CN102492018A - Tyrosinase polypeptide inhibitor - Google Patents
Tyrosinase polypeptide inhibitor Download PDFInfo
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- CN102492018A CN102492018A CN2010102377292A CN201010237729A CN102492018A CN 102492018 A CN102492018 A CN 102492018A CN 2010102377292 A CN2010102377292 A CN 2010102377292A CN 201010237729 A CN201010237729 A CN 201010237729A CN 102492018 A CN102492018 A CN 102492018A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
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- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
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- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
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- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
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- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0819—Tripeptides with the first amino acid being acidic
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Abstract
The invention relates to a tyrosinase polypeptide inhibitor, which consists of a polypeptide. In the polypeptide, one or more amino acids are further subjected to acetylation, amidation, formylation, hydroxylation, lipolyzation, methylation or phosphorylation modification. The tyrosinase inhibitor provided by the invention can be taken as a medical composition, comprises the polypeptide, and further comprises a pharmaceutically-acceptable supporting agent. The medicinal composition provided by the invention can be used for inhibiting the generation of black pigments under the action of activity inhibition of tyrosinase, and can be widely applied to cosmetics such as a whitening agent.
Description
Technical field
The present invention relates to a kind of tyrosinase inhibitor, particularly relate to a kind of tyrosinase inhibitor that contains polypeptide.
Background technology
1. melanic source and function
When fetal development; By the melanocyte (melanocytes) that neural crest (neuralcrest) differentiates, can be distributed in skin (basal layer of epidermis), eyes-retinal pigment epithelium, uveal tract (uvealtract), hair follicle matrix, ear-stria vascularis (striavascularis), mucous membrane and cns-pia mater (leptomeninges).In melanocyte, there is a film to be called melanosome (melanosomes) meeting synthesis of melanin (melanin) in conjunction with (membrane-bound) born of the same parents device; After melanin is synthesized; Can move to contiguous horn cell (keratinocytes) by the dendritic processes of melanocyte; And then present the color of skin, and the difference of skin color mainly is because melanic generation with distribute different.Melanic major function is the UV-light (UV) that absorbs in the sunlight, and protection skin avoids receiving the injury of UV-light, and can remove active oxygen (reactive oxygen species, ROS), to reduce the Normocellular injury of radical pair.
2. melanic intercrescence becomes the path
Tyrosine (tyrosine) is the important matter that receives during the melanochrome intercrescence becomes.In reaction; Tyrosine is earlier by hydroxylation (hydroxylation): via the catalysis of tyrosine oxidase (tyrosinase); Ortho position carbon at hydroxyl (hydroxyl group) adds a hydroxyl, forms DOPA (L-3,4-dihydroxyphenylalanine; L-dopa), then convert DOPA to DOPA quinone (dopaquinone) again.The DOPA quinone can be walked two approach then, and first approach can form the eumelanin (eumelanin) of being with palm fibre, black via the catalysis of tyrosinase-related protein; Another approach, DOPA quinone generate yellow, the red pitch black pigment (pheomelanin) of band via the effect of gsh (glutathione) or halfcystine (cysteine), and be as shown in Figure 1.
3. the catalyst mechanism of tyrosine oxidase
Tyrosine oxidase (EC 1.14.18.1) is played the part of very important role in melanic intercrescence becomes.It is a kind of cupric membrane-spanning protein of multi-functional, tool candy baseization; Be present in the melanocyte; The molecular weight size is about 60-70kD in mammals, and common single-minded showing in the melanocyte, belongs to the 3rd type cupric protein (Type 3copperprotein); When carrying out catalyzed reaction, cupric ion is very important cofactor.In catalytic process, the structure of activated sites have three multi-form, play the part of different roles separately: be respectively oxidation state (Oxy-form), go back ortho states (Deoxy-form), resting state (Met-form).Also tool is not active for the ortho states tyrosine oxidase, and the positive monovalence of cupric ion band and the oxygen-free ion of its activated sites are in catalyzed reaction; Also the ortho states tyrosine oxidase needs through oxygenizement, loses 2 electronics and forms the oxidation state tyrosine oxidase, has in the activated sites this moment to be with positive bivalent cupric ion and the negative monovalence oxonium ion of band; The oxidation state tyrosine oxidase can be accepted 2 kinds and receive matter; Be respectively tyrosine and DOPA, when combining, can generate resting state tyrosine oxidase-DOPA complex body (Met-E-Dopa) with tyrosine; After discharging the DOPA quinone, tyrosine oxidase becomes again goes back ortho states continuation circulation; On the other hand when combining with DOPA; Except generating the DOPA quinone; Tyrosine oxidase also becomes resting state by oxidation state simultaneously; If the tyrosine oxidase of this form and DOPA effect meeting generate the DOPA quinone, if combine with tyrosine, can form do not have katalysis complex body and can not continue melanochrome and generate approach.Hence one can see that, and in catalytic process, the oxidation state tyrosine oxidase is being played the part of important role, and is as shown in Figure 2.
4. the influence of tyrosine oxidase
Tyrosine oxidase is to cause fruits and vegetables storing or adding the reason that produces the brown stain of ferment property man-hour; Brown stain is to the manufacturing of some product; Can give special color and luster of product and local flavor; For example black tea, raisin, but as far as the fresh vegetables and fruits of major part, tyrosine oxidase be make vegetable and fruit color and smell change, organization softening, reduce its digestibility, arrestin hydrolysis and glycolytic ferment; Non-nutrition that tyrosine oxidase is produced in catalytic process and toxic compounds possibly further make the nutritive value forfeiture, even influence the safety of food.2003 Dr.Asanuma (reference Neurotox Res 5, p165-76,2003) point out that then tyrosine oxidase maybe be relevant with Parkinson's disease (Parkinson ' s disease) and other neurodegenerative disorders.
5. the application of tyrosinase inhibitor
5-1, in agricultural and foodstuffs industry:
After the vegetable and fruit generation brown stain, the taste that can influence its outward appearance, smell and eat, this is the problem that grower and foodstuffs industry person are concerned about.And the generation rate of ferment property brown stain is to decide according to activation tyrosine oxidase and conditions such as the concentration of phenolic cpd, available oxygen, pH value and temperature in the tissue.Therefore, the ferment property brown stain that utilizes different methods to stop to be caused by tyrosine oxidase is necessary.Tyrosinase inhibitor is applied in goodly in the foodstuffs industry has a year; The browning reaction suppressor factor of conventional has xitix (ascorbic acid), Hydrocerol A (citric acid) and sulphite etc.; Though the inhibition effect of sulphite is splendid; But severe side effect is arranged, and therefore, seeking natural and harmless tyrosinase inhibitor has its necessity.
5-2, in cosmetic industry:
Tyrosinase inhibitor is more and more important on cosmetic industry to be because its Pear Power function.The previous natural inhibitor of having found comprises Arbutin (Arbutin), kojic acid (Kojic acid), linolenic acid (Linoleic acid), Resorcinol (Hydroquinones) etc.; But only having minority to be used as skin-whitening agents, mainly is because these natural tyrosinase inhibitors may cause spinoff.
Department of Health checks and approves eight kinds of compositions that are used in skin-lightening cosmetic at present; Like vitamin C phosphoric acid magnesium salts (Magnesium Ascorbyl Phosphate), vitamin C sodium phosphate salt (Sodium Ascorbyl Phosphate), vitamin C candy glycosides (Ascorbyl Glucoside), kojic acid (Kojioc Acid), Arbutin (Arbutin), gallogen (Ellagic Acid), tranamic acid (Tranexamic acid) and Flos Matricariae chamomillae extract (Chamomile ET); Wherein kojic acid and Arbutin are tyrosinase inhibitor; Can reach the function of whitening via restraint of tyrosinase, also be the welcome compositions of skin-care article.
Arbutin is to be extracted and got by Vacciniaceae plant uva ursi, also can find the trace of Arbutin in some fruit, for example European pear, little sorb.It is similar that the structure of Arbutin and Department of Health bulletin is classified the Resorcinol of medicine as, after skin absorption, can be hydrolyzed into Resorcinol and glucose, therefore; It is identical with Resorcinol that its effect machine changes, and all is the activity that sees through restraint of tyrosinase, desalinates established melanochrome; Yet Resorcinol can suppress simultaneously that melanochrome forms and destroy melanocyte, and the use initial stage whitens and to remove the effect of spot fine, but can cause possible permanent damage to skin; As produce other spot or corrosion skin, because the texture ratio Resorcinol of Arbutin has been with glucose molecule more, so pungency is lower; And be able in skin care products, occur, but because it still must be reduced into Resorcinol and could act on, thereby cause that partly the personage suspects; Think the spinoff of still having an opportunity to produce similar Resorcinol; But Department of Health will the Arbutin bulletin be the whitening composition of endorsing extremely so far, and the concentration of regulation Arbutin in skin care products must avoid the Arbutin of high density that skin immunization power is descended below 7%.
Kojic acid is the composition that extracts from aspergillus, and in the melanochrome forming process, cupric ion is played the part of the catalysis role, and kojic acid can be caught cupric ion, suppresses melanochrome and forms, and makes the metabolism of pigment founder cell normal, suppresses blackspot or freckle, reaches white-skinned face function.Dr.Noh points out to add amino at the carboxylic acid end of kojic acid-tripeptides 2007 (reference Biopolymers 88, p300-7,2007), will help to improve the inhibition effect of its antiacid alkali ability, thermotolerance, the stability of depositing and tyrosine oxidase.Whether yet Japanese health ministry suspects that kojic acid has carcinogenic danger as food additives in the recent period, has stopped using at present among food, and toiletries requires to carry out clinical trial, forbid with the assessment kojic acid.Behind Japanese government's bulletin forbidding kojic acid food additives; Whether the skin care products that contains kojic acid safety; Each tame saying is diverse and confused; Do not have explicit data until now and confirm that with research it has harm, Taiwan Department of Health will the kojic acid bulletin be the whitening composition of endorsing at present, and the concentration of regulation kojic acid in skin care products must be below 2%.
Though Department of Health announces that checking and approving the composition that is used in skin-lightening cosmetic has eight kinds at present; But the part kind still has the doubt of security; We must clasp correct expectation to whitening, and the idea that does not have and take effect immediately is for having healthy and pale skin; How carrying out effective and safe whitening, is important problem in the present skin-lightening cosmetic field.
For solving the problem that present skin-lightening cosmetic field is run into, patent application 20090099093A1 provides a kind of tyrosinase inhibitor, and this suppressor factor is made up of a polypeptide; This peptide sequence comprises 6 to 8 amino acid, and as tyrosinase inhibitor, the employed polypeptide of this case has more security compared to compound that prior art is used; Effect is gentle and be easy to absorption of human body and metabolism; Yet polypeptide synthetic expense is a manufacturer carries out tyrosinase inhibitor commercial and considers that greatly the long more expense of polypeptide composition length is high more, and the method for shipment of polypeptide is also for considering emphasis in addition; Dr.Agarwal S (reference Int J Pharm 359 in 2008; 7-14,2008) propose to transport, can improve water-soluble, the seepage force of peptide class precursor (peptide prodrug) etc. with suitable medical composition; Avoid peptide class precursor to receive the decomposition of proteolytic enzyme during the course, and then keep drug concentrations.Therefore, research and develop a kind of both effectively, safety and the shorter tyrosinase inhibitor of polypeptide length, will be the problem that present anxious desire solves.
Summary of the invention
In view of the foregoing invention background, research and develop a kind of both effectively, safety and the shorter natural tyrosinase inhibitor of polypeptide length, be the problem of current anxious desire solution.The present invention is according to the structural performance of tyrosine oxidase; Design a series of tyrosinase inhibitor; Melanin content analysis via external tyrosinase activity experiment test, security test result and living animal experiment confirms that tyrosinase inhibitor proposed by the invention has significant inhibition effect.And this tyrosinase inhibitor is more effective than the peptide sequence that prior art proposed, safety and length are shorter.
The aminoacid sequence title definition synopsis that the present invention quoted:
English | Chinese | Abbreviation |
Glycine | Glycocoll | Gly(G) |
?Alanine | L-Ala | Ala(A) |
?Valine | Xie Ansuan | Val(V) |
?Leucine | Leucine | Leu(L) |
?Isoleucine | Isoleucine | Ile(I) |
?Serine | Serine | Ser(S) |
?Threonine | Threonine | Thr(T) |
?Cystine | Halfcystine | Cys(C) |
?Methionine | Methionine(Met) | Met(M) |
?Proline | Proline(Pro) | Pro(P) |
?Lysine | Methionin | Lys(K) |
?Arginine | L-arginine | Arg(R) |
?Phenylalanine | Phenylalanine(Phe) | Phe(F) |
?Tyrosine | Tyrosine | Tyr(Y) |
?Tryptophan | Tryptophane | Trp(W) |
?Histidine | Histidine | His(H) |
?Aspartate | Aspartic acid | Asp(D) |
?Glutamate | L-glutamic acid | Glu(E) |
?Asparagine | N | Asn(N) |
?Glutamine | Stimulina | Gln(Q) |
The amino acid whose classification of content indication of the present invention:
1. fatty amino acids (Aliphatic) comprising: L-Ala (Alanine, A), Isoleucine (Isoleucine, I), leucine (Leucine, L), Xie Ansuan (Valine, V), proline(Pro) (Proline, P).
2. aromatic amino acid class (Aromatic) comprising: phenylalanine(Phe) (Phenylalanine, F), tryptophane (Tryptophan, W), tyrosine (Tyrosine, Y).
3. acidic amino acid class (Acidic) comprising: aspartic acid (Aspartic acid, D), L-glutamic acid (Glutamicacid, E).
4. basic aminoacids class (Basic) comprising: l-arginine (Arginine, R), Histidine (Histidine, H), Methionin (Lysine, K).
5. hydroxyl amino acids (Hydroxylic) comprising: Serine (Serine, S),, Threonine (Threonine, T).
6. sulfur-containing amino acid class (Sulfur containing) comprising: halfcystine (Cysteine, C), methionine(Met) (Methionine, M).
7. amidoamino acid class (Amidic) comprising: N (Asparagine, N), Stimulina (Glutamine, Q).
One aspect of the present invention provides a kind of tyrosinase inhibitor, and its peptide sequence that contains does
R1n1-Xaa-R2n2-Yaa-R3n3
Wherein Xaa or Yaa are a kind of in tyrosine, halfcystine, glycocoll, L-glutamic acid or the l-arginine; Substituent R 1, R2 or R3 are selected from one or more in glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid or the amidoamino acid; And wherein n1, n2 or n3 are substituent number, and n1, n2, n3 are respectively 0 or 1.
The present invention provides a kind of tyrosinase inhibitor on the other hand, and its peptide sequence is: R1n1-Tyr-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Tyr-R3n3.
Another aspect of the invention provides a kind of tyrosinase inhibitor, and its peptide sequence is: R1n1-Cys-R2n2-Gly-R3n3 or R1n1-Gly-R2n2-Cys-R3n3.
Further aspect of the present invention provides a kind of tyrosinase inhibitor, and its peptide sequence is: R1n1-Glu-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Glu-R3n3.
The present invention also provides a kind of tyrosinase inhibitor, and its peptide sequence is: R1n1-Arg-R2n2-Tyr-R3n3 or R1n1-Tyr-R2n2-Arg-R3n3.
Wherein, Substituent R 1, R2 or R3 are selected from one or more in glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid or the amidoamino acid; And wherein n1, n2 or n3 are substituent number, and n1, n2, n3 are respectively 0 or 1.
The detailed description of the peptide sequence of tyrosinase inhibitor of the present invention:
(1) R1n1-Tyr-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Tyr-R3n3
Wherein, Substituent R 1, R2 or R3 are selected from one or more in glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid or the amidoamino acid; And wherein n1, n2 or n3 are substituent number, and n1, n2, n3 are respectively 0 or 1.
As shown in table 1 below, it is representative that the peptide sequence design selects one with each amino-acid functional base type, and cross arrangement becomes not homotactic short polypeptide.
Design of table 1 peptide sequence and example thereof
(2) R1n1-Cys-R2n2-Gly-R3n3 or R1n1-Gly-R2n2-Cys-R3n3
Wherein, Substituent R 1, R2 or R3 are selected from one or more in glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid or the amidoamino acid; And wherein n1, n2 or n3 are substituent number, and n1, n2, n3 are respectively 0 or 1.
As shown in table 2, it is representative that its peptide sequence design selects one with each amino-acid functional base type, and cross arrangement becomes the short polypeptide of different sequences.
Design of table 2 peptide sequence and example thereof
(3) R1n1-Glu-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Glu-R3n3
Wherein, Substituent R 1, R2 or R3 are selected from one or more in glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid or the amidoamino acid; And wherein n1, n2 or n3 are substituent number, and n1, n2, n3 are respectively 0 or 1.
As shown in table 3, it is representative that its peptide sequence design selects one with each amino-acid functional base type, and cross arrangement becomes not homotactic short polypeptide.
Design of table 3 peptide sequence and example thereof
(4) R1n1-Arg-R2n2-Tyr-R3n3 or R1n1-Tyr-R2n2-Arg-R3n3
Wherein, Substituent R 1, R2 or R3 are selected from one or more in glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid or the amidoamino acid; And wherein n1, n2 or n3 are substituent number, and n1, n2, n3 are respectively 0 or 1.
As shown in table 4, it is representative that its peptide sequence design selects one with each amino-acid functional base type, and cross arrangement becomes not homotactic short polypeptide.
Design of table 4 peptide sequence and example thereof
Wherein, tyrosinase inhibitor of the present invention, described peptide sequence is preferably:
(1) R1n1-Tyr-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Tyr-R3n3,
(2) R1n1-Cys-R2n2-Gly-R3n3 or R1n1-Gly-R2n2-Cys-R3n3,
(3) R1n1-Glu-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Glu-R3n3,
Or (four) R1n1-Arg-R2n2-Tyr-R3n3 or R1n1-Tyr-R2n2-Arg-R3n3,
Wherein, when n1=0, n2=0 and n3=1, substituent R 3 is selected from one or more in glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid or the amidoamino acid.
Particularly, tyrosinase inhibitor of the present invention, described peptide sequence is preferably:
(1) R1n1-Tyr-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Tyr-R3n3,
(2) R1n1-Cys-R2n2-Gly-R3n3 or R1n1-Gly-R2n2-Cys-R3n3,
(3) R1n1-Glu-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Glu-R3n3,
Or (four) R1n1-Arg-R2n2-Tyr-R3n3 or R1n1-Tyr-R2n2-Arg-R3n3,
Wherein, when n1=0, n2=1 and n3=0, substituent R 2 is selected from one or more in glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid or the amidoamino acid.
Particularly, tyrosinase inhibitor of the present invention, described peptide sequence is preferably:
(1) R1n1-Tyr-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Tyr-R3n3,
(2) R1n1-Cys-R2n2-Gly-R3n3 or R1n1-Gly-R2n2-Cys-R3n3,
(3) R1n1-Glu-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Glu-R3n3,
Or (four) R1n1-Arg-R2n2-Tyr-R3n3 or R1n1-Tyr-R2n2-Arg-R3n3,
Wherein when n1=1, n2=0 and n3=0, substituent R 1 is selected from one or more in glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid or the amidoamino acid.
Particularly, tyrosinase inhibitor of the present invention, described peptide sequence is preferably:
(1) R1n1-Tyr-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Tyr-R3n3,
(2) R1n1-Cys-R2n2-Gly-R3n3 or R1n1-Gly-R2n2-Cys-R3n3,
(3) R1n1-Glu-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Glu-R3n3,
Or (four) R1n1-Arg-R2n2-Tyr-R3n3 or R1n1-Tyr-R2n2-Arg-R3n3,
Wherein when n1=1, n2=0 and n3=1, substituent R 1 or R3 are selected from one or more in glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid or the amidoamino acid.
Particularly, tyrosinase inhibitor of the present invention, described peptide sequence is preferably:
(1) R1n1-Tyr-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Tyr-R3n3,
(2) R1n1-Cys-R2n2-Gly-R3n3 or R1n1-Gly-R2n2-Cys-R3n3,
(3) R1n1-Glu-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Glu-R3n3,
Or (four) R1n1-Arg-R2n2-Tyr-R3n3 or R1n1-Tyr-R2n2-Arg-R3n3,
Wherein when n1=1, n2=1 and n3=0, substituent R 1 or R2 are selected from one or more in glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid or the amidoamino acid.
Particularly, tyrosinase inhibitor of the present invention, described peptide sequence is preferably:
(1) R1n1-Tyr-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Tyr-R3n3,
(2) R1n1-Cys-R2n2-Gly-R3n3 or R1n1-Gly-R2n2-Cys-R3n3,
(3) R1n1-Glu-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Glu-R3n3,
Or (four) R1n1-Arg-R2n2-Tyr-R3n3 or R1n1-Tyr-R2n2-Arg-R3n3,
Wherein when n1=0, n2=1 and n3=1, substituent R 2 or R3 are selected from one or more in glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid or the amidoamino acid.
Particularly, tyrosinase inhibitor of the present invention, described peptide sequence is preferably:
(1) R1n1-Tyr-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Tyr-R3n3,
(2) R1n1-Cys-R2n2-Gly-R3n3 or R1n1-Gly-R2n2-Cys-R3n3,
(3) R1n1-Glu-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Glu-R3n3,
Or (four) R1n1-Arg-R2n2-Tyr-R3n3 or R1n1-Tyr-R2n2-Arg-R3n3,
Wherein when n1=1, n2=1 and n3=1, substituent R 1, R2 or R3 are selected from one or more in glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid or the amidoamino acid.
The present invention provides a kind of tyrosinase inhibitor, and it contains peptide sequence and is selected from:
Tyr-Cys-Cys; Glu-Cys-Val; Cys-Arg; Cys-Asp-Tyr; Arg-Tyr-Cys-Arg; Asp-Cys-Gly; Arg-Cys-Tyr-Arg; Cys-Gly-Ser; Asn-Cys-Tyr; Phe-Tyr-Cys; Arg-Cys-Tyr-Val; Val-Cys-Gly; Cys-Gly-Tyr; Tyr-Phe-Cys; Cys-Val; Arg-Phe-Tyr-Cys; Gly-Cys-Tyr; Phe-Tyr-Cys-Arg; Cys-Tyr-Gly; Arg-Cys-Tyr; Val-Ser-His-Tyr; One or more of Tyr-Phe-Arg or Tyr-Asp.
Further aspect of the present invention provides a kind of tyrosinase inhibitor, and it contains peptide sequence and is selected among Arg-Cys-Tyr, Val-Ser-His-Tyr, Gly-Cys-Tyr, Tyr-Phe-Arg or the Tyr-Asp one or more.
Wherein, Tyrosinase inhibitor of the present invention; One or more amino acid in its peptide sequence further pass through acetylize (Acetylated), amidation (Amidated), formylation (Formylated), hydroxylation (Hydroxylated), lipid-modified (Lipid Modified), methylate (Methylated) or the modification of phosphorylation (Phosphorylated); At Anan Abu Ubeid in 2009 equally also was the suppressor factor that the peptide sequence found can be used as tyrosine oxidase; And the patent of delivering at the same time (WO2009003034 (A1)) is also mentioned through the modified polypeptides sequence and also being calculated in claim, thinks that therefore it can't change the active mechanism of its effect through modified polypeptides sequence.
The present invention provides a kind of active medical composition of restraint of tyrosinase that contains above-mentioned tyrosinase inhibitor on the other hand.
Wherein, said medical composition also contains and comprises a kind of pharmaceutically acceptable carrier.
Particularly, said carrier is vehicle, thinner, thickening material, weighting agent, wedding agent, disintegrating agent, lubricant, grease or non-greasy base, interfacial agent, suspension agent, jelling agent, auxiliary, sanitas, inhibitor, stablizer, tinting material or spices.Medical composition of the present invention is through the active of restraint of tyrosinase and then suppress melanic generation, reduces melanin content in the cell, and can be applicable to makeup or agricultural-food, when it is applied to makeup, can be used as whitening agent.
Another aspect of the invention provides a kind of above-mentioned tyrosinase inhibitor is transferred to Mammals; Reduce the method for melanin content in the mammal skin; This mechanism mainly is the activity that sees through restraint of tyrosinase, this method comprise with above-mentioned tyrosinase inhibitor via oral, through skin absorb, the mode of injection or suction transfers to a Mammals.Wherein Mammals comprises biologies such as the mankind.
Description of drawings
Fig. 1 is that melanic intercrescence becomes approach.
Fig. 2 is the catalytic process of tyrosine oxidase.
Fig. 3 is the security test result of not homotactic short peptide inhibitor.
Embodiment
The following example is non-limiting and only as the typical example of the present invention in each side.
Embodiment 1: the test of external (In vitro) tyrosinase activity
I. medicine
The Mushroom tyrosine oxidase (Mushroom tyrosinase, 100U/ml), Arbutin (Arbutin), tyrosine (L-tyrosine, 0.5mM), kojic acid (Kojic acid) and 2 to 5 not homotactic short polypeptide (0.5mM).Short peptide sequence is R1n1-Xaa-R2n2-Yaa-R3n3; Xaa or Yaa are a kind of in tyrosine, halfcystine, glycocoll, L-glutamic acid and l-arginine five seed amino acids; The amino acid of substituent R 1, R2 or R3 is divided into following eight types according to the functional group: glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid and amidoamino acid; All types ofly select one; N1, n2 or n3 are substituent number, equal 0 or 1 respectively, become 2 to 5 not homotactic short polypeptide with the upper amino acid cross arrangement.
II. experimental procedure
Under 475nm, survey the OD value of dopachrome with spectrophotometer (Varian cary-50Bio UV-Visible spectrophotometer).Calculate the remaining activity per-cent of tyrosinase again with formula:
Tyrosinase activity (the residue tyrosinase activity, %)=(D-C)/(B-A) * 100%
A wherein: the 475nm light absorption value before the negative control group reaction;
B: the reacted 475nm light absorption value of negative control group;
C: the 475nm light absorption value before the sample sets reaction;
D: the reacted 475nm light absorption value of sample sets.
III. experimental result
Come comparison with Arbutin and kojic acid (previous experimental result shows, kojic acid is under concentration 0.4mM, and activity that can 100% restraint of tyrosinase, the test duration is 30 minutes) as positive controls.
Show 5-9 classify in the time of 5 minutes, the active effect of not homotactic short polypeptide restraint of tyrosinase.With short polypeptide that the present invention designed and commercially available whitening composition Arbutin and kojic acid relatively; Arbutin restraint of tyrosinase activity is 32.2%; The short polypeptide effect that the present invention designed is much better than Arbutin, and kojic acid restraint of tyrosinase activity is 0.10%, has same superior effect with short polypeptide of the present invention; Yet consider to be used for the safety issue of human body, short polypeptide of the present invention is more safer than kojic acid.
Table 5,5 minutes the time, the active effect (sequence of not homotactic short polypeptide restraint of tyrosinase
R1n1-Tyr-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Tyr-R3n3)
Sequence | Tyrosinase active (%) | Sequence | Tyrosinase active (%) |
YCC | 0 | ECY | 0.074653674 |
CDY | 0 | DYC | 0.087482961 |
YCN | 0 | VYCR | 0.091795925 |
CVY | 0 | CGY | 0.096860964 |
YGC | 0 | CYN | 0.097461159 |
RYC | 0 | DYCR | 0.101490686 |
RFYC | 0 | KA | 0.10591521 |
YNC | 0 | VCY | 0.109361087 |
RCYV | 0 | NYCR | 0.121654937 |
RCYC | 0 | YCS | 0.140878234 |
NCY | 0 | CYS | 0.148467869 |
VYC | 0 | CNY | 0.152249737 |
YSC | 0 | CCY | 0.170952487 |
RCYD | 0 | YCV | 0.201675903 |
RYCR | 0 | RCYW | 0.240532622 |
SYCR | 0 | YC | 0.282109105 |
CSY | 0 | RCYL | 0.306704013 |
YCG | 0 | RCYI | 0.315981809 |
YFC | 0 | RCY | 0.356030441 |
RCYN | 0 | CYR | 0.383016975 |
FYC | 0 | GCY | 0.388680245 |
GYC | 0 | RCYG | 0.422501613 |
RCYR | 0 | RCYA | 0.422863366 |
CYC | 0 | WCY | 0.433679474 |
GYCR | 0 | RCGY | 0.439602446 |
CYG | 0 | YCE | 0.440729397 |
YEC | 0 | CYD | 0.445290753 |
VRCY | 0 | CY | 0.516055046 |
SCY | 0 | YCD | 0.67074304 |
YRC | 0 | CFY | 0.872799404 |
YDC | 0 | CRY | 1.102088681 |
RCYF | 0.019169001 | RCYCR | 1.146788991 |
FYCR | 0.020633759 | YVC | 4.196121435 |
YCR | 0.036315672 | Arb | 32.242669 |
RCYS | 0.0382263 | |
100 |
YCF | 0.047937278 |
Table 6,5 minutes the time, the active effect of not homotactic short polypeptide restraint of tyrosinase (sequence R1n1-Cys-R2n2-Gly-R3n3 or R1n1-Gly-R2n2-Cys-R3n3)
Sequence | Tyrosinase active (%) | Sequence | Tyrosinase active (%) |
CGS | 0 | VCG | 0.16501671 |
CGR | 0 | CGN | 0.184239081 |
DCG | 0 | GCG | 0.194596694 |
CGD | 0 | CGV | 0.20573982 |
CGG | 0 | ECG | 0.332101409 |
CGC | 0 | NCG | 0.440803923 |
SCG | 0 | CG | 0.496941896 |
CCG | 0.00758032 | Arb | 32.242669 |
RCG | 0.028104759 | |
100 |
KA | 0.1059152 |
Table 7,5 minutes the time, the active effect of not homotactic short polypeptide restraint of tyrosinase (sequence R1n1-Glu-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Glu-R3n3)
Sequence | Tyrosinase active (%) | Sequence | Tyrosinase active (%) |
ECV | 0 | REC | 0.244581269 |
ECR | 0 | CEC | 0.268719348 |
ECN | 0 | ECG | 0.332101409 |
ECC | 0 | DEC | 0.350414781 |
ECS | 0.046361766 | NEC | 0.39675514 |
GEC | 0.05283631 | ECD | 0.39964605 |
KA | 0.10591521 | Arb | 32.242669 |
VEC | 0.207898268 | |
100 |
Table 8,5 minutes the time, the active effect of not homotactic short polypeptide restraint of tyrosinase (sequence R1n1-Arg-R2n2-Tyr-R3n3 or R1n1-Tyr-R2n2-Arg-R3n3)
Sequence | Tyrosinase active (%) | Sequence | Tyrosinase active (%) |
RSY | 0 | WRFY | 9.830538813 |
RFYW | 0 | RYY | 15.8876895 |
KA | 0.10591521 | Arb | 32.242669 |
RWY | 1.04109589 | YR | 44.9087323 |
RFY | 1.259403349 | YFR | 47.37618551 |
RIY | 2.4216621 | RGY | 51.92132116 |
RLY | 2.525159817 | RY | 54.22843594 |
RTY | 2.608200147 | RPYR | 82.384621 |
RMY | 2.708666667 | RFYE | 83.06501065 |
RAY | 3.633065449 | |
100 |
RVY | 4.551878234 |
Table 9,5 minutes the time, the not homotactic active effect of short polypeptide restraint of tyrosinase (sequence Val-Ser-His-Tyr)
Sequence | Tyrosinase active (%) |
KA | 0.105915208 |
VSHY | 1.366590214 |
Arb | 32.24266895 |
HY | 47.81793167 |
YH | 48.56735741 |
VY | 68.98319048 |
VH | 69.42109648 |
|
100 |
When further testing 5 and 30 minutes, the active effect (just listing out the part that sequence is R1n1-Tyr-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Tyr-R3n3) of not homotactic short polypeptide restraint of tyrosinase.The listed result of table 10 show 5 with different inhibition effects was arranged respectively in 30 minutes, short polypeptide of the present invention is the existing effect that suppresses at 5 minutes, the continuous and effective still to 30 minutes, and with the time economic consideration, the present invention is existing enough inhibition effects at 5 minutes.
With short polypeptide and Arbutin and kojic acid comparison that the present invention designed, Arbutin restraint of tyrosinase activity was 32.24% at 5 minutes, returned back to 49.14% during to 30 minutes; Can know by inference Arbutin 30 minutes by metabolism, suppresses effect and slowly reply, and kojic acid restraint of tyrosinase activity was 0.1% at 5 minutes; To 30 minutes was 0.24%, and effect is very remarkable, yet considers with effect; The short polypeptide effect that the present invention designed is much better than Arbutin, and with security consideration, short polypeptide of the present invention is more safer than kojic acid; Therefore generally speaking, whitening composition Arbutin and kojic acid that the present invention is more commercially available are more superior.
Table 10, respectively in the time of 5 and 30 minutes, tyrosinase activity is by the inhibition effect of homotactic short polypeptide (sequence R1n1-Tyr-R2n2-Cys-R3n3 or R1n1-Cys-R2n2-Tyr-R3n3) not
Embodiment 2: not homotactic short polypeptide carries out the security test result
I. medicine source
1. peptide sequence is YD, YFR, GCY and YC
II. experimental procedure
Utilize MTT to test to measure suppressor factor and whether contain cytotoxicity; Succinic acid dehydrogenase (succinate dehydrogenase) in the viable cell in the grain line body can reduce empurpled crystallization (formazan) with xanchromatic MTT; And then adding DMSO dissolves purple crystal (formazan); And with the light absorption value of this solution of spectrophotometer measurement under OD 595nm, and the influence of estimation test substances cell growth.
(1) preparation contains the MTT nutrient solution earlier, and per 500 μ l nutrient solutions add 80 μ l MTT (original concentration is 5mg/ml).
(2) cell culture fluid is all picked up, each 96 porose disc adds 100 μ l and contains MTT nutrient solution (then add 500 μ l in the 24-porose disc and contain the MTT nutrient solution), in 37 ℃ 5%C0
2Incubator left standstill one hour.
(3) substratum of removal cell cultures dish, the DMSO of adding proper volume (adding 200 μ l in the 96-porose disc) left standstill 10 minutes.Measure wavelength 550nm light absorption value with continuous wavelength micropore dish analytical system (Molecular Devices, SPECTRAMAX M2), the average light absorption value with the untreated control group is 100% afterwards, the light absorption value per-cent of experiment with computing group.
III. experimental result
The security test result of the short peptide inhibitor of different sequences that Fig. 3 classifies as.Different short polypeptide suppressed the effect of Tyrosinase activity in the time of 5 minutes.From the MTT experimental result, when Arbutin that adds 5mM or the kojic acid of 1mM, cytoactive has just been reduced to 95% Schwellenwert.In MTT assay experimental result, having added GCY 100 μ M does not still influence cytoactive.And other suppressor factor YC, YD, YFR also have identical situation, so by above experiment confirm: these four short polypeptide do not have toxicity and can not influence cytoactive.
Embodiment 3: (In vivo) melanin content analysis in the body
The suitable reverse compound that part is arranged in this piece patent; It suppresses effect can't receive suitable oppositely and to some extent difference; But also some forward can gap about 50% with the inhibition effect of reverse compound; On the other hand, part of compounds is dissolved in the situation that colour generation is arranged after the solution, and therefore may to influence light absorption value too high for the situation of getting rid of colour generation; And the suppressor factor that confirms this institute design also can have same good white-skinned face function at human body, carries out the melanin content analysis so we select part of compounds YD, YFR, GCY, YC.
I. medicine source
1. peptide sequence is YD, YFR, GCY and YC
II. experimental procedure
Melanocyte is cultivated in 24 porose discs, and with different suppressor factor, with 1,5,10,25,50 and the concentration of 100 μ M cultivated respectively seven days.After seven days, add the of short duration cultivation of trypsin/EDTA (0.25%/0.1%inphosphate bufferedsaline), make cellular segregation.Afterwards cell culture fluid is all picked up, add HBSS and clean twice, it is broken to utilize UW that cell is shaken, and adds 0.3ml 1N NaOH (70 ℃) again, and inserts 50 ℃ baking oven and left standstill 10 minutes.Behind melanochrome (melanin) mixing with stripping, get 0.2ml to 96 porose disc, at last with the light absorption value of spectrophotometric determination OD 405nm melanin.
III. experimental result
The melanin content analytical results of table 11, the short polypeptide of YD sequence
YD | Relative melanin content | SD |
Negative control group | 100.00 | 11.24 |
1 | 80.57 | 1.65 |
5 | 78.20 | 2.98 |
10 | 77.94 | 2.98 |
25 | 73.02 | 10.87 |
50 | 80.37 | 7.97 |
100 | 75.72 | 1.08 |
kojic?acid(0.5mM) | 81.87 | 3.01 |
kojic?acid(1mM) | 67.63 | 2.87 |
Arbutin(5mM) | 74.52 | 4.19 |
The melanin content analytical results of table 12, the short polypeptide of YFR sequence
YFR | Relative melanin content | SD |
Negative control group | 100.00 | 10.93 |
1 | 91.65 | 6.06 |
5 | 86.78 | 2.53 |
10 | 86.12 | 0.81 |
25 | 84.15 | 3.29 |
50 | 84.48 | 1.70 |
100 | 81.02 | 1.75 |
kojic?acid(1mM) | 67.63 | 2.87 |
kojic?acid(0.5mM) | 81.87 | 3.01 |
Arbutin(5mM) | 74.52 | 4.19 |
The melanin content analytical results of table 13, the short polypeptide of GCY sequence
GCY | Relative melanin content | SD |
Negative control group | 100.00 | 7.84 |
1 | 107.05 | 18.26 |
5 | 90.40 | 2.83 |
10 | 85.93 | 5.66 |
25 | 92.75 | 3.28 |
50 | 90.47 | 0.71 |
100 | 82.41 | 2.19 |
kojic?acid(1mM) | 67.63 | 2.87 |
kojic?acid(0.5mM) | 81.87 | 3.01 |
Arbutin(5mM) | 74.52 | 4.19 |
The melanin content analytical results of table 14, the short polypeptide of YC sequence
YC | Relative melanin content | SD |
|
100 | 5.75 |
1 | 96.33 | 5.13 |
5 | 95.00 | 2.53 |
10 | 95.39 | 1.60 |
25 | 100.97 | 2.19 |
50 | 92.26 | 1.86 |
100 | 91.21 | 4.28 |
kojic?acid(1mM) | 67.63 | 2.87 |
kojic?acid(0.5mM) | 81.87 | 3.01 |
Arbutin(5mM) | 74.52 | 4.19 |
From experimental result; Can find when Arbutin adds 5mM; Can make the content of melanochrome (melanin) reduce to 74.52%; And when adding kojic acid 1mM, just can make melanic content reduce to 67.63%, so that the inhibition effect of kojic acid also is the ratio Arbutin that shows in human tyrosine oxidase is good.
From the experimental result of table 11, we can see when adding YD 100 μ M, only need 0.02 multiple dose of Arbutin can reach identical inhibition effect, make melanic content reduce to about 75%; And when adding YD 1 μ M, can reach and the identical inhibition effect of adding kojic acid 0.5mM, make melanic content reduce to about 80%.From the experimental result of table 12, we can see when adding YFR 100 μ M, only need 0.2 multiple dose of kojic acid, can reach and the identical inhibition effect of adding kojic acid 0.5mM, make melanic content reduce to about 80%.
So the data results by above is learnt: YD, YFR in human tyrosine oxidase, have really and suppress effect, and its inhibition ability even be superior to kojic acid and Arbutin.So instead push back external Mushroom tyrosinase activity test experiments result; YD; Why the YFR compound can be mistaken for the inhibition poor effect, mainly is to receive compound has the colour generation situation in the middle of solution influence, and then produces too high light absorption value; On the other hand, above data have confirmed that also suitable reverse compound is that difference is little for the inhibition effect of tyrosinase.
According to the experimental result (table 13) of GCY, from data, can learn: when adding GCY 100 μ M, only need the dosage of a little, can reach and the identical inhibition effect of adding kojic acid 0.5mM, make the content of melanochrome (melanin) reduce to about 80%.On the other hand; The experimental result (table 14) of YC and the experimental data of GCY are in comparison; We can find: in human tyrosine oxidase, the inhibition effect of GCY also is to be superior to YC, this situation with in external Mushroom tyrosinase activity test result, be consistent.So according to above experimental result, our inference: for the Mushroom tyrosine oxidase compound that suppresses effect is arranged, in human tyrosine oxidase, might also have identical good inhibition situation.
Result from MTT assay; Learn the kojic acid of 1mM or the Arbutin of 5mM; Just make cytoactive reduce to Schwellenwert 95%, and compare external Mushroom tyrosinase activity test experiments result, learn that adding YD100 μ M can reach and kojic acid 1mM or seventy percent close inhibition effect of Arbutin 5mM; But can't influence its cytoactive when adding YD100 μ M; So from above two experiment confirms: these compounds not only have good inhibition effect, and do not have cytotoxicity compared to cosmetic industry kojic acid and Arbutin commonly used.
Claims (16)
1. tyrosinase inhibitor is characterized in that comprising following peptide sequence:
R1n1-Xaa-R2n2-Yaa-R3n3
Wherein Xaa or Yaa are a kind of in tyrosine, halfcystine, glycocoll, L-glutamic acid or the l-arginine; Substituent R 1, R2 or R3 are selected from one or more in glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid or the amidoamino acid; And wherein n1, n2 or n3 are substituent number, and n1, n2, n3 are respectively 0 or 1.
2. tyrosinase inhibitor according to claim 1 is characterized in that said peptide sequence is:
R1n1-Tyr-R2n2-Cys-R3n3
Or
R1n1-Cys-R2n2-Tyr-R3n3,
Wherein substituent R 1, R2 or R3 are selected from one or more in glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid or the amidoamino acid; And wherein n1, n2 or n3 are substituent number, and n1, n2, n3 are respectively 0 or 1.
3. tyrosinase inhibitor according to claim 1 is characterized in that said peptide sequence is:
R1n1-Cys-R2n2-Gly-R3n3
Or
R1n1-Gly-R2n2-Cys-R3n3,
Wherein substituent R 1, R2 or R3 are selected from one or more in glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid or the amidoamino acid; And wherein n1, n2 or n3 are substituent number, and n1, n2, n3 are respectively 0 or 1.
4. tyrosinase inhibitor according to claim 1 is characterized in that said peptide sequence is:
R1n1-Glu-R2n2-Cys-R3n3
Or
R1n1-Cys-R2n2-Glu-R3n3,
Wherein substituent R 1, R2 or R3 are selected from one or more in glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid or the amidoamino acid; And wherein n1, n2 or n3 are substituent number, and n1, n2, n3 are respectively 0 or 1.
5. tyrosinase inhibitor according to claim 1 is characterized in that said peptide sequence is:
R1n1-Arg-R2n2-Tyr-R3n3
Or
R1n1-Tyr-R2n2-Arg-R3n3,
Wherein substituent R 1, R2 or R3 are selected from one or more in glycocoll, fatty amino acid, aromatic amino acid, acidic amino acid, basic aminoacids, hydroxy-amino-acid, sulfur-containing amino acid or the amidoamino acid; And wherein n1, n2 or n3 are substituent number, and n1, n2, n3 are respectively 0 or 1.
6. tyrosinase inhibitor is characterized in that containing peptide sequence and is selected from one or more of Tyr-Cys-Cys, Glu-Cys-Val, Cys-Arg, Cys-Asp-Tyr, Arg-Tyr-Cys-Arg, Asp-Cys-Gly, Arg-Cys-Tyr-Arg, Cys-Gly-Ser, Asn-Cys-Tyr, Phe-Tyr-Cys, Arg-Cys-Tyr-Val, Val-Cys-Gly, Cys-Gly-Tyr, Tyr-Phe-Cys, Cys-Val, Arg-Phe-Tyr-Cys, Gly-Cys-Tyr, Phe-Tyr-Cys-Arg, Cys-Tyr-Gly, Arg-Cys-Tyr, Val-Ser-His-Tyr, Tyr-Phe-Arg or Tyr-Asp.
7. tyrosinase inhibitor is characterized in that containing peptide sequence and is selected among Arg-Cys-Tyr, Val-Ser-His-Tyr, Gly-Cys-Tyr, Tyr-Phe-Arg or the Tyr-Asp one or more.
8. according to the arbitrary described tyrosinase inhibitor of claim 1-7, it is characterized in that in the said peptide sequence one or more amino acid through acetylize, amidation, formylation, hydroxylation, lipid-modified, methylate or phosphorylation modification.
9. the active medical composition of restraint of tyrosinase is characterized in that containing arbitrary said tyrosinase inhibitor just like claim 1-7.
10. medical composition according to claim 9 is characterized in that also comprising a kind of pharmaceutically acceptable carrier.
11. medical composition according to claim 10 is characterized in that said carrier is vehicle, thinner, thickening material, weighting agent, wedding agent, disintegrating agent, lubricant, grease or non-greasy base, interfacial agent, suspension agent, jelling agent, auxiliary, sanitas, inhibitor, stablizer, tinting material or spices.
12. the application of a medical composition as claimed in claim 9 is characterized in that being applied to makeup, agricultural-food or whitening agent.
13. a method that reduces melanin content in the mammal skin is characterized in that comprising the arbitrary described tyrosinase inhibitor of claim 1-7 is transferred to Mammals.
14. method according to claim 13 is characterized in that said tyrosinase inhibitor is administered through oral, transmits through the mode of skin absorption, injection or suction.
15. method according to claim 13 is characterized in that described tyrosinase inhibitor also comprises a kind of pharmaceutically acceptable carrier.
16. method according to claim 13 is characterized in that described Mammals is for human.
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CN2010102377292A CN102492018A (en) | 2010-07-27 | 2010-07-27 | Tyrosinase polypeptide inhibitor |
BR112013002042A BR112013002042A2 (en) | 2010-07-27 | 2011-07-25 | polypeptide tyrosinase inhibitor |
PCT/CN2011/077578 WO2012013136A1 (en) | 2010-07-27 | 2011-07-25 | Polypeptidic tyrosinase inhibitor |
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CN2010102377292A CN102492018A (en) | 2010-07-27 | 2010-07-27 | Tyrosinase polypeptide inhibitor |
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CN107987124A (en) * | 2017-10-20 | 2018-05-04 | 南京斯拜科生化实业有限公司 | A kind of dipeptide compound and its application |
CN108201515A (en) * | 2016-12-20 | 2018-06-26 | 武汉弘跃医药科技有限公司 | Application of a kind of biologically active peptide in skin care and skin-whitening |
CN109180785A (en) * | 2018-11-08 | 2019-01-11 | 中国科学院上海应用物理研究所 | A kind of whitening reducing polypeptide and its application with inhibition melanin production and ultraviolet injury resistant effect |
CN109689676A (en) * | 2016-09-15 | 2019-04-26 | 帝斯曼知识产权资产管理有限公司 | New compound |
CN110218240A (en) * | 2019-06-14 | 2019-09-10 | 河北黄金龙农业科技有限公司 | A kind of tyrosinase peptide for inhibiting and its application |
CN113087767A (en) * | 2021-04-13 | 2021-07-09 | 江西师范大学 | Tripeptide RFY with blood pressure reducing function and application thereof |
CN116554264A (en) * | 2021-09-30 | 2023-08-08 | 中国农业大学 | Rosa roxburghii antioxidant oligopeptide, preparation method and application thereof and antioxidant product |
WO2024162342A1 (en) * | 2023-01-31 | 2024-08-08 | 三菱商事ライフサイエンス株式会社 | Composition for inhibiting tyrosinase activity |
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US9316075B2 (en) | 2012-12-17 | 2016-04-19 | Baker Hughes Incorporated | High pressure lock assembly |
US9212528B2 (en) | 2012-12-17 | 2015-12-15 | Baker Hughes Incorporated | Lock assembly with cageless dogs |
EP2875806A1 (en) * | 2013-11-20 | 2015-05-27 | Infinitec Activos, S.L. | Targeted capsules for the delivery of whitening agents in the skin |
WO2017108316A1 (en) | 2015-12-24 | 2017-06-29 | Unilever N.V. | Tyrosinase inhibitors |
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EP1194164B8 (en) * | 1999-06-23 | 2007-03-21 | IDEXX Laboratories Inc | Prion protein peptides and uses thereof |
WO2009003034A1 (en) * | 2007-06-27 | 2008-12-31 | The Board Of Trustees Of The Leland Stanford Junior University | Oligopeptide tyrosinase inhibitors and uses thereof |
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CN109689676B (en) * | 2016-09-15 | 2022-10-18 | 帝斯曼知识产权资产管理有限公司 | Novel compound |
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CN109180785A (en) * | 2018-11-08 | 2019-01-11 | 中国科学院上海应用物理研究所 | A kind of whitening reducing polypeptide and its application with inhibition melanin production and ultraviolet injury resistant effect |
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CN110218240A (en) * | 2019-06-14 | 2019-09-10 | 河北黄金龙农业科技有限公司 | A kind of tyrosinase peptide for inhibiting and its application |
CN110218240B (en) * | 2019-06-14 | 2022-06-03 | 河北黄金龙农业科技有限公司 | Tyrosinase inhibitory peptide and application thereof |
CN113087767A (en) * | 2021-04-13 | 2021-07-09 | 江西师范大学 | Tripeptide RFY with blood pressure reducing function and application thereof |
CN116554264A (en) * | 2021-09-30 | 2023-08-08 | 中国农业大学 | Rosa roxburghii antioxidant oligopeptide, preparation method and application thereof and antioxidant product |
CN116554264B (en) * | 2021-09-30 | 2023-11-28 | 中国农业大学 | Oligopeptide separated from Rosa roxburghii, preparation method, oxidation resistance application and product thereof |
WO2024162342A1 (en) * | 2023-01-31 | 2024-08-08 | 三菱商事ライフサイエンス株式会社 | Composition for inhibiting tyrosinase activity |
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BR112013002042A2 (en) | 2018-01-30 |
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