CN110312731A - From the biologically active peptide and application thereof of follistatin - Google Patents
From the biologically active peptide and application thereof of follistatin Download PDFInfo
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- CN110312731A CN110312731A CN201780086789.9A CN201780086789A CN110312731A CN 110312731 A CN110312731 A CN 110312731A CN 201780086789 A CN201780086789 A CN 201780086789A CN 110312731 A CN110312731 A CN 110312731A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0625—Epidermal cells, skin cells; Cells of the oral mucosa
- C12N5/0627—Hair cells
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/998—Proteins not provided for elsewhere
Abstract
The present invention relates to the biologically active peptide for deriving from growth factor, the biologically active peptide formed by the amino acid sequence selected from one or more of the group being made of sequence number 1 to 7 is provided.
Description
Technical field
The present invention relates to the new applications of the biologically active peptide from growth factor.
Background technique
Animal has the molt that hair is integrally replaced by season, and the mankind are to continue to replace a part in entire hair daily
To maintain similar quantity always.
The period (hair cycle) of hair can be divided into three periods, that is, growth period, catagen, stand-down, wherein raw
(anagen) is in the period of active cell division occurs in papilla and promotes the growth of new hair, in this period for a long time
Hair can be grown.
For the growth cycle of hair, male substantially 3 to 5 years, women substantially 4 to 6 years or so, on the whole, about
80 to 85% hair is equivalent to growth period.Catagen (catagen) is to taper off fissional period, substantially 3 to 4
Or so week.
Finally, stand-down (talogen) be papilla atrophy and hair is separated with capillary, to merely prick into head
The period of skin, substantially 3 months or so, the hair in stand-down are generally easy to be detached from from fur because of physical stimulation.
In general, alopecia refers to that the hair ratio in growth period in this period shortens, because catagen or the hair of stand-down increase
Add and a large amount of paratrichosis the case where falling off.
Although the hair of the mankind is unrelated with life, because on people impression and appearance generate conclusive influence due to by society
Many concerns can be gone up, in the past, it is believed that alopecia is a kind of symptom, but is different from, recently to be considered a kind of disease more.
In particular, recently, because High Level, industrialization accelerate caused by excess pressure, living habit a variety of Social Cultures because
Element, alopecia population sharply increase.
Also, it recently, is not only middle-aged male, the prime of life alopecia of layer also increases, for analyzing a variety of originals of alopecia
Because and solve its research and actively carry out.
For periodic hair growth, the regeneration of Ying Jinhang hair follicle and the activation of stem cell, it is well known that pass through Wnt/
The generation of beta-catenin (catenin) activates to realize.It is also known that the DKK-1 referred to is Wnt/ β-company before
The antagonist of cyclase protein, when regulating hair growth, above-mentioned signal scheme is extremely important.
On the other hand, transforming growth factor-β (transforming growth factor- β, TGF-β) superfamily is to adjust
Save organ prosperity and differentiation multi-functional growth and differentiation factor, in particular, when adjust hair follicle formation and hair circulation and
It is essential when growth.
Follistatin (follistatin) and the bon e formation factor (Bone morphogenic protein) and activin
(activin) (reference: Nakamura, Science.1990,247；4944, p836-838) transforming growth factor family etc
(for the dissociation constant Kd=540-680pmil/L of activin) consumingly is combined, and neutralizes their activity.Also, ovum
Steep the control that chalone directly or indirectly participates in the multiple biological activities of activin in vivo.
It is well known that being formed by the amino acid sequence of analysis follistatin by four domains, that is, N-terminal domain, ovarian follicle suppression
Prime field I, follistatin domain II, follistatin domain III (Shimasaki, Proc.Natl.Acad.Sci.1988,85；12,
p4218-4222).It is well-known, wherein the combination of follistatin domain participation activin.
The process of growth and the degeneration of hair is associated with very more factors, and this researcher executes application for promoting
Proliferation and adjusting into papilla (Human dermal papilla, HDP) cell of most important hair in the generation of hair follicle
The research of the growth factor of the bioactivity of scalp.
In particular, a variety of growth factors for adjusting growth and the degeneration of hair are formed from the hair papilla cell of hair follicle and are adjusted
Section.
It was reported that the activin referred to is also expressed from hair papilla cell to induce the formation of hair follicle before, and make hair
Growth cycle activate (Sung, Experimental dermatology.2017,26；2,p108-115).
The activity of activin interferes the systole phase for entering hair, a variety of come what is expressed by adjusting activin-follistatin
Protein plays an important role the growth and differentiation of hair, produces new hair cell.Moreover, the adjusting of activin
The necessary signal transmitting effect of stability adjusting to epidermis is executed by adjusting proliferation and the division of epidermis.
Up to now the treatment or prevention preparation for the baldness developed has comprising will be used to promote blood circulation, strengthen hair
The female hormone of root functionality, moisturizing scalp and inhibition male sex hormone makees preparation or minoxidil as main component
(minoxidil), the preparation etc. of Fei Nasitelai (finasteride), mucopolysaccharide auxin (trichosaccharide) etc.,
But it is much limited on due to the side effect of sex dysfunction, deformed child childbirth possibility, whole body hair tonic etc..
Also, above-mentioned pharmaceuticals are expensive and need the use of duration, when interruption in use, in the presence of causing to take off again
The shortcomings that hair.Also, exist it is big for everyone difference of effect, and for side effect everyone difference the shortcomings that.
The privileged site of the present inventor's Authenticate afresh follistatin is worked using activin binding motif, and confirms packet
Peptide containing above-mentioned motif is competitively combined in the binding site of activin etc, by inhibiting natural follistatin and activation
The combination of element promotes the growth of hair.
Also, the present inventor provides above-mentioned peptide not only for baldness, and for relevant to above-mentioned signal scheme a variety of
The application possibility of the treatment of disease.
Summary of the invention
Technical problem
The present invention is proposed to solve above-mentioned problem of the prior art, and the object of the present invention is to provide lifes
Object stability is outstanding, promotes hair tonic and the outstanding biologically active peptide of skin condition improvement.
Technical solution
According to an embodiment of the present invention, it provides by the ammonia selected from one or more of the group being made of sequence number 1 to 7
The biologically active peptide that base acid sequence is formed.
In one embodiment, above-mentioned peptide can promote the growth of fibroblast, horn cell or hair follicle cell.
In one embodiment, above-mentioned peptide can be such that the growth factor of hair papilla cell activates.
A further embodiment according to the present invention provides the biologically active peptide structural body indicated by following formula 1.
[chemical formula 1]
R1–A–R2
In above-mentioned chemical formula, above-mentioned A is connexon, above-mentioned R1For by one in the group being made of sequence number 1 to 3
Kind or more amino acid sequence formed peptide, above-mentioned R2For the peptide formed by the amino acid sequence of sequence number 4.
In one embodiment, above-mentioned A can be the compound indicated by following formula 2.
[chemical formula 2]
H2N(CH2)nCO2H
In above-mentioned chemical formula, n is the integer of 1≤n≤18.
In one embodiment, above-mentioned A can be 6-aminocaprolc acid (6-aminohexanoic acid).
In one embodiment, above-mentioned biologically active peptide structural body can promote fibroblast, horn cell or hair follicle cell
Growth.
In one embodiment, above-mentioned biologically active peptide structural body can be such that the growth factor of hair papilla cell activates.
Another embodiment according to the present invention is provided comprising above-mentioned peptide or above-mentioned peptide structural body as the de- of effective component
Hair prevents and hair tonic composition for promoting.
A further embodiment according to the present invention provides the wrinkle comprising above-mentioned peptide or above-mentioned peptide structural body as effective component
Line improves, skin elasticity improves, skin moisture-keeping improves or skin regeneration composition.
Another embodiment according to the present invention provides the change comprising above-mentioned peptide or above-mentioned peptide structural body as effective component
Cosmetic compositions.
Another embodiment according to the present invention provides the skin comprising above-mentioned peptide or above-mentioned peptide structural body as effective component
Skin preparation composition for external use.
Another embodiment according to the present invention is provided comprising above-mentioned peptide or above-mentioned peptide structural body as the de- of effective component
Pharmaceutical compositions are used in hair prevention or treatment.
Beneficial effect
According to an embodiment of the present invention, by using big slight peptide, it can be achieved that outstanding skin permeation rates, thus
Hair and skin condition improvement can be improved.
Above-mentioned peptide can be applied to a variety of purposes such as pharmaceuticals, the outer product of medicine, health food, cosmetics because of bioactivity
Product.
Effect of the invention is not limited to above-mentioned effect, it is thus understood that including can be from detailed description of the invention or invention
The institute of the structure inference of documented invention is effective in claimed range.
Detailed description of the invention
Fig. 1 is that the high performance liquid chromatography (HPLC) of the peptide of one embodiment of the invention analyzes result.
Fig. 2A is cell growth-promoting effect in the horn cell for indicating to handle the peptide of one embodiment of the invention
Chart.
Fig. 2 B is cell growth-promoting effect in the fibroblast for indicating to handle the peptide of one embodiment of the invention
Chart.
Fig. 2 C is the chart of cell growth-promoting effect in the hair follicle cell handled the peptide of one embodiment of the invention.
Fig. 3 A is confirmed to the peptide of one embodiment of the invention using microscope and by three-dimensional extracellular matrix culture method
Cell growth-promoting effect in the hair follicle cell of reason.
Hair follicle cell sphere is big in the 3 D stereo cell that Fig. 3 B expression handles the peptide of one embodiment of the invention
It is small.
Fig. 4 confirms that the SMAD2 phosphorylation of peptide processing according to an embodiment of the invention increases.
The increase of the signaling mechanism for the hair follicle activation that Fig. 5 confirmation handles peptide according to an embodiment of the invention.
Fig. 6 confirms the self assembly rush of the papilla of peptide processing according to an embodiment of the invention by immunostaining chemical method
Expression into effect and the hair growth factor increases.
Hair growth in the positions such as the mouse that Fig. 7 observation handles the peptide of one embodiment of the invention.
Specific embodiment
Term used in this specification considers that selection is currently being widely used as far as possible while the function in the present invention
General terms, but this can the intention of person of an ordinary skill in the technical field or legal precedent, the appearance of new technology according to the present invention
Deng and it is different.Also, under specific condition, the term for also having applicant arbitrarily selected, at this point, in corresponding specification part in detail
Carefully record its meaning.Therefore, term used in the present invention should be based in meaning possessed by its term and full text of the invention
Appearance is defined, rather than the title of simple term.
Unless there are different definition, then all terms as used herein including technology or scientific term have and this hair
The identical meaning of the bright normally understood meaning of person of an ordinary skill in the technical field.It should be interpreted that on usually used dictionary
The term of definition have the meaning consistent with possessed meaning on the context of the relevant technologies, unless have in the application it is clearly fixed
Justice is not interpreted ideal or excessively formality meaning then.
Numberical range includes the numerical value defined in above range.All greatest measures limitation in this specification is as clear
It is limited with low numerical value, including all lower numerical value limitations.All minimum value limitations are as clearly write in this specification
There is higher numerical value to limit, including all higher numerical value limitations.All numerical value limitations are as clear with more in this specification
Narrow numerical value limitation, including better all numberical ranges in broader numberical range.
Hereinafter, describing the embodiment of the present invention in detail, but the present invention is not limited to following embodiment, this is apparent
's.
One embodiment of the present invention is provided by the amino acid selected from one or more of the group being made of sequence number 1 to 7
The biologically active peptide that sequence is formed.
The present inventor has biologically effective active peptide and sharp study finally finds out above-mentioned peptide to excavate
Biological in vivo bioactivity, in particular, finding out the skin condition improvement and hair growth promotion effects of above-mentioned peptide.
Moreover, concept of the above-mentioned biologically active peptide as the peptide with defined biological effect in general designation organism,
By adjusting genetic expression and biological function, can ought in vivo because participate in function point analysis substance lack or excessive secretion
And play the role of correcting it when being presented abnormal ill.
Above-mentioned peptide can be formed by the amino acid sequence of above-mentioned sequence number 1 to 7 or may include above-mentioned amino acid sequence as one
Part.
Above-mentioned peptide (peptide) refers to is gathered by the amino acids formed of more than one connected by amido bond (or peptide bond)
Close object.Purpose according to the present invention, above-mentioned peptide can refer to that wrinkle improvement, the peptide of skin elasticity improvement or its segment is presented.
It, can be based on 3 letters or 1 letter amino acid if naming the general rule of above-mentioned peptide without the exception item specifically indicated
Code.For example, the central part of amino acid structure is indicated by 3 alphanumeric codes (for example, Ala, Lys), by before 3 alphanumeric codes
It records " D- ", when the case where not specifically instruction D- solid shape (for example, D-Ala, D-Lys), it may be assumed that be L- solid shape.
The amino acid residue for forming above-mentioned peptide can be natural or non-natural amino acids residue.
Multiple positions of above-mentioned peptide randomly partially synthetic follistatin protein are come to combinable for receptor protein
Position carry out first time exploration after, the amino acid sequence at the position predicted is optimized, and by will be in candidate peptide
The classic peptide of activity is screened to complete.
Above-mentioned peptide include natural follistatin activin binding motif, interfered by being combined with activin with naturally
The combination of follistatin can promote the activity of activin.
There is above-mentioned peptide fibroblast, horn cell or hair follicle cell to grow promotion ability, even if there are natural
Follistatin can also transmit the signal of activin.
Above-mentioned peptide expresses Wnt5, FGF7, Versican, Lef1 of the oligogene as hair follicle, can increase peptide, and
Increase the size of hair papilla cell by three-dimensional extracellular matrix culture.
Especially, it is well known that above-mentioned Wnt ligand inhibits de- by making the activation of beta-catenin signaling mechanism in the cell
Hair.Above-mentioned Wnt can be combined with the frizzled receptors of hair follicle cell activate hair papilla cell, and inhibits to include TGF-b, DKK-
1, the hair follicle cell including BMP etc. destroys substance to inhibit alopecia.That is, above-mentioned peptide can be such that the production quantity of Wnt increases significantly, and
Promote the growth of hair follicle cell prevents and hair tonic facilitation effect to realize outstanding alopecia.
Above-mentioned peptide and natural follistatin protein competitively act on the function to inhibit natural follistatin, with day
Right follistatin protein is compared, and stability and Cutaneous permeation degree are outstanding.
Above-mentioned peptide can promote fibroblast or the growth of horn cell to assign elasticity to skin, thus can inhibit wrinkle
It is formed.In turn, above-mentioned peptide can promote the growth of hair follicle cell to induce the growth of hair.
Horn cell and fibroblast can be more because of stress, external adverse factor, intrinsic aging etc. in skin
Kind of reason and it is impaired cause to degenerate, and reduce density.In particular, horn cell caused by external and internal pressure and fibroblastic impaired
The density of Skin Cell is reduced, and interferes the synthesis of collagen (collagen), thus the formation of wrinkle of skin can be deepened.
Above-mentioned collagen is the main component in conjunction with tissue, is the ingredient for being distributed mainly on bone and skin, is to maintain
The structure and form of skin, and the scleroprotein of firm intensity and elasticity is provided.When skin aging or it is exposed at ultraviolet light, heat etc.
When, collagen synthesis ability is likely to decrease, and collagen amount substantially reduces.When above-mentioned collagen amount is reduced, nothing
Faville holds the form of muscle, thus produces wrinkle of skin (wrinkle).
Above-mentioned peptide is from follistatin in human body, and skin permeation rates are high due to small molecular weight and size, and skin is raw
Long facilitation effect is outstanding.
Above-mentioned peptide promotes the growth of fibroblast and horn cell, and promotes collagen synthesis, thus can make skin
Cuticula, epithelial layer, skin corium growth, and present wrinkle improve, skin elasticity improve, skin aging prevent, skin moisture-keeping
The effect of improvement, skin regeneration etc..
When above-mentioned peptide is applicable locally for skin, skin condition improvement, the alopecia that wrinkle improvement etc can be achieved at the same time change
The entire effect of kind, hair growth promotion etc..
Above-mentioned peptide is handled after extracting the intracorporal protein of biology using protein decomposition enzyme, low to realize
Molecule quantization can perhaps realize biology preparation or by closing using peptide using genetic recombination and protein expression system
It is prepared at the chemical synthesis process of instrument etc..
For example, above-mentioned peptide passes through chemical synthesis process well known in the art, in particular, can pass through solid phase synthesis technique
(solid-phase synthesis techniques) prepared (reference: Merrifield, J.Amer.Chem.1963,
Soc.85:2149-54；Stewart,et al.Solid Phase Peptide Synthesis,2nd.ed.,Pierce
Chem.1984,Co.:Rockford,111)。
The fused protein formed by fusion partner and above-mentioned peptide is encoded for example, can be prepared by genetic manipulation
Gene, and after converting host microorganism using said gene, with fused protein shape in host microorganism
State is expressed.
Above-mentioned fused protein available protein catabolic enzyme or compound are cut off and are separated, and can be obtained above-mentioned
Peptide.It specifically, will be to protein decomposition enzyme, CNBr or azanol using the factor (Factor) Xa or enterokinase etc etc
Compound is inserted into above-mentioned fusion partner come DNA (DNA) sequence that the amino acid residue that cuts off is encoded
And between the gene of above-mentioned peptide.
The end N or C- of above-mentioned peptide may incorporate acetyl group, fluorenylmethyloxycarbonyl, formoxyl, palmityl, myristyl,
Stearyl or polyethylene glycol (PEG).Above-mentioned peptide can significantly improve stability by above-mentioned deformation.Aforementioned stable be include body
The concept of interior (in vivo) stability and storage stability.Above-mentioned protecting group can attacking from biological intracorporal protein incision enzyme
It hits and protects peptide of the invention.
Above-mentioned peptide may include the function coordinate of the peptide containing above-mentioned amino acid sequence.Above-mentioned " function coordinate " is because of amino
Acid addition, substitution or missing, result have above-mentioned amino acid sequence and at least 40% or more, preferably 80% or more, more
Preferably 90% or more, more preferably 95% or more sequence homology, referring to has substantially together with above-mentioned amino acid sequence
The protein of the bioactivity of matter.
Above-mentioned " bioactivity of substantial homogeneity " refers to anti-inflammatory activity caused by the structural of above-mentioned peptide, function homology
Equal skin conditions improve activity.Above-mentioned sequence homology compares two sequences arranged in optimal manner and comparison domain and true
It is fixed, a part of nucleic acid sequence in comparison domain can be added or deleted.
A further embodiment according to the present invention provides the biologically active peptide structural body indicated by following formula 1.
[chemical formula 1]
R1–A–R2
In above-mentioned chemical formula, above-mentioned A is connexon, above-mentioned R1For by one in the group being made of sequence number 1 to 3
Kind or more amino acid sequence formed peptide, above-mentioned R2For the peptide formed by the amino acid sequence of sequence number 4.
Above-mentioned peptide structural body includes the peptide that is formed by one of above-mentioned sequence number 1 to 3 amino acid sequence and by above-mentioned sequence
The peptide that the amino acid sequence of row number 4 is formed, above-mentioned peptide can be connected by connexon.
Above-mentioned connexon can be flexible linker (flexible linker), specially peptide connexon or non-peptide connection
Son.
Above-mentioned " non-peptide connexon " refers to that recurring unit combines 2 or more biocompatibility connexons, above-mentioned to repeat list
Position can be connected by any covalent bond of non-peptide bond.
Above-mentioned non-peptide connexon can be polyethylene glycol (polyethylene glycol, PEG) homopolymer, polypropylene glycol
Homopolymer, ethylene glycol and 1,2-propylene glycol copolymer, polyoxyethylated polyols, polyvinyl alcohol, polysaccharide, dextran, polyethylene second
Ether, biodegradation high molecular, lipid polymer, chitosan kind, hyaluronic acid or their combination, but not limited to this.
Specifically, above-mentioned A can be the compound indicated by following formula 2, be preferably 6-aminocaprolc acid (6-
aminohexanoic acid)。
[chemical formula 2]
H2N(CH2)nCO2H
In above-mentioned chemical formula, n is the integer of 1≤n≤18.
Above-mentioned 6-aminocaprolc acid (6-aminohexanoic acid) can be indicated by following formula 3, and above-mentioned peptide is risen
To connexon effect while can more increase bioactivity for above-mentioned peptide.
[chemical formula 3]
Another embodiment according to the present invention is provided comprising above-mentioned peptide or above-mentioned peptide structural body as the de- of effective component
Hair prevents and hair tonic composition for promoting.
Above-mentioned " alopecia ", which refers to, answers existing position, the state of hair in normal hair, in general, refer to scalp at
The case where hair is fallen down.The problem of colourless and thin fur of Cheng Maoyu is different, and when defect is possible to cause in terms of beauty.
Above-mentioned alopecia can divide into the case where clinically forming scar and really not so two kinds, form the alopecia of scar
(cicatricial) hair will not regenerate due to hair follicle is destroyed, on the contrary, the alopecia (non-cicatricial) for not forming scar maintains hair follicle, because
And after symptom position disappears, hair is possible to regenerate.
Above-mentioned alopecia can be round alopecia (alopecia areata), full head alopecia (alopecia totalis), general
Hair property alopecia (alopecia universalis), male pattern alopecia (androgenic alopecia), telogen effluvim
Alopecia caused by (telogen effluvium), growth period alopecia (anagen effluvium) or chemotherapy
(chemotherapy-induced alopecia), but not limited to this.
Since above-mentioned peptide can promote the growth of hair follicle cell, thus can fundamentally promote have while the growth of hair
The hair of effect protection growth.
Above-mentioned " alopecia prevents " or " hair tonic promotion " can be used with similar meaning, this can include and use with this field
Another term, that is, alopecia, which improves, supports hair, which promotes, educates hair promotes identical meaning.
A further embodiment according to the present invention provides the wrinkle comprising above-mentioned peptide or above-mentioned peptide structural body as effective component
Line improves, skin elasticity improves, skin moisture-keeping improves or skin regeneration composition.
The reason of above-mentioned " wrinkle " refers to the microgroove of skin decline and generation, can be caused by gene is present in dermis of skin
Collagen and reduction, the external environment etc. of elasticity induce.
Above-mentioned " wrinkle improvement " refers to inhibition or hinders to generate wrinkle in skin, or the phenomenon that alleviation generated wrinkle.
Above-mentioned " skin elasticity " refer to reason be present in skin corium elastin laminin (elastin) formed elastomer and
The elasticity of realization, above-mentioned elastomer such as rubber there is low elasticity modulus therefore can easily deform because of external force,
When external force is removed, it is easy to be restored to original state.
Above-mentioned elastomer has microfibril (microfibrils) in the unbodied matrix bundle of referred to as elastin laminin,
Above-mentioned elastin laminin refers to by being only referred to as desmosine (desmosine) and isodensmosine from lysine
(isodesmosine) the unique amino acids formed protein found in elastomer.Above-mentioned desmosine and isodensmosine
Crosslinking (cross-links) can be formed in long peptide chain, above structure can assign rubbery character to elastin laminin.
Above-mentioned " skin elasticity improvement " refers to existed together with collagen by the elastomer that elastin laminin is formed, upper
Elastin laminin is stated and in the state that collagen sufficiently exists, the phenomenon that maintaining or improve skin elasticity.
Above-mentioned " including ... as effective component " can refer to comprising can present alopecia prevent, hair tonic promotion or skin improve effect
Fruit, for example, Wnt activity promotion relevant to hair growth effect can be presented, improving effect with wrinkle, relevant collagen closes
At or elasticity improve etc. degree effective quantity.
Another embodiment according to the present invention provides the change comprising above-mentioned peptide or above-mentioned peptide structural body as effective component
Cosmetic composition or Dermatologic preparation composition.
Above-mentioned skin preparations for extenal use or cosmetic composition can carry out dosage form by conventional method.In the agent of skin preparations for extenal use
In type, Remington's Pharmaceutical Science, Mack Publishing Company can refer to,
The content disclosed in Easton PA can refer to International cosmetic in the dosage form of cosmetic composition
ingredient dictionary,6th ed.,The cosmetic,Toiletry and Fragrance
The content disclosed in Association, Inc., Washington, 1995.
Above-mentioned skin preparations for extenal use or cosmetic composition may include generally acceptable carrier, for example, can appropriate formulated oil
Point, water, surfactant, moisturizer, lower alcohol, tackifier, chelating agent, pigment, preservative, fragrance etc., but not limited to this.
Also, above-mentioned composition also may include the adjustable base ingredient assigned in general scalp and hair external preparation, tool
Body, may include dissolution aids, surfactant, moisturizer, it is viscous increase agent, pH adjusting agent, preservative, antioxidant, metal from
Sub- chelating agent, fungicide, anti-inflammatory agent, antimicrobial, solvent, colorant or fragrant agent etc..
On the other hand, above-mentioned composition can be used as lotion, creams, paste, gel, toner, facial mask, shin moisturizer, muffin,
The composition for processing hair of spray, perfumed soap etc. carries out dosage form, specifically, can by selected from by refreshing shampoo, hair lotion, hair cream,
Surely agent, hair mousse, hair jelly, hair soap, shampoo, hair conditioner, hair film are sent out Ji one or more of group for the treatment of wax composition carries out
Dosage form specifically can carry out dosage form with liquid-type shampoo.
In above-mentioned dosage form, other than above-mentioned neccessary composition, other compositions can according to the purposes of other external preparations or
It is suitably selected by general technical staff of the technical field of the invention to deploy using purpose.
For example, as carrier components, can be used animal fine when the dosage form of above-mentioned composition is paste, creams or gel
Dimension, plant fiber, wax, paraffin, starch, bassora gum, cellulose derivative, polyethylene glycol, silicon, bentonite, silica, talcum
Or zinc oxide etc..
When the dosage form of above-mentioned composition is muffin or spray, as carrier components, using lactose, talcum, titanium dioxide
Silicon, aluminium hydroxide, calcium silicates or polyamide muffin, in particular, additionally, also may include hydrochlorofluorocar.on, propane, butane or
The propellant of dimethyl ether etc.
When the dosage form of above-mentioned composition is solution or emulsion, as carrier components, can be used solvent, resolvating agent or
Emulsifier, for example, can be used water, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Ergol, propylene glycol,
The aliphatic ester of 1,3 butylene glycol oil, glycerin fatty race ester, polyethylene glycol or sorbitan.
When the dosage form of above-mentioned composition is suspension, as carrier components, water, ethyl alcohol or propylene glycol etc can be used
The suspension of liquid diluent, ethoxylated isostearyl alcohols, polyoxyethylene sorbitan ester and polyoxyethylene sorbitol acid anhydride ester etc
Agent, microcrystalline cellulose, inclined aluminium hydroxide, bentonite, agar or bassora gum etc..
Only, above-mentioned auxiliary agent and its blending ratio can be selected suitably, to prevent the preferred property to product of the invention from producing
It is raw to influence.
Another embodiment according to the present invention is provided comprising above-mentioned peptide or above-mentioned peptide structural body as the de- of effective component
Pharmaceutical compositions are used in hair prevention or treatment.
Above-mentioned " prevention " refers to all behaviors for reducing the generation frequency or degree of pathological phenomena.Prevention can it is complete or
Part.At this point, compared with can refer to intraindividual alopecia symptom with without using above-mentioned composition the case where, the phenomenon that reduction.
Above-mentioned " treatment " refers to change the natural process of object or cell to be treated and clinically intervenes all
Behavior can execute during clinical pathology state carries out or in order to prevent it.The therapeutic effect of purpose may include prevention disease
The generation or recurrence of disease, or alleviate symptom, or reduce all direct or indirect pathology results or pre- anti-rotation caused by disease
It moves, or reduces disease and carry out speed, or mitigation or temporary relief morbid state, or improve prognosis.
Above-mentioned composition can be administered in the form of oral delivery, non-oral transmitting.Above-mentioned composition can be with complete
The mode of body or part is administered, and above-mentioned administration may include oral administration and non-oral administration.Above-mentioned composition can with it is appropriate
The excipient pharmaceutically received or carrier of amount carry out dosage form together, to provide in the form of administration appropriate.
Above-mentioned composition also may include carrier used in the preparation of pharmaceutical compositions, excipient and diluent.As upper
State carrier, excipient and diluent, can enumerate lactose, glucose, sucrose, D-sorbite, mannitol, xylitol, antierythrite,
Maltitol, starch, Arabic gum, alginate, gelatin, calcium phosphate, calcium silicates, cellulose, methylcellulose, microcrystalline cellulose
Element, polyvinylpyrrolidone, water, methyl hydroxybenzoate, nipasol, talcum, magnesium stearate or mineral oil, but not
It is confined to this.
Also, above-mentioned composition can be with powder, granule, tablet, capsule, suspension, lotion, syrup, aerosol
Deng oral type dosage form, external preparation, suppository and sterilizing injecting solution form carry out formulation use.
Tablet, pill, powder, granule, capsule etc., above-mentioned solid system can be used in solid pharmaceutical preparation for oral administration
Agent can be by mixing more than one excipient in above compound and its fraction, for example, starch, calcium carbonate, sucrose, lactose
Or gelatin etc. is deployed.Also, other than above-mentioned excipient, the lubricant of magnesium stearate, talcum etc can be used.
Suspending agent, solution, emulsion, syrup for oral administration etc. can be used in liquid preparation for oral administration, in addition to conduct
Merely except the water of diluent, atoleine, a variety of excipient can be used, for example, wetting agent, sweetener, aromatic, antistaling agent
Deng.
Preparation for non-oral administration can be used the aqueous solution of sterilizing, non-aqueous solvent, suspending agent, emulsion, freeze and do
Dry preparation, suppository.Propylene glycol (propylene glycol), polyethylene glycol, olive can be used in above-mentioned non-aqueous solvent, suspending agent
The ester of the injectable of the vegetable oil of oil etc, ethyl oleate etc.As the base of above-mentioned suppository, Wei Taisuo Lovell can be used
(witepsol), polyethylene glycol (macrogol), tween (tween) 61, cocoa butter, lauryl (laurinum), glycerin gelatine.
Above-mentioned pharmaceutical compositions can be administered with effectively measuring to object in pharmacy.It is above-mentioned " effective in pharmacy
Amount " refer to that available capacity level can be applicable to the substantial amount of the reasonable benefit of therapeutic treatment/risk-benefit risks treatment disease
According to include the type of disease of patient, severe degree, the activity of drug, for the susceptibility, administration time, administration route of drug
And in discharge ratio, the factor of the drug used during treatment, simultaneously and other medical domains well-known factor and determine.
Above-mentioned pharmaceutical compositions can be administered using individualized treatment agent, or with other therapeutic agents and be used to carry out to
Medicine can be sequentially or simultaneously administered with previous therapeutic agent, can be administered in single or multiple mode.Preferably,
It can be administered in the absence of side effects with the minimum amount for obtaining maximum efficiency with considering above-mentioned factor, this can
It is easy to determine by general technical staff of the technical field of the invention.
By following embodiment, the present invention will be described in more detail, but the present invention is not limited to following embodiment, this
It is obvious.
Preparation example: the preparation of peptide
The dimethylformamide (DMF) that amide methylbenzhydrylamine resin (147mg, 0.1mmol) is put into 3mL will be linked
In anhydrous (anhydrous) organic solvent, and swelling about 30 minutes.
The Fmoc-Lys (Boc)-of 0.3mmol is added and mixed in the dimethylformamide anhydrous organic solvent of 1.5mL
OH (141mg), the N as carboxyl group activating agent, N- diisopropylcarbodiimide (DIC, N, N-Diisopropyl
Carbodiimde, 48 μ l) and as addition auxiliary agent N- hydroxybenzotriazole (HOBt, N-Hydrobenzotriazole,
40mg) come make they activate about 20 minutes.
After the solution of activation and resin agitating 2 hours are reacted, reaction solution is filtered, and utilizes diformazan
Base formamide and methanol are cleaned multiple times after resin, execute ninhydrin detection (kaiser test).
When ninhydrin detection is shown as the positive, above-mentioned activation solution is prepared to be added.When test result is yin
When property, mixed with the piperidine solution for the 3mL for being dissolved in solvent dimethylformamide with 20 weight percent concentrations, and react
After about 15 minutes Fmoc groups to remove the end N-, in the same way by the amino acid activation of next sequence, thus with knot
It is reacted together in the amino acid of solid-like resin.
After the synthesis of the amino acid moiety of final nucleotide sequence terminates, piperidines/dimethyl formyl of 20 weight percent is utilized
Amine removes the Fmoc group of the end N-, and after cleaning resin for several times using dimethylformamide and methanol, is dried.
The peptide combined with resin under normal temperature conditions with cracking (cleavage) solution (trifluoroacetic acid
(trifluoroacetic acid, 80%), tri isopropyl silane (triisopropylsilane, 5%), thioanisole
(Thioanisole, 5%), 1,2- dithioglycol (1,2-Ethanedithiol, 5%), water (5%)) it is reacted to remove
Side chain (side chain) protecting group (protection group) of (4hr) amino acid, and the separation from resin (resin)
Peptide.
Nitrogen is blown into remove the trifluoroacetic acid of peptide solution (trifluoroacetic acid), and is added cold with -20 DEG C
But after diethyl ether (diethyl ether), the peptide of precipitation and separation is carried out using whizzer (3000rpm, 20 minutes).
The peptide of acquisition is carried out pure using rp-hplc (HPLC) (C-18 column C18-120A, 50mm*250mm)
Change (water/acetonitrile (water/ in the trans-fatty acid (TFA) (gradient, gradient) of Eluent:0.1%
Acetonitrile): flow velocity (Flow Rate) 50mL/ minutes).1308 molecules are confirmed using ESI-Mass mass-synchrometer
The substance of amount.
The peptide synthesized according to the above method such as following table 1.
[table 1]
Experimental example 1: the evaluation of hair papilla cell proliferation facilitation effect
Inhibit effect and activin activity function to analyze the natural follistatin of the sequence peptide for synthesizing in synthesis example
Effect, human epidermal keratinocyte (Human epidermal keratinocytes, HEK), people are measured using MTT decoration method
Class dermal fibroblast (Normal Human dermal fibroblasts, nHDF), mankind's hair papilla cell (Human
Dermal papilla, HDP) Cell growth ability.
To separately include 10% fetal calf serum (FBS) Dulbecco (family name) improve Iger (family name) culture medium (DMEM,
Dulbecco ' s modified Eagle ' s medium, U.S. Ji Bike (gibco, U.S.A)) it is used as culture medium, in 37C temperature
Degree and 5% CO2Under the conditions of incubator in cultivate human epidermal keratinocyte (Lonza, Switzerland) and human dermal
Fibroblast, mankind's hair papilla cell.
It is centrifuged after the cell strain that culture vessel bottom surface is separately cultured using 1% trypsin solution,
To obtain cell precipitate.
It improves in Iger (family name) culture medium culture solution in the Dulbecco (family name) not comprising fetal calf serum (FBS) and hangs again
After floating, become 3 × 10 with each hole3The mode of cell is put into the hole 96- tissue cultures plate, and in 37 DEG C of temperature and 5%
CO2Under the conditions of cultivate 24 hours.
After 24 hours, after exchanging culture medium with the identical culture solution completely other than serum, with sterilizing
The empty sample for being used to determine standard and synthetic peptide are dissolved in after 10% dimethyl sulfoxide (DMSO) by state, with 1ng/mL,
10ng/mL, 100ng/mL, 1 μ g/mL, 10 μ g/mL and 100 μ g/mL concentration with same as described above CMC model 48 hours.
After culture terminates, survival rate (viability) is measured using the MTT of packet.
Cell (the negative control of any processing is not done each cell of the processing peptide (10 μ g/mL) of above-described embodiment and
Group) cell proliferation rate be compared, and will be shown in following table 2 based on this relative value.
[table 2]
Referring to Fig. 2, it is known that the peptide of embodiment 8 promotes horn cell, fibroblast, hair follicle thin in a manner of concentration dependant
The growth of born of the same parents.
Referring to Fig. 3, it is known that formed by the papilla sphere of hair papilla cell 3 D stereo culture (Sung,
J.Invest.Dermatol.2012,132；237), the peptide of embodiment 8 effectively facilitates growth and the morphology hair cream of hair follicle cell
Head shoot body self-forming.
The peptide that the above results enlighten embodiment promotes the proliferation of mankind's hair papilla cell, and hair tonic or alopecia prevent effect excellent
It is elegant.
Also, the above-mentioned peptide of enlightenment is not only outstanding to the stability of skin or human body, also effectively facilitates synthesis collagen
Fibroblastic growth, and can be used as beautifying skin, in particular, wrinkle of skin improved purposes is applied.
Experimental example 2: the evaluation of gene expression amount
Mankind's hair papilla cell of culture is handled the peptide of embodiment, after 48 hours, measurement as by
The expression quantity of the growth factor of the phosphorylation amount and hair of the SMAD2 of the signal for the activin that follistatin is adjusted.
Utilize Phospho-SMAD2 antibody (Abcam) and beta-catenin (β-catenin) antibody (Abcam) Lai Zhihang
Western blot, for the table of FGF7, WNT5a, LEF1, VCAN as the hair growth factor activated using activin
It reaches, the expression quantity of growth factor is evaluated by Real time reverse transcription-polymerase chain reaction (Real-time RT-PCR), and will knot
Fruit is shown in following table 3.
[table 3]
| It distinguishes | VCAN mRNA | FGF7 mRNA | WNT5a mRNA | LEF1 mRNA |
| Embodiment 1 | 2.0 | 2.5 | 1.4 | 2.7 |
| Embodiment 2 | 2.1 | 2.4 | 1.5 | 2.6 |
| Embodiment 3 | 2.0 | 2.5 | 1.4 | 2.8 |
| Embodiment 4 | 1.9 | 2.6 | 1.5 | 2.7 |
| Embodiment 5 | 2.1 | 2.7 | 1.3 | 3.0 |
| Embodiment 6 | 1.9 | 2.6 | 1.4 | 2.7 |
| Embodiment 7 | 2.2 | 2.5 | 1.5 | 2.9 |
| Embodiment 8 | 2.3 | 3.0 | 1.6 | 3.3 |
Referring to Fig. 4, the peptide knot of Processing Example 8 in the state that the expression of natural follistatin in the cell is maintained
When structure body, the phosphorylation for confirming SMAD2 is increased by the activation of activin, β-company of the Main Factors of the growth as hair
The expression of cyclase protein increases.
Referring to Fig. 5, when the peptide structural body of Processing Example 8, confirm as the hair growth generated in papilla because
The expression of FGF7, WNT5a, LEF1, VCAN of son increase.
The above results enlightenment not only has the function of that the very outstanding hair tonic promotion of the peptide of embodiment and alopecia inhibit, and anti-ageing
It is also outstanding to change effect.
Experimental example 3: the evaluation of proteoglycans (versican) expression quantity
Whether the peptide of evaluation embodiment increases the table of the proteoglycans as the hair papilla cell sphere self-assembly activity factor
It reaches.
Become 1 × 10 with each hole4Hair papilla cell is put into the low adhesion tissue culture plate in the hole 96- by the mode of cell,
And in 37 DEG C of temperature and 5% CO2Under the conditions of cultivate 48 hours.
When being put into cell, addition will be used to determine the peptide structural body of the empty sample and embodiment 8 of standard with sterilizing state
It is dissolved in the culture medium of 10% dimethyl sulfoxide.
Referring to Fig. 6, hair papilla cell sphere is fixed on to 2% formaldehyde after confirming 48 hours
(Formaldehyde), phosphate buffer (PBS), and immunofluorescence staining is executed, and confirm intracellular protein glycan
Expression increase.
Peptide structural body of the above results enlightenment using embodiment 8 promotes papilla sphere come the self-assembly activity factor activated
Self assembly, due to the peptide of embodiment, the hair growth promotive factor activity of hair papilla cell increases, it can be achieved that hair tonic promotes and takes off
Send out the effect inhibited.
Experimental example 4: hair tonic promotes active evaluation
Go hair removal be in stand-down birth about 50 days mouse (C57BL/6) hair after, evaluate embodiment and
The hair growth promotion effects of comparative example.
In this experiment, by every group 10, after the similar mouse of the characteristics such as weight, size is divided into 9 groups, individual breeding
To measure the extent of growth of hair.
It after solution of the coating comprising the peptide of embodiment, raises 30 days, and separates the hair that grows at defeathering position to survey
Determine weight.By apply phosphorylation buffer solution mouse be set as control group come more explicit evaluation based on peptide hair growth promote
Effect.Measurement result such as following table 4.
[table 4]
| It distinguishes | Hair weight (mg) |
| Embodiment 1 | 194.1±10.1 |
| Embodiment 2 | 195.7±11.2 |
| Embodiment 3 | 193.2±11.5 |
| Embodiment 4 | 188.3±10.6 |
| Embodiment 5 | 193.4±11.4 |
| Embodiment 6 | 196.5±12.1 |
| Embodiment 7 | 194.9±11.4 |
| Embodiment 8 | 212.1±12.2 |
| Control group | 69.5±4.5 |
Referring to Fig. 7, the back of the mouse of the peptide structural body of observation coating embodiment 8, as a result, with the naked eye confirm through
It crosses after 10 days, back blackening, coating is by compared with negative control group, there is a large amount of hair growth after 15 days.
Hair growth promotion effects namely based on the peptide of embodiment are very outstanding, thus are evaluated as that hair health can be promoted,
And inhibit alopecia.
Experimental example 5: collagen biosynthesis induction experiment
Whether the synthesis for confirming collagen promotes according to fibroblastic growth.With 1.0 × 104Cell/mL
Concentration, the human dermal fibroblast of every 100 μ L is dispensed in 96 orifice plates, and in 37 DEG C of temperature and 5% CO2Humidify item
It is cultivated 3 days under part.
Using in culture medium (Medium) 106S (Kurashiki Boshiki corporation is standby) of every 100 μ L of hole include 10
Low serum growth replenishers (LSGS, Low Serum the Growth Supplement, Kurashiki of weight percent
Boshiki corporation is standby) culture medium.
Above-mentioned culture medium is exchanged for Dulbecco (family name) and improves Iger (family name) culture medium (DMEM, Dulbecco's
Modified Eagle's Medium, Sigma (Sigma) corporation are standby), and after handling above-mentioned peptide with the concentration of 50mg/L
It is cultivated.The case where above-mentioned peptide not being handled and adding purified water, is as a control group.
After above-mentioned cell culture 7 days, culture solution is acquired, and pass through enzyme combination immunoassay (precollagen I type c- peptide
EIA kit, the preparation of Procollagen type I c-peptide EIA Kit, TaKaRa biotech firm) quantitative culture liquid
The I-type collagen concentration of middle secretion.
(100%) calculates the collagen in each test specimen culture solution on the basis of the I-type collagen amount of control group
Protein content, measurement result such as following table 5.
[table 5]
| It distinguishes | Collagen output (%) |
| Embodiment 1 | 185.1 |
| Embodiment 2 | 179.5 |
| Embodiment 3 | 182.2 |
| Embodiment 4 | 184.8 |
| Embodiment 5 | 182.4 |
| Embodiment 6 | 185.7 |
| Embodiment 7 | 183.1 |
| Embodiment 8 | 189.5 |
| Control group | 100 |
[control group %]
Not only hair growth promotion effects are outstanding for the peptide that the above results enlightenment is formed by the amino acid sequence of above-described embodiment,
Skin elasticity improves and wrinkle of skin improvement is also outstanding.
Experimental example 6: laminin and hyaluronic acid generate facilitation effect test
It is surveyed after 72 hours with the HaCaT cell that above-described embodiment 1 and the processing of the peptide of embodiment 2 are cultivated 48 hours
It is set for the laminin of the label improved for wrinkle of skin and the concentration of hyaluronic acid.At this point, concentration mensuration utilizes layer adhesion
Enzyme linked immunological adsorption experiment (Laminin ELISA) kit and the enzyme-linked immunoadsorption assay of hyaluronic acid
(Hyaluronic acid ELISA) kit is implemented.
That is, comparing the HaCaT cell of the peptide of Processing Example and not doing the HaCaT cell (negative control group) of any processing
Laminin and hyaluronic acid concentration, and will be shown in following table 6 based on this relative value.
[table 6]
Referring to table 6, when the peptide of Processing Example, the concentration of laminin and hyaluronic acid is compared with negative control group
Increase all significantly.
The effect improving wrinkles that the above results enlighten the peptide of embodiment are brilliant, improve effect so as to which entire skin condition is presented
Fruit.
For illustrating, general technical staff of the technical field of the invention should be appreciated that above-mentioned explanation of the invention
In the case where not changing technical idea or essential feature of the invention, can be easily deformed in the form of other are specific.Therefore,
Being interpreted as multiple embodiments of the above description is illustrative, and non-limiting in all respects.For example, illustrated with single type
Each structural element can be implemented in decentralized manner, equally, illustrate that multiple structural elements of dispersion also can be with the shape of combination
State is implemented.
Range Representation is claimed by appended invention in the scope of the present invention, should be interpreted that from the claimed range of invention
Meaning and range and the derived form for having altered or deforming of its equivalents are included in the scope of the present invention.
Sequence catalogue (free text)
Sequence serial number 1: from the biologically active peptide 1 of follistatin
Sequence serial number 2: from the biologically active peptide 2 of follistatin
Sequence serial number 3: from the biologically active peptide 3 of follistatin
Sequence serial number 4: from the biologically active peptide 4 of follistatin
Sequence serial number 5: from the biologically active peptide 5 of follistatin
Sequence serial number 6: from the biologically active peptide 6 of follistatin
Sequence serial number 7: from the biologically active peptide 7 of follistatin
<110>generation spinning is attained by Co., Ltd.
<120>biologically active peptide and application thereof of follistatin is derived from
<130> 17PP11089
<160> 7
<170> KoPatentIn 3.0
<210> 1
<211> 5
<212> PRT
<213>artificial sequence (Artificial Sequence)
<220>
<223> SEQ ID NO.1
<400> 1
Gly Asn Cys Trp Leu
1 5
<210> 2
<211> 5
<212> PRT
<213>artificial sequence (Artificial Sequence)
<220>
<223> SEQ ID NO.2
<400> 2
Gly Asn Met Trp Leu
1 5
<210> 3
<211> 5
<212> PRT
<213>artificial sequence (Artificial Sequence)
<220>
<223> SEQ ID NO.3
<400> 3
Gly Asn Ser Trp Leu
1 5
<210> 4
<211> 5
<212> PRT
<213>artificial sequence (Artificial Sequence)
<220>
<223> SEQ ID NO.4
<400> 4
Asn Thr Leu Phe Lys
1 5
<210> 5
<211> 10
<212> PRT
<213>artificial sequence (Artificial Sequence)
<220>
<223> SEQ ID NO.5
<400> 5
Gly Asn Cys Trp Leu Asn Thr Leu Phe Lys
1 5 10
<210> 6
<211> 10
<212> PRT
<213>artificial sequence (Artificial Sequence)
<220>
<223> SEQ ID NO.6
<400> 6
Gly Asn Met Trp Leu Asn Thr Leu Phe Lys
1 5 10
<210> 7
<211> 10
<212> PRT
<213>artificial sequence (Artificial Sequence)
<220>
<223> SEQ ID NO.7
<400> 7
Gly Asn Ser Trp Leu Asn Thr Leu Phe Lys
1 5 10
Claims (13)
1. a kind of biologically active peptide, which is characterized in that by the amino selected from one or more of the group being made of sequence number 1 to 7
Acid sequence is formed.
2. biologically active peptide according to claim 1, which is characterized in that promote fibroblast, horn cell or hair follicle
The growth of cell.
3. biologically active peptide according to claim 1, which is characterized in that activate the growth factor of hair papilla cell.
4. a kind of biologically active peptide structural body, which is characterized in that
It is indicated by following formula 1,
[chemical formula 1]
R1–A–R2
In the chemical formula, the A is connexon, the R1For by selected from one of group for being made of sequence number 1 to 3 with
On amino acid sequence formed peptide, the R2For the peptide formed by the amino acid sequence of sequence number 4.
5. biologically active peptide structural body according to claim 4, which is characterized in that
The A is the compound indicated by following formula 2,
[chemical formula 2]
H2N(CH2)nCO2H
In the chemical formula, n is the integer of 1≤n≤18.
6. biologically active peptide structural body according to claim 4, which is characterized in that the A is 6-aminocaprolc acid.
7. according to biologically active peptide structural body described in any one in claim 4 to 6, which is characterized in that promote into fibre
Tie up the growth of cell, horn cell or hair follicle cell.
8. according to biologically active peptide structural body described in any one in claim 4 to 6, which is characterized in that make papilla
The growth factor of cell activates.
9. a kind of alopecia prevents and hair tonic composition for promoting, which is characterized in that include any one of claims 1 to 3 institute
Peptide structural body is as effective component described in any one of the peptide stated or claim 4 to 8.
10. a kind of wrinkle improves, skin elasticity improves, skin moisture-keeping improves or skin regeneration composition, which is characterized in that packet
Being used as containing peptide structural body described in any one of peptide or claim 4 to 8 described in any one of claims 1 to 33 has
Imitate ingredient.
11. a kind of cosmetic composition, which is characterized in that wanted comprising peptide or right described in any one of claims 1 to 3
Peptide structural body is as effective component described in asking any one of 4 to 8.
12. a kind of Dermatologic preparation composition, which is characterized in that include peptide or power described in any one of claims 1 to 3
Benefit require any one of 4 to 8 described in peptide structural body as effective component.
13. a kind of alopecia prevention or treatment pharmaceutical compositions, which is characterized in that include any one of claims 1 to 3 institute
Peptide structural body is as effective component described in any one of the peptide stated or claim 4 to 8.
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| KR10-2017-0106023 | 2017-08-22 | ||
| KR1020170106023A KR101822633B1 (en) | 2017-08-22 | 2017-08-22 | A follistatin-derived peptide, and uses thereof |
| PCT/KR2017/009296 WO2019039630A1 (en) | 2017-08-22 | 2017-08-25 | Follistatin-derived bioactive peptide and use thereof |
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| CN110312731A true CN110312731A (en) | 2019-10-08 |
| CN110312731B CN110312731B (en) | 2022-10-25 |
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Citations (7)
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|---|---|---|---|---|
| US20040001803A1 (en) * | 2001-12-03 | 2004-01-01 | Hancock Robert E.W. | Effectors of innate immunity determination |
| US20060259996A1 (en) * | 2002-06-17 | 2006-11-16 | Carlson William D | Single domain TDF-related compounds and analogs thereof |
| US20100015150A1 (en) * | 2004-06-17 | 2010-01-21 | Thrasos Therapeutics, Inc. | Tdf-related compounds and analogs thereof |
| CN101724632A (en) * | 2009-07-15 | 2010-06-09 | 吉林大学 | Bullfrog skin active peptide, gene and application thereof in pharmacy |
| US20160132631A1 (en) * | 2013-06-10 | 2016-05-12 | Iogenetics, Llc | Bioinformatic processes for determination of peptide binding |
| US20160367463A1 (en) * | 2015-06-17 | 2016-12-22 | Avon Products, Inc. | Peptides and Their Use in the Treatment of Skin |
| CN106488928A (en) * | 2014-05-13 | 2017-03-08 | 凯尔格恩有限公司 | With anti-inflammatory, bon e formation and hair tonic promote activity peptide and its purposes |
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|---|---|---|---|---|
| US6891082B2 (en) * | 1997-08-01 | 2005-05-10 | The Johns Hopkins University School Of Medicine | Transgenic non-human animals expressing a truncated activintype II receptor |
| US7572763B2 (en) * | 2002-02-21 | 2009-08-11 | Wyeth | Follistatin domain containing proteins |
| KR102253597B1 (en) * | 2013-01-25 | 2021-05-17 | 샤이어 휴먼 지네틱 테라피즈 인크. | Follistatin in treating duchenne muscular dystrophy |
| CN106795224B (en) * | 2014-06-04 | 2021-05-18 | 阿塞勒隆制药公司 | Methods and compositions for treating conditions with follistatin polypeptides |
| KR101801227B1 (en) * | 2016-01-14 | 2017-11-24 | 고려대학교 산학협력단 | Nucleic Acid Aptamer Capable of Specifically Binding to Follistatin and Uses Thereof |
-
2017
- 2017-08-22 KR KR1020170106023A patent/KR101822633B1/en active IP Right Grant
- 2017-08-25 WO PCT/KR2017/009296 patent/WO2019039630A1/en active Application Filing
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Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040001803A1 (en) * | 2001-12-03 | 2004-01-01 | Hancock Robert E.W. | Effectors of innate immunity determination |
| US20060259996A1 (en) * | 2002-06-17 | 2006-11-16 | Carlson William D | Single domain TDF-related compounds and analogs thereof |
| US20100015150A1 (en) * | 2004-06-17 | 2010-01-21 | Thrasos Therapeutics, Inc. | Tdf-related compounds and analogs thereof |
| CN101724632A (en) * | 2009-07-15 | 2010-06-09 | 吉林大学 | Bullfrog skin active peptide, gene and application thereof in pharmacy |
| US20160132631A1 (en) * | 2013-06-10 | 2016-05-12 | Iogenetics, Llc | Bioinformatic processes for determination of peptide binding |
| CN106488928A (en) * | 2014-05-13 | 2017-03-08 | 凯尔格恩有限公司 | With anti-inflammatory, bon e formation and hair tonic promote activity peptide and its purposes |
| US20160367463A1 (en) * | 2015-06-17 | 2016-12-22 | Avon Products, Inc. | Peptides and Their Use in the Treatment of Skin |
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| WO2019039630A1 (en) | 2019-02-28 |
| KR101822633B1 (en) | 2018-01-26 |
| CN110312731B (en) | 2022-10-25 |
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