the invention can be prepared into a preparation for use on the skin, and the skin has very high tolerance degree to the CHP-9, so that the hexapeptide-9 cyclopeptide CHP-9 can be used at higher concentration, and the maximum content is up to 20%.
Example 4: in vitro anti-wrinkle efficacy test of hexapeptide-9 cyclopeptides (acetylcholine receptor antagonism)
The active substance can relax nerve, block muscle traction, reduce wrinkle caused by fine lines and pressure, and has certain effect on dynamic lines such as emotion lines. In this embodiment, neuronal cells are used as a study object, and the anti-wrinkle effect of the test object is evaluated by observing the change of acetylcholine release and acetylcholine receptor antagonism of the neuronal cells after sequential administration of the test object, thereby evaluating the inhibition of the sample on nerve impulse.
The assay is based on M1-CHO cells and detects the inhibition of M1 receptor activity by compounds. Acetylcholine receptor M1 is a G protein-coupled receptor, mainly coupled to Gq protein, activating Gq pathway; when the receptor is activated by the ligand, the receptor conformation changes, triggering activation of the intracellular G-protein. The activated G protein has the ability to induce various intracellular messengers (including calcium) cascades.
Main reagent
F-12(Hyclone)、FLIPR CALCIUM 6ASSAY KIT(Molecul Device)、Fetal Bovine Serum(FBS)(AusGeneX)、Hygromycin B(Solarbio)、DMSO(Sigma)、HBSS(Gibco)。
Main equipment
Carbon dioxide cell incubator (Esco), inverted microscope (OPTEC), low speed centrifuge (YIDA), low ultra clean bench (HDL).
The test packets and groups are shown in Table 5, with Atropine (Atropine) as a negative control.
Table 5, test packet and group design of experiments
The testing steps are as follows:
1) Cell plating: M1-CHO cells were collected by digestion and inoculated into 384 well plates after resuspension counting at a density of: 1X 10 4 cells/25. Mu.L/well, then the cell plates were placed at 37℃with 5% CO 2 Culturing in an incubator for about 12 hours;
2) The following day: assay Buffer was prepared according to the FLIPR Caldium 6Assay Kit instructions. Freezing and thawing 20 XComponent A to room temperature, diluting to 1 Xloading buffer with Assay buffer, and standing at room temperature for use;
3) Removing the culture medium in the cell plate, rapidly adding 35 mu L of 1×loading buffer into each hole, centrifuging, and incubating the cell plate at 37 ℃ in the dark for 120min;
4) Preparing working solutions of positive compounds and compounds to be tested, transferring 5 mu L of working solutions into corresponding cell holes, and incubating for 30min at 37 ℃ in a dark place;
5) Preparing working solutions of positive compounds and compounds to be tested, and transferring 20 mu L/well into a 384-well compound source plate;
6) The cell plate, source plate and gun head were placed in the corresponding positions of the FLIPR instrument, 10. Mu.L of the compound diluted in step 5) was added to each experimental well using FLIPR Tetra, and data were collected at wavelengths between 515nm and 575 nm.
Compound IC50: y=bottom+ (Top-Bottom)/(1+10.
The results are shown in FIG. 10, wherein the left graph shows the results of antagonizing acetylcholine receptor in the sample at 2.0% concentration and the right graph shows the results of antagonizing acetylcholine receptor in the sample at 5.0% concentration. The M1 receptor inhibition of sample CHP-9 at 2.0% concentration was 6.70%; the M1 receptor inhibition of sample CHP-9 at 5.0% concentration was 24.54%, while HEX-9 had no inhibition.
The obtained cyclized CHP-9 has obvious effect of inhibiting the activation of the acetylcholine receptor, so that the dynamic skin lines can be improved, and the original linear HEX-9 has no corresponding effect, thus proving that the cyclized CHP-9 is beneficial.
On the other hand, when taken alone, CHP-9 and the snake venom peptide have no obvious difference under the action of inhibiting the activation of the acetylcholine receptor at the same concentration. When the CHP-9 and the snake venom peptide are combined, as shown in figure 11, the CHP-9 and the snake venom peptide have the function of synergistically inhibiting the activation of an acetylcholine receptor, thereby providing a new application prospect for remarkably improving dynamic lines in the field of cosmetics.
The specific gravity of hexapeptide-9 cyclic peptide and snake venom-like peptide is (0.1-20): the effect of the composition of (0.1-20) on inhibiting the activation of acetylcholine receptor was studied, and it was confirmed that the specific gravity of hexapeptide-9 cyclic peptide and snake venom peptide was (0.1-20): the compositions in the range of (0.1 to 20) have the effect of synergistically inhibiting the activation of acetylcholine receptors.
Example 5: effect test of anti-dynamic skin texture composition (inhibition of acetylcholine Release)
This example is based on neuronal cell HT22, and detects the inhibitory effect of compounds on acetylcholine release. And (3) taking the neuron cells as a research model, and evaluating the inhibition effect of the object to be tested on the expression lines by detecting the change of the content of the acetylcholine after the treatment to be tested. Acetylcholine is a neurotransmitter, and in nerve cells, acetylcholine is synthesized by choline and acetyl-coa under the catalytic action of choline acetyltransferase (choline acetylase); the release of acetylcholine is Ca caused by depolarization of nerve endings 2+ An inflow, thereby inducing acetylcholine; further action on muscle cells following acetylcholine release results in muscle cell contraction. Thus, the inhibition of acetylcholine achieves the effect of inhibiting muscle contraction. The wrinkle-removing mechanism of the toxoid cosmetic mainly aims at inhibiting the contraction of muscles by inhibiting the release of acetylcholine, thereby smoothing wrinkles.
1. Test system
The cells used in this test are neuronal cells, obtained commercially.
2. Main reagent
High sugar DMEM medium (Boxi organism), fetal bovine serum (bright Rong, lanzhou), PBS (Boshide), and acetylcholine kit (Nanjing).
3. Main equipment
CO 2 Incubator (Thermo, 150I), ultra clean bench (Suzhou Antai, SW-CJ-1F), microplate reader (BioTek, epoch).
4. Test samples CHP-9, hex-9, acetyl hexapeptide-8, acetyl hexapeptide-8+CHP-9.
5. Anti-wrinkle efficacy test
6.1 test protocols are shown in Table 6.
TABLE 6 test packet and group design of experiments
6.2 working fluid preparation
Preparing liquid: test article working fluids were prepared according to the test protocol (table 6).
The operation steps are as follows:
1) Inoculating: according to 2X 10 5 Cell/well seeding Density cells were seeded into 6-well plates, incubator (37 ℃,5% CO) 2 ) Incubate overnight.
2) Administration: according to the test scheme of Table 9, 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, and the incubator (37 ℃,5% CO) 2 ) And incubated for 24h.
3) And (3) detecting a kit: cell culture supernatants were collected and assayed by ELISA according to the test kit instructions.
4) Data processing analysis GraphPad Prism was used to plot and the results were expressed as mean±sd.
Comparisons between groups were performed using t-test statistical analysis. Statistical analysis was double tailed. P < 0.05 indicates significant differences, and P < 0.01 indicates very significant differences. The results are shown in FIG. 12.
As can be seen from fig. 12, the sample CHP-9 at 1% concentration, the acetyl hexapeptide-8 at 0.75% concentration, and the acetyl hexapeptide-8+chp-9 at 0.75% +1% compound concentration had significantly reduced acetylcholine content compared to BC group.
The obtained cyclized CHP-9 has the function of obviously inhibiting the synthesis of acetylcholine by neuron cells, while the original straight-chain HEX-9 has no corresponding function, which proves that the cyclized CHP-9 is beneficial and can achieve the anti-wrinkle effect.
On the other hand, as shown in fig. 12, compared with the single use of CHP-9 or acetyl hexapeptide-8, the composition of CHP-9 and acetyl hexapeptide-8 has the effect of synergistically inhibiting the synthesis of acetylcholine, thereby providing a new application prospect for remarkably improving dynamic wrinkles in the cosmetic field.
The specific gravity of hexapeptide-9 cyclic peptide and acetyl hexapeptide-8 in this example was also (0.1 to 20): the effect of the composition of (0.1-20) on inhibiting the synthesis of acetylcholine was studied and it was confirmed that the specific gravity of hexapeptide-9 cyclic peptide and acetyl hexapeptide-8 was (0.1-20): the compositions in the range of (0.1 to 20) all have the effect of synergistically inhibiting the synthesis of acetylcholine.
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 (10)
1. Use of a hexapeptide-9 cyclic peptide for the preparation of an anti-dynamic skin texture formulation, wherein the hexapeptide-9 cyclic peptide has a structural formula as shown in formula (1):
2. the use of claim 1, wherein the hexapeptide-9 cyclic peptide promotes skin anti-dynamic skin texture by inhibiting acetylcholine receptor activation, or inhibiting acetylcholine synthesis.
3. The use according to claim 2, wherein the amount of hexapeptide-9 cyclic peptide is between 0.1% and 20%.
4. Use of a hexapeptide-9 cyclic peptide for the preparation of a formulation for inhibiting activation of an acetylcholine receptor, or inhibiting synthesis of acetylcholine, characterized in that it has a structural formula as shown in formula (1):
5. the use according to claim 4, wherein the amount of hexapeptide-9 cyclic peptide is 0.1% to 20%.
6. A skin care composition comprising a hexapeptide-9 cyclic peptide and an acetyl hexapeptide-8, or a hexapeptide-9 cyclic peptide and a snake venom-like peptide.
7. The composition of claim 6, wherein the hexapeptide-9 cyclic peptide has a structural formula as shown in formula (1):
8. the composition of claim 7, wherein the hexapeptide-9 cyclic peptide and acetyl hexapeptide-8 have a specific gravity of (0.1-20): (0.1-20); the specific weight of hexapeptide-9 cyclic peptide and snake venom-like peptide is (0.1-20): (0.1-20).
9. Use of a composition according to any one of claims 6 to 8 for the preparation of an anti-dynamic skin texture formulation.
10. Use of a composition according to any one of claims 6 to 8 for the preparation of a formulation for inhibiting the activation of acetylcholine receptors, or for inhibiting the synthesis of acetylcholine.
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