CN102442931B - Methionine-deviated peptide mimics and use in protection for mitochondrions of skin cells - Google Patents
Methionine-deviated peptide mimics and use in protection for mitochondrions of skin cells Download PDFInfo
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- CN102442931B CN102442931B CN201110274029.5A CN201110274029A CN102442931B CN 102442931 B CN102442931 B CN 102442931B CN 201110274029 A CN201110274029 A CN 201110274029A CN 102442931 B CN102442931 B CN 102442931B
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Abstract
The present invention relates to methionine-deviated peptide mimics and use in protection for mitochondrions of skin cells. The invention relates to a group of peptide mimics which are selected and are deviated from methionine amino acid, and to the use of the peptide mimics as protection agents for the mitochondrions of the skin cells. The invention also relates to a cosmetic composition or dermatopathology composition for preventing and treating skin diseases which are related with mitochondrion dysfunction.
Description
Technical Field
The present invention relates to a group of selected peptide mimetics derived from methionine amino acids and their use as a protective agent for the mitochondria of skin cells. The invention also relates to compositions intended to prevent or combat skin conditions associated with mitochondrial dysfunction.
Background
Mitochondria play a crucial role for plant cells and animal cells as cytoplasmic organelles present in these cells. In fact, mitochondria are called "cellular energy generation plants" because they produce and store Adenosine Triphosphate (ATP), a universal energy component required for the operation of all eukaryotic cells.
In the above-mentioned production by a series of redox chemical reactions (commonly referred to as "mitochondrial respiratory chain"), the necessary oxidant is oxygen. Oxygen is therefore essential for cellular operations, but paradoxically, oxygen is also the primary and concurrent source of reactive species known as "reactive oxygen species" (ERO in french, ROS in english), which are potentially toxic to cellular biochemical macromolecules (DNA, proteins, lipids, etc.).
To neutralize this ROS formation, all cells naturally form some enzymatic or non-enzymatic antioxidant defense system that requires some energy to operate, and the preferred energy is just the above-mentioned ATP released by the mitochondrial respiratory chain (Singh K.K., FEMS Yeast Res.,2004,5: 127-. However, when an imbalance occurs between the production of ROS and the clearance of ROS by the intracellular defence system due to an excessive amount of ROS, the resulting oxidative stress can therefore gradually cause a decline in mitochondrial function, which is manifested in particular by a disruption of the electron flow generating energy and by the formation of ROS inside the mitochondria (known as "intramitochondrial ROS") (Jones D.P., Chemico Biological Comm.,2006,163: 38-53). This imbalance at the cellular level and lack of energy will impair the ability of the cell to adapt to the physiological stress to which it is exposed. In conclusion this promotes the senescence phenomenon of cells (Trifunovic A. et al, J.of Internal medicine, 263: 167-. It is also confirmed that these mitochondrial-derived disruptions are apparently associated with The development of a wide variety of pathological conditions or tissue disorders (Barlow-Stewart k., The australian Genetics resources Book,2007, pages 1-3, and references cited therein).
Mitochondria remain the primary target as a source of intracellular ROS. Thus, one of the problems currently being addressed by many researchers is to reduce the mitochondrial-derived oxidative metabolism and promote or protect mitochondrial function in order to best maintain functional and/or structural integrity of all mitochondria.
In the prior art with the same goals as demonstrated in the past years, the following existing strategies and systems have generally been adopted:
selecting strong antioxidants, such as lipoic acid (more commonly known as alpha-lipoic acid), which carry one or more thiol or phenolic moieties and are present in nature in the animal or plant kingdom, which have proven to have a beneficial effect against mitochondrial ageing (palaianipan a.r. et al, neurochem.res.,2007,32:1552-1558), or ergothioneine (ergothionine), which is a thiourea derivative, said to protect the mitochondrial membrane of mammals (us patent No. 6,479,533),
the use of some molecules or conventional antioxidant proteins, but which have been modified for greater internal storage by the addition/grafting of groups or sequences with strong affinity for mitochondria (hydrophobic cations, etc.) (Kagan V.E. et al, adv. drug Delivery Rev. 2009,61:1375-1385),
the development of small peptides purportedly having "permeabilization", replacing some basic and aromatic amino acid residues by having the ability to penetrate the inner mitochondrial membrane and subsequently exhibit some cytoprotective and mitochondrial protective properties within mitochondria (Szeto h.h., associations & Redox Signaling,2008,3: 1-15).
The present invention was made in the same context of identifying new products or articles, with the aim of satisfying the overall need of "improving mitochondrial function" (b. lacriox, Nutranews, 4 months 2008), but mainly because these products or articles are applied topically to the skin, also the needs of cosmetic and/or dermatological applications, while also satisfying the needs of the following coexistence objectives:
-maintaining/restoring a high metabolic activity of the skin cell mitochondria when the skin cell is physiologically affected;
exhibit acceptable bioavailability at the deep layer of the skin. On the one hand, it is recognized that this is an essential prerequisite for achieving mitochondrial protection of skin cells in vivo. On the other hand, this can be used to avoid premature metabolism in the superficial layers of the skin even before it can act on the epidermal and dermal cells.
Against the harmful effects of reactive oxygen species on the own cells and against the mitochondrial produced ROS rather than those of extracellular origin (uv radiation, pollution, oxidative environmental toxins, etc.).
To achieve these objectives, the applicant has studied various forms of excited oxygen (e.g., O)2°-And1O2) Thioether compounds that inactivate ("quench") the ability (Cohen S.G. and L., J.am.chem.Soc.,1975,97: 5633-5631 and references cited therein).
More particularly, the applicant is concerned with methionine, i.e. in which the sulfur atom is involved in the same thioether functionEnergetic group (S-CH)3) But some of the properties attached to methionine are contrary to the sought aim: sulfur-containing organic derivative odors unsuitable for cosmetic/dermatological applications, lower skin penetration capacity, more importantly evidence of oxidative damage of intramitochondrial ROS and mitochondrial DNA produced by methionine food supplements (Caro p. et al, rev. esp. geriatr. gerntol., 2009,44: 194-199; Sanz a. et al, FASEB j.,2006,20: 1064-1073). In addition, it is predicted that the sensitivity of the oligomethionine-type peptides (di-methionine, tri-methionine, etc.) to skin proteases is too high.
The above is why the applicant will eventually study the synthesis of peptide mimetics derived against methionine.
Disclosure of Invention
Thus, through further structure-activity studies, the applicant will choose to lock onto a few original compounds derived from methionine that do not have the drawbacks shown by methionine or oligomethionine, according to their good compliance with the combination of criteria described above. The good agreement appears to be:
-an excellent ability to maintain the metabolic activity of skin cells exposed to stress conditions, said ability being reflected by the maintenance of ATP production levels [ see test 1 below ];
extremely good, even exceeding, the skin absorption of the stratum corneum, which is reflected in the logarithmic value ("Log Kp") of the permeability coefficient of the compound [ see test 2 below ], which is similar to that of osmotic compounds such as caffeine;
the ability to reduce mitochondrial oxidative stress, and to modulate the quality of mitochondria produced in response to the same stress conditions (referred to as "mitochondrial biogenesis") [ see test 3 below ];
high degree of cytoprotection, particularly on the V79 fibroblast line [ see test 4 below]The cell line is characterized in that: for the respiratory chain derived from mitochondriaDisordered hydrogen peroxide H2O2Sensitive (Tatsumi T. et al, Basic Res. Cardiol.,1993,88: 199-;
strong antioxidant properties, expressed in relation to oxidative species (hydroxyl radical OH °, peroxynitrite ion ONOO) known to affect mitochondria-Singlet oxygen1O2) With scavenging capacity of, e.g. ascorbic acid or TroloxTMIso-reference to the ability of antioxidants to clear similarly [ see test 5 and test 6 below]；
Weak odor released by these methionine derivatives.
It is therefore a first object of the present invention to provide a group of methionine-derived peptidomimetics, characterized in that they are represented by the following general formula (I):
r ═ X-C (o) -NH-, wherein X ═ alkyl or alkoxy (C)1～C8)；R'＝H
Or
R ═ -C (o) -OX, wherein X ═ alkyl (C)1～C8)；R＝H。
According to a preferred embodiment of the invention, formula (I) is defined as following formula (II), wherein the R' groups are only hydrogen atoms and R is a group wherein X is a group having 1 to 4 carbon atoms (C)1～C4) Of a linear or branched hydrocarbyl chain, of an alkyl or alkoxy type:
r ═ X-C (o) -NH-, wherein X ═ alkyl or alkoxy (C)1～C4)；R'＝H
More advantageously, the aboveX in the formula (II) is C having 1 to 4 carbon atoms1～C4) Linear or branched hydrocarbyl chain.
As non-limiting examples of compounds of formula (II), the following compounds may be mentioned in particular:
-N-acetyl- (DL) -methionyl-4- (methylthio) propylamine
-N-propionyl- (DL) -methionyl-4- (methylthio) propylamine
-N-pentanoyl- (DL) -methionyl-4- (methylthio) propylamine
-N-tert-butoxy- (DL) -methionyl-4- (methylthio) propylamine
According to a more advantageous embodiment of the invention, the above formula (I) and formula (II) are defined in particular as N-acetyl- (DL) -methionyl-4- (methylthio) propylamine compound (R ═ CH)3-c (o) -NH-and R' ═ H).
According to a second aspect, the present invention also relates to a composition, preferably for cosmetic or dermatological use, designed to prevent or combat skin conditions associated with mitochondrial dysfunction, comprising a peptidomimetic derived from methionine having the general formula (I) as defined above as the main active ingredient, together with any physiologically compatible additives.
Within the scope of the present invention, it is understood that a "primary active ingredient" is an active substance capable of limiting the functional or structural alterations of the skin cell mitochondria under physicochemical or environmental stress, by means of an enhanced mitochondrial protection and/or an enhanced stimulation of some essential functions of the mitochondria, such as cellular energy metabolism.
In particular, the above-mentioned composition is designed to protect the skin from stress induced by ultraviolet radiation (ultraviolet-induced stress), and the methionine derivative conforms to formula (II). More specifically, it is an N-acetyl- (DL) -methionyl-4- (methylthio) propylamine compound.
Advantageously, in the above composition, the derivative of formula (I) is present in an amount of 0.1 to 10% by weight, preferably 0.3 to 3% by weight, relative to the total weight of the composition.
The compositions of the invention, preferably for cosmetic or dermatological use, are suitable for topical application to the skin and take up all the forms commonly used for such applications. Advantageously, the composition may have the form: powders, emulsions, microemulsions, nanoemulsions, suspensions, lotions, creams, aqueous or hydroalcoholic gels, foams, slurries, solutions or dispersions for spraying or dispersions of lipid vesicles.
The composition may also be formulated for administration by the oral route (oral administration) in the form of, for example, tablets, capsules, sealed bottles (seals), bulb bottles (bulbs), syrups, drops.
Examples of additives physiologically compatible with the skin include compounds selected from the group consisting of: oils, waxes, silicone elastomers, surfactants, co-surfactants, thickeners and/or gelling agents, humectants, lubricants, organic filters, inorganic filters, filtration enhancers and light stabilizers, preservatives, colorants, fillers, nacres, matting agents, tightening agents, masking agents, fragrances, and mixtures thereof.
These examples may be present in the composition in an amount of about 0.01% to 20% by weight of the total composition, and are specifically mentioned in the Dictionary published by the "personal care products committee (PCPC, pre-CTFA)" of the american Cosmetic association, "International Cosmetic Ingredient Dictionary and Handbook" (13 th edition, 2010). Examples of these may be (but are not limited to) the following: silicone oils, natural or synthetic oils, straight or branched chain hydrocarbons, synthetic esters and ethers, hydrocarbonated waxes, emulsifying surfactants, straight or branched chain fatty alcohols, reticulated homo-and copolymers, gums, cellulose derivatives, alginate esters, polyols, sugars, glycosaminoglycans and other amino acids, mineral or organic fillers, vegetable proteins, polysaccharides and mixtures thereof.
The compositions of the invention may also comprise additional active ingredients, but the addition of these active ingredients does not affect the effect of the compositions of the invention per se, in particular at least one active ingredient chosen from: agents stimulating the production of growth factors, anti-glycation or deglycation agents, agents increasing collagen synthesis or preventing its degradation, agents increasing elastin synthesis or preventing its degradation, agents increasing glycosaminoglycan or proteoglycan synthesis or preventing its degradation, agents increasing keratinocyte proliferation or differentiation, agents increasing fibroblast proliferation, depigmenting, anti-colouring or pro-colouring agents, anti-oxidants or anti-radical or anti-fouling agents, agents stimulating hydration and/or protecting the barrier function of the skin, agents increasing epidermal lipid synthesis, agents stimulating lipid breakdown, agents inhibiting lipogenesis and/or inhibiting adipocyte differentiation, drainage or detoxification agents, anti-inflammatory agents, penetration enhancers, desquamative agents (desquamative agents), soothing and/or anti-irritant agents, astringents, agents acting on the microcirculation, agents acting on cellular metabolism, and mixtures of the above.
These examples of additional active ingredients may be present in the composition in an amount of about 0.001% to about 10% by weight of the total composition, and may be chosen in particular from: plant extracts, silicon derivatives, yeast extracts and algae extracts, plant protein hydrolysates, (acylated or not) oligopeptides, coffee extracts, carinine (carnitine) and its derivatives, carnosine and its derivatives, N-acetyl cysteine and its derivatives, water-soluble vitamins such as vitamins B1, B2, B3, B6, B12, C, H, fat-soluble vitamins such as vitamins A, D2, D3, E and carotene, urea and its derivatives, taurine and its derivatives, polyphenols, oligosaccharides and polysaccharides, lactic acid, glycolic acid, citric acid and salicylic acid and esters or salts thereof, and mixtures of the above.
Another object of the invention also relates to the use of peptidomimetics derived from methionine as cosmetic agents for protecting and/or stimulating the mitochondria of skin cells, said derivatives having the following general formula (III):
r ═ X-C (o) -NH-, wherein X ═ alkyl or alkoxy (C)1～C8) (ii) a R' ═ H or-C (O) R ", where R ″ ═ O alkyl (C)1～C4)、NH2。
According to a preferred embodiment of the invention, the aim is to prevent or combat the symptoms of cutaneous ageing, and preferably the symptoms of light-induced ageing, in particular the damage to the skin caused by ultraviolet radiation, by the above-mentioned use of said derivatives.
A final object of the invention relates to a peptide mimetic derived from methionine for use in a composition for the skin, useful for treating the symptoms of skin ageing, and preferably against the damage caused to the skin by ultraviolet radiation, said derivative conforming to the following general formula (III):
r ═ X-C (o) -NH-, wherein X ═ alkyl or alkoxy (C)1～C8) (ii) a R' ═ H or-C (O) R ", where R ″ ═ O alkyl (C)1～C4)、NH2。
As non-limiting examples of compounds of formula (III), the following compounds may be mentioned in particular:
-N-acetyl- (DL) -methionyl-4- (methylthio) propylamine
-N-propionyl- (DL) -methionyl-4- (methylthio) propylamine
-N-pentanoyl- (DL) -methionyl-4- (methylthio) propylamine
-N-tert-butoxy- (DL) -methionyl-4- (methylthio) propylamine
-N-4- (methylthio) -butyryl-L-methionine methyl ester
-N-acetyl- (DL) -methionyl-L-methionine ethyl ester
In the last two objects of the invention, preference is given to the derivatives of formula (III) below: for example, R is defined as where X is a group containing 1 to 4 carbon atoms (C)1～C4) And R' is a group of hydrogen atoms only.
More preferably, the compound N-acetyl- (DL) -methionyl-4- (methylthio) propylamine is specifically selected.
Detailed Description
Example 1
By way of illustration, the following are some formulation examples of the compositions of the invention containing the derivatives of the general formula (I) above:
formulation A (cream)
Formulation B (gel)
Formulation C (Capsule, oral administration)
N-acetyl- (DL) -methionyl-4- (methylthio) propylamine (200mg powder/capsule)
Or
N-4- (methylthio) -butyryl-L-methionine methyl ester (200mg powder/capsule)
Excipients filling a gelatin capsule: microcrystalline cellulose, magnesium stearate.
Example 2
Purely by way of example, the invention is elucidated hereinafter by the following tests (test 1 to test 6) which have been mentioned above in the description of the invention. It should also be noted that in vivo studies are ongoing and preliminary results may also elucidate the use of some methionine-derived peptide mimetics of the present invention.
Test 1: peptide mimetics derived from methionine have the ability to restore exposure to stress conditions (H)2O2) (ii) the ability of cellular ATP levels in cells
An experimental study was performed on a fibroblast cell line designated V79, and cells were seeded into 96-well plates containing 5000 cells per well in 100 μ l of medium (containing 10% fetal bovine serum). The original medium was then replaced in each well with 100. mu.l of medium containing some peptide mimetics of the invention at a concentration of 7.5mM or 10 mM. After 2 hours of incubation, the medium was removed from all wells. Then by adding H containing 50. mu.l hydrogen peroxide2O2(4ppm) of medium to subject the cells to stress. After an additional 8 hours of incubation, the average ATP concentration was measured by luminometry (luminometry) in the presence of fluorescein ("ATPLITE 1 step" kit) and a standard curve drawn from high purity ATP.
The results are expressed as the mean values obtained from three independent experiments and are shown in table 1 below, and compared to a control.
TABLE 1
| Compound (I) | ATP(×10-7M) |
| Control | 4.42 |
| Control + H2O2 | 0.4 |
| N-acetyl- (DL) -methionyl-4- (methylthio) propylamine 7.5mM | 5.91 |
| N-acetyl- (DL) -methionyl-4- (methylthio) propylamine 7.5mM + H2O2 | 4.83 |
| 10mM N-propionyl- (DL) -methionyl-4- (methylthio) propylamine | 5.28 |
| N-propionyl- (DL) -methionyl-4- (methylthio) propylamine 10mM + H2O2 | 4.49 |
The large decrease in the amount of ATP observed in the control is largely avoided in the presence of the compounds of the invention, indicating that the compounds of the invention have the ability to restore ATP production in cells exposed to stress conditions.
And (3) testing 2: transdermal absorption studies of methionine-derived peptidomimetics on explanted human skin
Permeability coefficient (Kp) values were obtained from previously frozen abdominal plastic human skin following the protocol described in OCDE guidelines n ° 428 for skin absorption studies.
In the experiment, explanted skin was placed on a Frantz-type device (Frantz-type cell) with passive diffusion and guided by the "MicroettePlus Hanson Research" system. The tested product is laid in a non-closed manner. After the skin was placed on the devices, 500 μ l of a peptidomimetic of the invention (1% solution) was placed in each device and contacted for a total of 24 hours. Thereafter, the remaining product is sampled and rinsed off the skin surface for extraction and measurement of the absorption, and subsequently for determination of the permeability coefficient (Log Kp) expressed in logarithmic form.
Data are collected in table 2 below.
TABLE 2
| Compound (I) | Kp(cm.h-1) | Log Kp |
| Caffeine | 1.10-4** | -4.0 |
| N-acetyl- (DL) -methionyl-4- (methylthio) propylamine | 1.09.10-4 | -3.96 |
| N-propionyl- (DL) -methionyl-4- (methylthio) propylamine | 9.7.10-5 | -4.0 |
| N-pentanoyl- (DL) -methionyl-4- (methylthio) propylamine | 3.7.10-4*** | -3.43 |
| N-tert-butoxy- (DL) -methionyl-4- (methylthio) propylamine | 4.6.10-4*** | -3.34 |
| N-4- (methylthio) -butyryl-L-methionine methyl ester | 2.10-4*** | -3.71 |
| N-acetyl- (DL) -methionyl-L-methionine ethyl ester | 1.64.10-4*** | -3.78 |
**：Mitragotri S.,J.Controlled Release,(2003),86:69-92.
***: according to the prediction software "ChemDraw ultra version 11.0", supplier: cambridge Soft Ltd.
The permeability coefficient of the obtained compounds of the invention is similar to that of the known trans-stratum corneum permeate caffeine.
And (3) testing: evidence for a protective role for mitochondrial oxidative stress and mitochondrial biogenesis for N-acetyl- (DL) -methionyl-4- (methylthio) propylamine compounds
The principle is as follows: measurement of oxidative stress within mitochondrial cells and detection of mitochondrial biogenesis is achieved by flow cytometry using the following fluorescent markers:
red fluorescent probe "MitoSOXTMRed, hereinafter referred to as "MitoSOX" (detection at. lambda. ═ 580 nm; supplier: Invitrogen) makes it possible to specifically detect the superoxide anion O present in mitochondria2°-(due to its strong affinity with mitochondria),
-Green fluorescent Probe "Green FM ", hereinafter" Mitogreen "(detection at λ 516 nm; supplier: Invitrogen) allows the quality of mitochondria (or the relative number of mitochondria per cell) to be quantified.
In the experiment, the test was performed on a hamster fibroblast cell line "V79" obtained by incubating at 37 ℃ and 5% CO2Maintained in a humid atmosphere in "EMEM" complete medium (containing 10% fetal bovine serum). V79 cells were seeded into 96-well plates at 2.5X 10 cells per well5The cells were incubated with 3ml of the same medium for 24 hours, followed by addition of H-containing hydrogen peroxide2O2(15ppm) of medium and exposed to stress conditions for 1 hour 30 minutes.
After trypsinization, cells were incubated for 15 minutes at 37 ℃ in 1ml of EMEM complete medium containing "MitoSOX" (final concentration 5. mu.M) and "MitoGreen" (final concentration 200nM) as described above, to detect:
mitochondrial oxidative stress (expressed as% of positive cells)
Mitochondrial mass per cell (expressed as% MFI relative to control ("mean fluorescence intensity")).
The results are expressed as mean values obtained from four independent experiments and are shown in tables 3a and 3b below and compared with the results corresponding to N-acetyl cysteine at a concentration of 5mM selected as a reference protectant.
TABLE 3a
| % of Mitosox positive cells% | |
| Control | 18 |
| Control + H2O2 | 85.7 |
| N-acetyl cysteine 5ppm + H2O2 | 15.2 |
| N-acetyl- (DL) -methionyl-4- (methylthio) propylamine 7.5mM + H2O2 | 40.3 |
TABLE 3b
| MFI (% control) | |
| Control | 100 |
| Control + H2O2 | 177.3 |
| N-acetyl cysteine 5ppm + H2O2 | 74.4 |
| N-acetyl- (DL) -methionyl-4- (methylthio) propylamine 7.5mM + H2O2 | 123.5 |
| N-acetyl- (DL) -methionyl-4- (methylthio) propylamine 10mM + H2O2 | 127.5 |
In both cases, the results highlight the ability of the N-acetyl- (DL) -methionyl-4- (methylthio) propylamine compound to reduce the effects of intramitochondrial stress.
And (4) testing: evidence for the cytoprotective effects of N-acetyl- (DL) -methionyl-4- (methylthio) propylamine and N-tert-butoxy- (DL) -methionyl-4- (methylthio) propylamine
The experiment was performed on a hamster fibroblast cell line "V79" maintained at 37 ℃ and 5% CO2In a humid atmosphere, then at a rate of 0.5X 10 per hole4Density of individual cells were seeded into 96-well plates. Followed by a reaction with a gas containing hydrogen peroxide H2O2(4ppm) the medium supplemented with the compound of the invention was replaced with the original medium, thereby exposing the cells to a toxic stress state for 24 hours. After removal of the medium, by the "MTT method" or 3- (4, 5-dimethylthiazol-2-yl)Bromide of 2, 5-diphenyltetrazole (500. mu.g/ml solution) and the viability of the fibroblasts was measured using spectrophotometry (absorbance at 540 nm).
The results are expressed as mean values obtained from three independent experiments and are shown in table 4 below and again compared with the results corresponding to a concentration of 5mM of N-acetyl cysteine (complete recovery of cell viability) selected as the reference cytoprotective agent.
TABLE 4
| % cell viability | |
| Control | 100 |
| Control + H2O2 | 54.8 |
| N-acetyl cysteine 5ppm | 103.8 |
| N-acetyl- (DL) -methionyl-4- (methylthio) propylamine 7.5mM + H2O2 | 83.5 |
| N-acetyl- (DL) -methionyl-4- (methylthio) propylamine 10mM + H2O2 | 91.9 |
| N-tert-butoxy- (DL) -methionyl-4- (methylthio) propylamine 7.5mM + H2O2 | 70.1 |
| N-tert-butoxy- (DL) -methionyl-4- (methylthio) propylamine 10mM + H2O2 | 77.3 |
The results in table 4 highlight the cell viability depending on the dose of the compounds of the invention and their ability to protect cells from cytotoxic stress.
And (5) testing: proof of antioxidant Effect of N-acetyl- (DL) -methionyl-4- (methylthio) propylamine and N-propionyl- (DL) -methionyl-4- (methylthio) propylamine on hydroxyl radicals
The rate constants for the clearance of hydroxyl radicals [ Ks (OH °) ] were determined using the methods described by Rehman A. and coll. (British J. Pharmacol. (1997),122:1702-1706), and the peptide mimetics of the present invention were compared to two reference antioxidants, mannitol and ascorbic acid (vitamin C).
In the experiment, the test substance was dissolved in a buffered medium at pH 7.4 and an OH ° generating system (ascorbate/iron/EDTA) was added to the medium in the presence of deoxyribose. After incubation at 37 ℃ for 1 hour, the reaction was stopped with the aid of trichloroacetic acid. After colorimetric imaging with thiobarbituric acid, the absorbance was measured at 532nm for different concentrations, and then the relative Ks (OH °) for each substance was calculated. The results are shown in table 5 below.
TABLE 5
**:Cabelli D.E.,J.Phys.Chem.(1983),87:1809-1812
***:Rehman A.,British J.Pharmacol.(1997),122:1702-1706
The results, expressed as the average values obtained from three independent experiments, highlight that the peptidomimetics of the present invention are significantly more efficient at scavenging hydroxyl radicals (OH) than mannose and closely resemble ascorbic acid.
And 6, testing: evidence for antioxidant effect of N-acetyl- (DL) -methionyl-4- (methylthio) propylamine compound on peroxynitrite ion
The peroxynitrite ion (ONOO) was determined using the so-called "Pyrogallol Red (PR) whitening test" method described by Nath V.B. and coll. (BBRC (2001),285:262--) The inhibitory effect on oxidized Pyrogallol Red (PR) was compared with the water-soluble equivalent of "Trolox" or vitamin E (6-hydroxy-2, 5,7, 8-tetramethylchroman) -2-carboxylic acid, which is a reference antioxidant, by comparing the N-acetyl- (DL) -methionyl-4- (methylthio) propylamine compound of the present invention with that of "Trolox".
In the experiment, the test substance was dissolved in a buffer medium having a pH of 7.0 in a 96-well plate, and 50. mu.M PR and 25. mu.M peroxynitrite ion ONOO were added thereto-(in 0.1M NaOH solution). After 5 minutes, the absorbance was measured at 540nm by spectrophotometry, and then the IC of each substance was calculated50Value (50% inhibitory concentration). The results are shown in table 6 below.
TABLE 6
| Compound (I) | IC50(mM) |
| Trolox | 0.083 |
| N-acetyl- (DL) -methionyl-4- (methylthio) propylamine | 1.012 |
Although the activity is lower than that of the reference antioxidant, the inhibitory effect of the compound of the present invention on the oxidation of PR by peroxynitrite ions can be clearly observed.
Claims (11)
1. A methionine-derived peptidomimetic, characterized in that the peptidomimetic is represented by the following general formula (II):
wherein,
r ═ X-C (o) -NH-, and X ═ C1～C4Alkyl or alkoxy of (a); r ═ H.
2. The peptidomimetic of claim 1, wherein X is methyl.
3. Composition for use in the prevention or combating of skin disorders associated with mitochondrial dysfunction, characterized in that it comprises methionine-derived peptide mimetics of general formula (II):
wherein,
r ═ X-C (o) -NH-, and X ═ C1～C4Alkyl or alkoxy of (a); r ═ H.
4. The composition of claim 3, wherein X in the peptidomimetic is methyl.
5. The composition of claim 3 or 4, wherein the amount of the peptidomimetic is from 0.1% to 10% by weight of the total weight of the composition.
6. The composition of claim 3 or 4, wherein the composition is suitable for topical application to the skin in the form of: powders, emulsions, microemulsions, suspensions, lotions, creams, aqueous or hydroalcoholic gels, foams, slurries, solutions or dispersions for spraying.
7. The composition of claim 3 or 4, wherein the composition is suitable for topical application to the skin in the form of: a nanoemulsion or a lipid vesicle dispersion.
8. The composition according to claim 3 or 4, characterized in that it comprises additional active ingredients selected from: agents stimulating the production of growth factors, anti-glycation or deglycation agents, agents increasing collagen synthesis or preventing collagen degradation, agents increasing elastin synthesis or preventing elastin degradation, agents increasing glycosaminoglycan or proteoglycan synthesis or preventing glycosaminoglycan or proteoglycan degradation, agents increasing keratinocyte proliferation or differentiation, agents increasing fibroblast proliferation, depigmenting agents, anti-colouring agents or pro-colouring agents, anti-oxidants or anti-free radicals or anti-staining agents, agents stimulating hydration and/or protecting the barrier function of the skin, agents increasing epidermal lipid synthesis, agents stimulating lipolysis, inhibiting lipogenesis and/or inhibiting adipocyte differentiation, drainage or antidote, anti-inflammatory agents, permeation enhancers, desquamating agents, soothing agents and/or anti-irritants, astringents, agents acting on the microcirculation, agents acting on the metabolism of the cells, and mixtures of the above.
9. The composition of claim 3 or 4, wherein the composition is for protecting skin from ultraviolet-induced stress.
10. Use of a methionine-derived peptidomimetic having the following general formula (III) as a cosmetic agent for protecting and/or stimulating the mitochondria of skin cells:
wherein R ═ X-C (O) -NH-, and X ═ C1～C8Alkyl or alkoxy of (a); r ═ H or-C (o) R ", and R ═ C1～C4Oalkyl, NH of2。
11. A methionine-derived peptidomimetic for use in a dermatological composition for treating symptoms of skin aging, the peptidomimetic having the following general formula (III):
wherein R ═ X-C (O) -NH-, and X ═ C1～C8Alkyl or alkoxy of (a); r ═ H.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MC2573A MC200132A1 (en) | 2010-09-17 | 2010-09-17 | Peptidomimetics derived from methionine and their use in the protection of cutaneous cell mitochondria. |
| MC002573 | 2010-09-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102442931A CN102442931A (en) | 2012-05-09 |
| CN102442931B true CN102442931B (en) | 2015-06-03 |
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| CN201110274029.5A Expired - Fee Related CN102442931B (en) | 2010-09-17 | 2011-09-15 | Methionine-deviated peptide mimics and use in protection for mitochondrions of skin cells |
Country Status (7)
| Country | Link |
|---|---|
| CN (1) | CN102442931B (en) |
| AR (1) | AR083004A1 (en) |
| BR (1) | BRPI1104914B1 (en) |
| CO (1) | CO6640060A1 (en) |
| MC (1) | MC200132A1 (en) |
| MX (1) | MX2011009741A (en) |
| PE (1) | PE20120527A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4956173A (en) * | 1987-11-25 | 1990-09-11 | Societe Anonyme: Sanofi | Composition and use of ademetionine against ageing of the skin |
| CN101232877A (en) * | 2005-04-21 | 2008-07-30 | 格伦·A·戈尔茨坦 | N-acetylcysteine amide (NAC amide) for the treatment of diseases and conditions associated with oxidative stress |
-
2010
- 2010-09-17 MC MC2573A patent/MC200132A1/en unknown
-
2011
- 2011-09-15 MX MX2011009741A patent/MX2011009741A/en active IP Right Grant
- 2011-09-15 CN CN201110274029.5A patent/CN102442931B/en not_active Expired - Fee Related
- 2011-09-16 AR ARP110103374 patent/AR083004A1/en active IP Right Grant
- 2011-09-16 CO CO11120638A patent/CO6640060A1/en unknown
- 2011-09-16 BR BRPI1104914-6A patent/BRPI1104914B1/en active IP Right Grant
- 2011-09-16 PE PE2011001659A patent/PE20120527A1/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4956173A (en) * | 1987-11-25 | 1990-09-11 | Societe Anonyme: Sanofi | Composition and use of ademetionine against ageing of the skin |
| CN101232877A (en) * | 2005-04-21 | 2008-07-30 | 格伦·A·戈尔茨坦 | N-acetylcysteine amide (NAC amide) for the treatment of diseases and conditions associated with oxidative stress |
Non-Patent Citations (3)
| Title |
|---|
| Bioavailability of L-methionine oligomers in rats;Soichi ARAI et al.;《Agricultural and Biological Chemistry》;19881231;第52卷(第7期);1873 * |
| Studies on Peptides. CXV. Synthesis of Hylambatin, a New Frog Skin Peptide of the Kassinin Family;KENJI OKAMOTO et al.;《Chem. Pharm. Bull.》;19841231;第32卷(第2期);433 * |
| Utilization of Methionine-containing Peptides and Their Derivatives by a Methionine-requiring Auxotroph of Saccharomyces cerevisiae;FRED NAIDER et al.;《J.Biol.Chem.》;19740110;第249卷(第1期);11 * |
Also Published As
| Publication number | Publication date |
|---|---|
| MX2011009741A (en) | 2012-06-22 |
| MC200132A1 (en) | 2011-03-30 |
| CN102442931A (en) | 2012-05-09 |
| PE20120527A1 (en) | 2012-05-17 |
| AR083004A1 (en) | 2013-01-23 |
| BRPI1104914B1 (en) | 2019-06-18 |
| CO6640060A1 (en) | 2013-03-22 |
| BRPI1104914A2 (en) | 2013-03-19 |
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