CN116003518B - Engineered peptides, compositions and uses thereof - Google Patents
Engineered peptides, compositions and uses thereof Download PDFInfo
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- CN116003518B CN116003518B CN202310033376.1A CN202310033376A CN116003518B CN 116003518 B CN116003518 B CN 116003518B CN 202310033376 A CN202310033376 A CN 202310033376A CN 116003518 B CN116003518 B CN 116003518B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention provides a compound of formula (I) R 1 ‑Glu‑Asp‑Tyr‑Tyr‑Arg‑Nle‑R 2 Or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a cosmetic or pharmaceutical composition thereof, and their use in the preparation of a cosmetic or pharmaceutical composition for the antioxidation, the delay of aging, the treatment or care of a condition, disorder or disease caused by muscle contraction, the treatment, prevention or repair of skin aging or photoaging.
Description
Technical Field
The invention relates to the technical field of medicines and cosmetics, in particular to a peptide with the effects of resisting oxidation and delaying aging and inhibiting muscle contraction, a cosmetic composition or a medicinal composition containing the peptide and application thereof.
Background
Skin is used as the largest organ of human body, and is influenced by aging or external bad environmental stimulus, and intradermal elastic fiber and collagen fiber have reduced functions, and simultaneously the nerve activity of the organism is excessive, so that facial muscle is repeatedly contracted, and wrinkles or expression lines are formed in specific areas, thereby showing aging signs such as relaxation, elasticity reduction, wrinkles and the like. In addition to age and external adverse environmental stimuli, uncontrolled oxygen radicals play an important role in the skin aging process. Under the action of harmful stimulus, when active oxygen is excessively generated or metabolic disorder occurs and the removal capacity of an endogenous antioxidant defense system is exceeded, cell oxidative damage is directly or indirectly caused, so that skin aging is accelerated.
The human body contains various endogenous antioxidant enzymes and low-molecular antioxidants, which can capture free radicals harmful to the human body, so that the generation and elimination of the free radicals in the human body are in a dynamic balance, and the human body is not damaged. With the increase of age, the activities of antioxidant enzymes such as superoxide dismutase in human body are reduced, the capability of scavenging oxygen free radicals in the body is reduced, and the oxygen free radicals with excessive concentration act on nucleic acid, protein, cell membrane and the like to cause irreversible damage, thereby causing physiological disorder and even pathological change of the body and accelerating the aging of skin. Therefore, excessive oxygen free radicals in the human body are a great threat to human body aging, and eating unhealthy, sun-drying, pressure, environmental pollution and the like can cause the free radicals of the skin to be flooded, so that oxidation phenomena such as dark complexion, water shortage and the like are generated. Research shows that the antioxidant system of human body is one system with perfect and complex functions, which is comparable to the immune system, and has the advantages of powerful antioxidant capacity, health, long life and slow aging. Therefore, there is a need for a compound having excellent antioxidant effect, which is widely used in the medical or cosmetic field to delay aging.
The most obvious signal of skin aging in humans is the generation of facial wrinkles, which are caused by muscle contraction when receptors on muscle fibers receive neurotransmitters released from neurite vesicles, and frequent muscle contraction causes the formation of wrinkles. Inhibiting muscle contraction can improve wrinkles on the skin surface. Inhibition of muscle contraction may be achieved by inhibiting acetylcholine release or preventing acetylcholine binding to its receptors. The Agrin-LRP4-MuSK signaling pathway is known to mediate clustering of acetylcholine receptors with prominent effects on the establishment and maintenance of normal function of neuromuscular junctions. Abnormalities in the Agrin-LRP4-MuSK signaling pathway interfere with acetylcholine receptor clustering, resulting in a disorder of neuromuscular junctions, thereby inhibiting muscle contraction. Therefore, the interference of acetylcholine clusters is of great significance for inhibiting muscle contraction, reducing the formation of wrinkles and delaying skin aging.
Several methods have been discovered for reducing and/or eliminating expression wrinkles. For example, topical botulinum toxin injection induces muscle relaxant paralysis for removing wrinkles, thinning the face, eliminating intereyebrow lines and fish tail lines, and the like; the use of an acetyl hexapeptide-8 and acetyl octapeptide-3 containing product interferes with neurotransmitter release from presynaptic membranes, inhibits facial muscle contraction, and reduces or eliminates local wrinkles. However, these compounds present the risk of eliciting an immune response that results in a loss of therapeutic effect or are not effective in inhibiting muscle contraction. Thus, there remains a need to find compounds that inhibit other mechanisms of action for the treatment or care of those conditions, disorders and/or diseases that are ameliorated or prevented by inhibiting muscle contraction, and to meet the increasing need for treating or caring for the skin.
Disclosure of Invention
The invention aims to provide peptides with the effects of resisting oxidation and delaying aging and inhibiting muscle contraction, and a cosmetic composition or a pharmaceutical composition containing the peptides. The method can inhibit muscle contraction, improve wrinkles on the surface of skin, reduce the depth of wrinkles and achieve the effect of removing wrinkles by interfering acetylcholine receptor clustering, preventing acetylcholine from being combined with the receptor, and can be used for treating, preventing or repairing skin aging or photoaging in the cosmetic or medical field, and treating or nursing conditions, disorders or diseases caused by muscle contraction; meanwhile, the tea has the functions of antioxidation and can delay aging.
In view of this, the present invention provides a peptide represented by the formula (I), or a stereoisomer thereof, or a mixture of its stereoisomers, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof,
R 1 -Glu-Asp-Tyr-Tyr-Arg-Nle-R 2 (I)
in the formula (I) of the present invention,
R 1 selected from: H. or R is 3 -CO-, wherein R 3 Selected from: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl;
R 2 selected from: -NR 4 R 5 OR-OR 4 Wherein each R is 4 And R is 5 Independently of each other selected from: H. substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl;
alkyl refers to a saturated aliphatic linear or branched alkyl group having 1 to 24 carbon atoms (optionally having 1 to 16 carbon atoms; optionally having 1 to 14 carbon atoms; optionally having 1 to 12 carbon atoms; optionally having 1, 2, 3, 4, 5, or 6 carbon atoms); optionally selected from: methyl, ethyl, isopropyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, 2-ethylhexyl, 2-methylbutyl, or 5-methylhexyl;
The alkenyl group refers to a straight or branched alkenyl group having 2 to 24 carbon atoms (optionally having 2 to 16 carbon atoms; optionally having 2 to 14 carbon atoms; optionally having 2 to 12 carbon atoms; optionally having 2, 3, 4, 5, or 6 carbon atoms); the alkenyl group has one or more carbon-carbon double bonds, optionally 1, 2 or 3 conjugated or non-conjugated carbon-carbon double bonds; the alkenyl group is bound to the remainder of the molecule by a single bond; optionally selected from: vinyl, oleyl, or linoleyl;
optionally, the substituents in the "substituted alkyl", "substituted alkenyl" are selected from C 1 -C 4 An alkyl group; a hydroxyl group; c (C) 1 -C 4 An alkoxy group; an amino group; c (C) 1 -C 4 An aminoalkyl group; c (C) 1 -C 4 A carbonyloxy group; c (C) 1 -C 4 An oxycarbonyl group; halogen (e.g., fluorine, chlorine, bromine, and iodine); cyano group; a nitro group; an azide; c (C) 1 -C 4 An alkylsulfonyl group; a mercaptan; c (C) 1 -C 4 Alkylthio; c (C) 6 -C 30 Aryloxy groups such as phenoxy; -NR b (C＝NR b )NR b R c Wherein R is b And R is c Is independently selected from: H. c (C) 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 10 Cycloalkyl, C 6 -C 18 Aryl, C 7 -C 17 Aralkyl groups, heterocyclic groups having three to ten members, or protecting groups for amino groups.
Alternatively, R 1 Selected from: H. acetyl, t-butyryl, hexanoyl, 2-methylhexanoyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl or linoleoyl; r is R 4 、R 5 Independently of each other selected from: H. methyl, ethyl, hexyl, dodecyl or hexadecyl;
alternatively, R 1 Selected from H, acetyl, lauroyl, myristoyl or palmitoyl; r is R 4 Is H and R 5 Selected from: H. methyl, ethyl, hexyl, dodecyl or hexadecyl;
alternatively, R 1 Is H or acetyl; r is R 2 is-OH or-NH 2 。
Alternatively, the peptide of formula (I), or a stereoisomer thereof, or a mixture of its stereoisomers, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, is selected from the following peptides (1) - (8):
(1)H-Glu-Asp-Tyr-Tyr-Arg-Nle-OH；
(2)H-Glu-Asp-Tyr-Tyr-Arg-Nle-NH 2 ；
(3)Ac-Glu-Asp-Tyr-Tyr-Arg-Nle-OH；
(4)Ac-Glu-Asp-Tyr-Tyr-Arg-Nle-NH 2 ；
(5)Palm-Glu-Asp-Tyr-Tyr-Arg-Nle-OH；
(6)Palm-Glu-Asp-Tyr-Tyr-Arg-Nle-NH 2 ；
(7)Myr-Glu-Asp-Tyr-Tyr-Arg-Nle-OH；
(8)Myr-Glu-Asp-Tyr-Tyr-Arg-Nle-NH 2 。
the peptide of formula (I) of the present invention may exist as stereoisomers or as mixtures of stereoisomers; for example, the amino acids they comprise may have the L-, D-configuration, or be racemic independently of each other. Thus, it is possible to obtain isomeric mixtures as well as racemic mixtures or diastereomeric mixtures, or pure diastereomers or enantiomers, depending on the number of asymmetric carbons and what isomers or isomeric mixtures are present. The preferred structure of the peptides of formula (I) of the present invention is the pure isomer, i.e., enantiomer or diastereomer.
For example, when-Glu-is described herein, it is understood that-Glu-is selected from-L-Glu-, -D-Glu-, or a mixture of both, is racemic or non-racemic. The preparation methods described in this document enable one of ordinary skill in the art to obtain each stereoisomer of the peptides of the invention by selecting amino acids with the correct configuration.
The invention also includes all suitable isotopic variants of the peptides of formula (I). Isotopic variations of these peptides of the present invention are understood herein to mean those compounds: wherein at least one atom is replaced by another atom of the same atomic number within the peptide of the invention, but the atomic mass of said other atom is different from the atomic mass normally or predominantly present in nature. Examples of isotopes that can be incorporated into the peptides of the invention are: those of hydrogen, carbon, nitrogen or oxygen, e.g. 2 H (deuterium), 3 H (tritium), 13 C、 14 C、 15 N、 17 O or 18 O. Specific isotopic variations of the peptides of the present invention (particularly those into which one or more radioisotopes have been incorporated) may be advantageous, for example, for examining the mechanism of action or distribution of active compounds in vivo; due to relatively simple producibility and detectability, especially with 3 H or 14 C isotopically labeled compounds are suitable for this purpose. In addition, due to the greater metabolic stability of the compounds, the incorporation of isotopes (e.g., deuterium) may yield particular therapeutic benefits, such as increased in vivo half-life or reduced amounts of active agent required; thus, in some cases, such an alteration of the peptides of the inventionBut may also constitute a preferred embodiment of the invention. Isotopic variants of the peptides of the invention can be prepared by methods known to those skilled in the art, for example, by methods further described below and in the examples, by using the respective reagents and/or corresponding isotopic modifications of the starting materials.
In addition, the invention also includes prodrugs of the peptides of the invention. The term "prodrug" means herein such compounds: which may be biologically active or inactive in itself, but which react (e.g., metabolize or hydrolyze) to form the peptides of the invention during their residence time in the body.
The term "cosmetically or pharmaceutically acceptable salt" refers to a salt that is approved for use in animals, and more specifically in humans, including metal salts of peptides of formula (I), including, but not limited to: lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc, or aluminum, etc.; including salts of peptides of formula (I) with organic bases including, but not limited to: ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine or piperazine and the like; including salts of peptides of formula (I) with inorganic or organic acids including, but not limited to: acetic acid, citric acid, lactic acid, malonic acid, maleic acid, tartaric acid, fumaric acid, benzoic acid, aspartic acid, glutamic acid, succinic acid, oleic acid, trifluoroacetic acid, oxalic acid, pamoate (pamoate), gluconic acid, or the like; the inorganic acids include, but are not limited to: hydrochloric acid, sulfuric acid, boric acid or carbonic acid.
The synthesis of the peptide of formula (I) of the present invention, or a stereoisomer thereof or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, may be carried out according to conventional methods known in the art, such as solid phase synthesis, liquid phase synthesis or a combination of solid and liquid phases, and may also be prepared by biotechnological methods aimed at producing the desired sequence, or by controlled hydrolysis of proteins of animal, fungal or plant origin.
For example, a method for obtaining a peptide of formula (I) comprises the steps of:
-coupling an amino acid having a protected N-terminus and a free C-terminus with an amino acid having a free N-terminus and a protected or solid carrier-bound C-terminus;
-elimination of the group protecting the N-terminal end;
-repeating the coupling sequence and elimination of the N-terminal protecting group until the desired peptide sequence is obtained;
-elimination of the C-terminal protecting group or cleavage from the solid support.
Preferably, the C-terminus is bound to a solid support and the method is performed on a solid phase, comprising coupling an amino acid having a protected N-terminus and a free C-terminus with an amino acid having a free N-terminus and a C-terminus bound to a polymeric support; eliminating the group protecting the N-terminus; and repeating this sequence as many times as necessary to thereby obtain a peptide of the desired length, followed by cleavage of the synthesized peptide from the original polymer carrier.
The functional groups of the side chains of these amino acids remain fully protected with temporary or permanent protecting groups throughout the synthesis and may be deprotected simultaneously or orthogonally to the process of cleaving the peptide from the polymeric carrier.
Alternatively, solid phase synthesis may be performed by a pooling strategy (convergent strategy) of coupling a dipeptide or tripeptide to a polymeric support or to a dipeptide or amino acid previously bound to a polymeric support.
The functional groups of the ends may be subsequently modified using standard conditions and methods known in the art to deprotect the N-and C-termini and/or cleave the peptide from the polymeric support in a non-defined order. The peptide of formula (I) bound to the polymeric support may be optionally modified at the N-and C-termini, or after the peptide has been cleaved from the polymeric support.
In another aspect of the present invention there is provided a cosmetic or pharmaceutical composition comprising an effective amount of a peptide of formula (I) above, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, together with at least one excipient and optionally a cosmetically or pharmaceutically acceptable adjuvant.
Optionally, the adjuvant is selected from: agents that inhibit acetylcholine receptor clustering, other agents that inhibit TRPV1 activity, analgesics, agents that inhibit PAR-2 activity, collagen synthesis stimulators, agents that modulate PGC-1 alpha synthesis, agents that modulate ppary activity, agents that increase or decrease triglyceride levels in adipocytes, agents that stimulate or retard adipocyte differentiation, lipolytic or lipolysis-stimulating agents, lipolytic agents, lipogenic agents, inhibitors of acetylcholine receptor aggregation, agents that inhibit muscle contraction, anticholinergic agents, elastase inhibitors, matrix metalloproteinase inhibitors, melanin synthesis stimulators or inhibitors, whitening or decolourizing agents, pigmentation-promoting agents, self-tanning agents, anti-aging agents, NO-synthase inhibitors, 5 alpha-reductase inhibitors, inhibitors of lysyl hydroxylase and/or prolyl hydroxylase, antioxidants free radical scavengers and/or agents against atmospheric pollution, active carbonyl scavengers, anti-glycation agents, antihistamines, antiviral agents, antiparasitic agents, emulsifiers, emollients, organic solvents, liquid propellants, skin conditioning agents, moisture retaining substances, alpha hydroxy acids, beta hydroxy acids, moisturizers, epidermohydrolases, vitamins, amino acids, proteins, pigments, dyes, biopolymers, gel polymers, thickeners, surfactants, softeners, adhesives, preservatives, anti-wrinkle agents, agents capable of reducing or treating the lower eye bags, keratolytic agents, antimicrobial agents, antifungal agents, bactericides, bacteriostats, agents capable of stimulating the synthesis of dermis or epidermis macromolecules and/or inhibiting or preventing their degradation, agents capable of stimulating elastin synthesis, agents capable of stimulating the synthesis of decorin, agents capable of, agents that stimulate laminin synthesis, agents that stimulate defensin synthesis, agents that stimulate chaperonin synthesis, agents that stimulate cAMP synthesis, agents that stimulate HSP70 synthesis, agents that stimulate heat shock protein synthesis, agents that stimulate hyaluronic acid synthesis, agents that stimulate fibronectin synthesis, agents that stimulate deacetylase synthesis, agents that stimulate synthesis of lipids and stratum corneum components, ceramides, fatty acids, agents that inhibit collagen degradation, agents that inhibit elastin degradation, agents that inhibit serine proteases, agents that stimulate fibroblast proliferation, agents that stimulate keratinocyte proliferation, agents that stimulate adipocyte proliferation, agents that stimulate melanocyte proliferation, agents that stimulate keratinocyte differentiation, agents that inhibit acetylcholinesterase, skin relaxants, agents that stimulate glycosaminoglycan synthesis, anti-hyperkeratosis agents, acne lytic agents antipsoriatic, antiplaque, DNA repair, DNA protectant, stabilizer, antipruritic, agent for treating and/or caring for sensitive skin, solidifying, tightening, restructuring, stretch inhibitor, sebum production regulating, antiperspirant, healing-stimulating, healing-aiding, re-epithelialization-stimulating, re-epithelialization-aiding, cytokines, sedatives, anti-inflammatory, anesthetics, agents acting on capillary circulation and/or microcirculation, agents stimulating angiogenesis, agents inhibiting vascular permeability, venous tension, agents acting on cellular metabolism, agents for improving dermal-epidermal junction, agents inducing hair growth, hair growth inhibition or delay agents, fragrances, chelating agents, plant extracts, essential oils, marine extracts, agents from biofermentation processes, inorganic salts, cell extracts, essential oils, marine extracts, agents from biofermentation processes, sunscreens, and organic or inorganic photoprotective agents effective against a and/or B ultraviolet rays, or mixtures thereof.
Alternatively, the formulation of the cosmetic or pharmaceutical composition is selected from: cream, oil, balm, foam, lotion, gel, wipe, slurry, ointment, mousse, powder, stick, pen, spray, aerosol, capsule, tablet, granule, chewing gum, solution, suspension, emulsion, elixir, polysaccharide film, jelly, or gelatin;
optionally, the capsule comprises: soft capsule and hard capsule, optionally gelatin capsule; the tablet comprises: sugar-coated tablets.
The peptides of the invention have variable solubility in water depending on the nature of their sequences or any possible modification in the N-terminal and/or C-terminal. The peptides of the invention may thus be incorporated into the composition by aqueous solutions, and those that are insoluble in water may be dissolved in conventional cosmetically or pharmaceutically acceptable solvents such as, but not limited to, ethanol, propanol, isopropanol, propylene glycol, glycerol, butylene glycol or polyethylene glycol, or any combination thereof.
The cosmetically or pharmaceutically effective amount of the peptides of the invention to be administered, as well as their dosage, will depend on a number of factors including the age, the state of the patient, the severity of the condition or disease, the route and frequency of administration, and the particular nature of the peptide to be used.
By "cosmetically or pharmaceutically effective amount" is meant an amount of one or more peptides of the invention that is non-toxic but sufficient to provide the desired effect. The peptides of the invention are used in the cosmetic or pharmaceutical compositions of the invention in cosmetically or pharmaceutically effective concentrations to obtain the desired effect; in a preferred form, between 0.00000001% and 20% by weight, preferably between 0.000001% and 15% by weight, more preferably between 0.0001% and 10% by weight, and even more preferably between 0.0001% and 5% by weight, relative to the total weight of the composition.
In another aspect of the present invention there is provided a cosmetically or pharmaceutically acceptable delivery system or sustained release system for achieving better penetration of the active ingredient and/or improving its pharmacokinetic and pharmacodynamic properties, comprising an effective amount of a peptide of formula (I) above, or a stereoisomer, or a mixture of stereoisomers, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a cosmetic or pharmaceutical composition of the above.
The term "delivery system" refers to a diluent, adjuvant, excipient or carrier with which the peptides of the invention are administered, selected from the group consisting of: water, oils or surfactants, including those of petroleum origin, animal origin, vegetable origin, or synthetic origin, such as, and not limited to, peanut oil, soybean oil, mineral oil, sesame oil, castor oil, polysorbates, sorbitan esters, ether sulfates, betaines, glucosides, maltosides, fatty alcohols, nonoxynol, poloxamers, polyoxyethylene, polyethylene glycols, dextrose, glycerol, digitonin, and the like. Diluents which can be used in different delivery systems to which the peptides of the invention can be administered are known to those of ordinary skill in the art.
The term "sustained release" is used in a conventional sense to refer to a delivery system that provides a gradual release of a compound over a period of time, and preferably, but not necessarily, has a relatively constant level of release of the compound over the entire period of time.
Examples of delivery systems or slow release systems are liposomes, oleosomes, nonionic surfactant liposome vesicles, ethosomes, millimeter-capsules, microcapsules, nanocapsules, nanostructured lipid carriers, sponges, cyclodextrins, lipid vesicles, micelles, millimeter-spheres, microspheres, nanospheres, lipid spheres, microemulsions, nanoemulsions, millimeter-particles, microparticles or nanoparticles. Preferred delivery systems or slow release systems are liposomes and microemulsions, more preferably water-in-oil microemulsions having an internal structure of reverse micelles.
Sustained release systems can be prepared by methods known in the art and can be administered, for example, by: by topical or transdermal administration, including adhesive patches, non-adhesive patches, occlusive patches, and microelectronic patches; or by systemic administration, such as and without limitation, oral or parenteral routes, including nasal, rectal, subcutaneous implantation or injection, or direct implantation or injection into a particular body part, and preferably a relatively constant amount of these peptides of the invention should be released. The amount of peptide contained in the sustained release system will depend, for example, on the site where the composition is to be administered, the kinetics and duration of release of the peptide of the invention, and the nature of the condition, disorder and/or disease to be treated and/or cared for.
In another aspect of the invention, there is provided the use of a peptide of formula (I) above, or a stereoisomer thereof, or a mixture of its stereoisomers, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a cosmetic or pharmaceutical composition as described above, or a cosmetically or pharmaceutically acceptable delivery system or sustained release system as described above, for the preparation of a cosmetic or pharmaceutical composition for the treatment or care of a condition, disorder or disease caused by muscle contraction;
optionally, the disorder or disease is dystonia;
optionally, the dystonia is focal dystonia; such dystonias include, but are not limited to, facial spasms, torsionally dystonias, cervical dystonias or torticollis, laryngeal dystonias or spasmodic dysphonia, oromandibular dystonias, limb dystonias such as writers or musicians spasms or foot dystonias, night molars, hemifacial spasms, tics and/or strabismus, segmental dystonias, mejie's syndrome, multifocal dystonias, hemidystonias, dopamine responsive dystonias and sier dystonias.
In another aspect of the present invention, there is provided a use of a peptide of formula (I) above, or a stereoisomer thereof, or a mixture of its stereoisomers, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a cosmetic or pharmaceutical composition as described above, or a cosmetically or pharmaceutically acceptable delivery system or sustained release system as described above, for the preparation of a cosmetic or pharmaceutical composition for the treatment, prevention or repair of skin aging or photoaging, wherein the treatment, prevention or repair of skin aging or photoaging is reduction, prevention or treatment of facial wrinkles.
In another aspect of the present invention, there is provided the use of a peptide of formula (I) above, or a stereoisomer thereof, or a mixture of its stereoisomers, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a cosmetic or pharmaceutical composition as described above, or a cosmetically or pharmaceutically acceptable delivery system or sustained release system as described above, for the preparation of a cosmetic or pharmaceutical composition for use in antioxidative.
In another aspect of the present invention, there is provided the use of a peptide of formula (I) above, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a cosmetic or pharmaceutical composition as described above, or a cosmetically or pharmaceutically acceptable delivery system or sustained release system as described above, in the preparation of a cosmetic or pharmaceutical composition for delaying aging.
In order to facilitate understanding of the invention, the meaning of some terms and expressions used in the present invention is described as follows:
in the present invention, the term "skin" is understood to mean the layers that make up it, from the uppermost or stratum corneum to the lowermost or subcutaneous tissue, both endpoints being included. These layers are composed of different types of cells, such as keratinocytes, fibroblasts, melanocytes, and/or adipocytes, among others. In the present invention, the term "skin" includes the scalp.
The term "treatment" refers to administration of a peptide according to the invention to reduce or eliminate a disease or condition, or to reduce or eliminate one or more symptoms associated with such a disease or condition. The term "treating" also encompasses the ability to reduce or eliminate the physiological consequences of the disease or disorder.
The term "care" includes prophylaxis of diseases and/or conditions.
The term "preventing" refers to the ability of a peptide of the invention to prevent, delay, or hinder the appearance or progression of a disease or disorder prior to its appearance.
The term "repair" refers to the ability of a peptide of the invention to improve, alleviate or restore its original shape after the appearance of a disease or condition.
The term "aging" refers to changes experienced by skin with age (natural aging), or by exposure to sunlight (photoaging) or to environmental pollutants such as chemical dirt or pollutants, tobacco smoke, etc., and includes all externally visible and/or perceivable changes by touch, such as, and not limited to: the development of discontinuities in the skin (e.g., wrinkles, fine lines, expression lines, stretch lines, streaks, grooves, irregularities or roughness, increased pore size, loss of moisture, loss of elasticity, loss of firmness, loss of smoothness, loss of deformability, loss of resilience), sagging skin (e.g., sagging cheek, under-eye appearance of bags, or appearance of double chin, etc.), changes in skin color (e.g., scarring, redness, bags, or appearance of hyperpigmented areas such as age spots or freckles, etc.), abnormal differentiation, hyperkeratinization, elastosis, keratosis, alopecia, orange-peel-like skin, loss of collagen structure, and other histological changes in the stratum corneum, dermis, epidermis, vascular system (e.g., appearance of spider veins or telangiectasia), or those tissues adjacent to the skin.
The term "photoaging" refers to premature aging of the skin due to prolonged exposure of the skin to ultraviolet radiation, which exhibits the same physiological characteristics as natural aging, for example and without limitation: relaxation, sagging, color changes or pigmentation irregularities, abnormalities and/or hyper-keratinization.
In the present specification, abbreviations for amino acids follow the rules specified in the European journal of biochemistry (Eur.J. biochem.1984, 138:9-37) by the IUPAC-IUB Biochemical nomenclature Commission (IUPAC-IUB Commission of Biochemical Nomenclature).
Thus, for example, glu represents NH 2 -CH(CH 2 CH 2 COOH) -COOH, glu-represents NH 2 -CH(CH 2 CH 2 COOH) -CO-, -Glu represents-NH-CH (CH) 2 CH 2 COOH) -COOH, and-Glu-represents-NH-CH (CH) 2 CH 2 COOH) -CO-. Thus, the hyphen representing the peptide bond eliminates the OH in the 1-carboxyl group of the amino acid (represented here in conventional non-ionized form) when located to the right of the symbol, and eliminates the H in the 2-amino group of the amino acid when located to the left of the symbol; both modifications can be applied to the same symbol (see table 1).
TABLE 1 Structure of amino acid residues and their single and three letter abbreviations
The abbreviation "Ac-" is used in the present invention to denote acetyl (CH) 3 -CO-), the abbreviation "Palm-" is used in the present invention to represent palmitoyl, and the abbreviation "Myr-" is used in the present invention to represent myristoyl; glu (Glu): glutamic acid; asp: aspartic acid; tyr: tyrosine; arg: arginine; nle: norleucine.
The invention has the following advantages and effects:
1. the peptide is obtained through artificial design, is convenient to synthesize, and is safe and non-irritating to human bodies.
2. The peptide of the invention can inhibit muscle contraction, improve wrinkles on the surface of skin, reduce the depth of wrinkles, achieve the effect of removing wrinkles, and can be used for treating, preventing or repairing skin aging or photoaging in the field of cosmetics or medicines, and treating or nursing conditions, disorders or diseases caused by muscle contraction.
3. The peptide has the effects of resisting oxidization and reducing the damage of free radicals to organisms, so that the peptide can delay aging, has the anti-aging effect, and can be applied to the fields of cosmetics, medicines and the like.
Drawings
In order to more clearly illustrate the technical solutions of the present invention, the drawings that are needed in the description of the present invention will be briefly described below, it being obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a peptide (4) Ac-Glu-Asp-Tyr-Tyr-Arg-Nle-NH 2 (formula C) 41 H 58 N 10 O 13 ) Mass spectrum, [ M+H ]] + The mass to charge ratio (m/z) of the excimer ion peak was 899.5229 and the mass spectrum measured molecular weight was 898.52.
FIG. 2 is a graph of the effect of test samples on muscle contraction.
FIG. 3 is a graph of the effect of a test sample on the ability of the nematode to exercise.
Detailed Description
In order that the described objects, features and advantages of the invention will be readily understood, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In the present invention, the abbreviations used for amino acids follow the rules specified by the IUPAC-IUB Biochemical nomenclature Commission in Eur.J.biochem. (1984) 138:9-37 and J.chem. (1989) 264:633-673.
Amide Resin: a starting resin for polypeptide synthesis (crosslinking degree 1%, substitution degree 1.72mmol/g, granularity 100-200 meshes); fmoc-Linker:4- [ (2, 4-Dimethoxyphenyl) (Fmoc-amino) methyl ]Phenoxyacetic acid; ac (Ac) 2 O: acetic anhydride; DMF: n, N-dimethylformamide; DIPEA: diisopropylethylamine; DIC: diisopropylcarbodiimide; piperidine: piperidine; HOBt: 1-hydroxybenzotriazole; TFA: trifluoroacetic acid; TIS: triisopropylsilane; EDT:1, 2-ethanedithiol; glu: glutamic acid; asp: aspartic acid; tyr: tyrosine; arg: arginine; nle: norleucine; fmoc: 9-fluorenylmethoxycarbonyl; tBu: a tertiary butyl group; otBu: t-butoxy; pbf:2, 4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl.
EXAMPLE 1Ac-Glu-Asp-Tyr-Tyr-Arg-Nle-NH 2 Is prepared from
1.1 preparation of Fmoc-Linker-Amide Resin
5g of Amide Resin was weighed into a solid phase synthesis reaction column, swollen with DMF, washed the Resin and the solvent was removed.
7.0g Fmoc-Linker, 2.10g HOBt were weighed into a drying flask. Dissolving with DMF solvent, cooling in ice water bath for 10min, and activating with DIC for 10min to avoid water vapor.
Adding the activated Fmoc-Linker into the swelled resin, reacting for 2.5 hours, pumping out the reaction liquid, washing the resin, and pumping out the solvent.
Continuing to add Ac 2 O and DIPEA were capped for 1.5h. The resin was washed and the solvent was pumped away.
1.2 Fmoc removal
Fmoc-Linker-Amide Resin was Fmoc-removed twice with 20% piperidine/DMF for 10min each time, sampled K for detection, and developed dark blue. The resin was washed 7 times with DMF and the solvent was removed.
1.3 feeding reaction
4.1g Fmoc-Nle-OH and 3.71g HOBt were weighed into a dry flask, dissolved in DMF and sealed in a-18℃refrigerator for 30min. 2.892g DIC was added and activated for 3min to avoid moisture. And adding the activated amino acid into the deprotected resin for reaction for 2 hours, and pumping away the reaction solution. K detection resin is colorless and transparent, which indicates that the reaction is complete.
The N-terminal Fmoc group was deprotected and 10.0g of activated Fmoc-Arg (Pbf) -OH was coupled to the peptidyl resin in the presence of 3.71g HOBt and 2.892g DIC using DMF as solvent and the reaction continued for 2h. These resins were then washed and the deprotection treatment of the Fmoc group was repeated to couple the next amino acid. In each coupling, 5.4g of Fmoc-Tyr (tBu) -OH were coupled sequentially using DMF as solvent in the presence of 3.71g of HOBt and 2.892g of DIC; 5.4g Fmoc-Tyr (tBu) -OH;5.6g of Fmoc-Asp (OtBu) -OH and then 5.8g of Fmoc-Glu (OtBu) -OH; after the reaction was completed, the resin was washed and the solvent was removed.
The N-terminal Fmoc group of the peptidyl resin was deprotected and Fmoc was removed twice with 20% piperidine/DMF for 10min each time, sampling K and developing dark blue. The resin was washed 6 times with DMF and the solvent was removed.
2.1g of Ac in the presence of DIPEA were treated with DMF as solvent 2 O is coupled to the peptide-based Resin, the reaction is continued for 1.5h, the Resin is washed, the solvent is pumped away, and 20.3g of Ac-Glu (OtBu) -Asp (OtBu) -Tyr (tBu) -Tyr (tBu) -Arg (Pbf) -Nle-Linker-Amide Resin is obtained after shrinkage and drying.
1.4 cleavage
114mL of TFA, 3mL of TIS and 3mL of water are measured, mixed and stirred uniformly to obtain a lysate, and the lysate is sealed and placed in a refrigerator at the temperature of minus 18 ℃ for standby; the isopropyl ether is placed in a refrigerator at the temperature of minus 18 ℃ for refrigeration for standby.
20.3g of Ac-Glu (OtBu) -Asp (OtBu) -Tyr (tBu) -Tyr (tBu) -Arg (Pbf) -Nle-Linker-Amide Resin was weighed, added to a round-bottomed flask, the above frozen lysate was added, and the reaction was stirred for 2h. Suction filtering, concentrating the filtrate to 15mL, adding isopropyl ether, stirring, centrifuging, washing for 6 times until pH value is 3-4, and vacuum drying to obtain 72g of Ac-Glu-Asp-Tyr-Tyr-Arg-Nle-NH 2 Crude peptide.
1.5 purification
7.2g of crude peptide was weighed out and dissolved in 600mL of methanol: in pure water (V: v=1:3), a clear and transparent solution was obtained by filtration through a microporous filter membrane having a pore size of 0.22 μm, and purification by reverse phase HPLC, the purification gradient was as shown in the following table:
| time (min) | Flow rate (mL/min) | A% (0.1% acetic acid + acetonitrile) | B% (0.1% acetic acid + pure water) |
| 0 | 40 | 10 | 90 |
| 15 | 40 | 20 | 80 |
| 60 | 40 | 40 | 60 |
Purifying the filtered sample, collecting the fraction, concentrating and freeze-drying to obtain the peptide (4) Ac-Glu-Asp-Tyr-Tyr-Arg-Nle-NH with the purity of 98.5% 2 。
Other peptides of formula (I) of the present invention may be prepared by similar methods.
The molecular weight of these peptides was determined by ESI-MS, and the test result of the peptide (4) is shown in FIG. 1, and the mass spectrometry analysis result is 898.52.
Example 2 muscle contraction inhibition experiment
2.1 laboratory animals
Female and male SD rats of 8-9 weeks of age.
2.2 laboratory apparatus
HW-400S constant temperature smooth muscle groove, BL-420E biological function experimental system, tension transducer, other instruments are conventional experimental instrument.
2.3 Experimental reagents
Acetylcholine, chloral hydrate.
2.4 sample to be tested
Acetyl hexapeptide-30 (Ac-Glu-Asp-Tyr-Tyr-Arg-Leu-NH) 2 ) The test concentrations were 100ppm and 200ppm, respectively;
peptide (4) at test concentrations of 100ppm and 200ppm, respectively.
2.5 purpose of experiment
The purpose of this experiment was to determine whether the peptides of the present invention inhibit muscle contraction by taking rat ileal smooth muscle as a subject, administering and observing the rhythmic condition of the ileal smooth muscle by the test sample after acetylcholine stimulation, and evaluating the influence of the test sample on muscle contraction.
2.6 Experimental methods
The experimental rats were fasted for 12 hours without water deprivation prior to the experiment. Injecting 10% chloral hydrate into abdominal cavity according to dosage of 0.1mL/25g, cutting off abdominal cavity after the rat is anesthetized, exposing enlarged cecum, taking out one section of ileum from the ileocecum, washing in desk type liquid with oxygen introduced for 10min in advance, cutting off a plurality of sections of 4cm long ileum, and incubating in desk type liquid at 4 ℃ for later use; the ileum was partially tied and knotted with cotton thread at each end to form a loop.
Opening a HW-400S constant temperature smooth muscle groove and BL-420E biological function experimental system, connecting a tension transducer to the channel 1, adjusting the incubation temperature to 37 ℃, preheating the instrument for 0.5h, and introducing oxygen for more than 10 min. One end of the intestinal section is fixed at the inlet bracket opening by cotton thread, the other end is connected with the tension transducer, and the position and the height of the transducer are properly adjusted, so that the isolated intestinal section is placed in the center of the smooth muscle groove, and the intestinal activity condition starts to be recorded.
After the muscle contraction is stabilized, adding acetylcholine with the final concentration of 0.1-0.4 mug/mL until the high-order stable waveform of the muscle activity appears, and taking the action for 5 minutes as an initial control; after 5 minutes of equilibration, the samples to be tested were added separately. For each replacement of one of the test drugs, the new ileum segment was replaced, the instrument recorded the relevant data, and the ileal smooth muscle contraction inhibition rate was calculated according to the following formula.
Ileal smooth muscle contraction inhibition = (post-acetylcholine-administration contractility-post-administration contractility of test sample)/post-administration contractility of acetylcholine x 100%
Experimental data are expressed as Mean ± SD.
2.7 experimental results
Skin muscle relaxation is an important manifestation of aging, and inhibiting contraction of facial expression muscles can improve wrinkles. Acetylcholine acts as a neurotransmitter and directly agonizes the acetylcholine receptors of the postsynaptic membrane, triggering a signaling cascade that causes muscle contraction. Muscle contraction may be inhibited by inhibiting acetylcholine release from the presynaptic membrane or preventing acetylcholine binding to its receptors. The peptides of the invention inhibit muscle contraction by inhibiting the binding of acetylcholine to its receptor. The ileal smooth muscle contraction inhibition results of the test samples are shown in table 2 below and fig. 2.
TABLE 2 ileal smooth muscle contraction inhibition of test samples (%)
The result shows that a section of high-order signal peak can be generated after the acetylcholine is given, the peak starts to weaken when the acetylcholine is given at 200ppm, the inhibition is generated, and the inhibition rate at 200ppm is 48.09%; the peptide (4) of the invention has obvious inhibition effect on the high-order signal peak generated by acetylcholine at the low concentration of 100ppm, the inhibition rate of 100ppm is 27.72 percent, and the inhibition rate of 200ppm is 64.08 percent; the inhibition effective rate of the peptide (4) is obviously higher than that of acetyl hexapeptide-30 under the same concentration, which proves that the peptide (4) has better technical effect compared with the prior art.
Therefore, the peptide has obvious effect of inhibiting muscle contraction, can improve the wrinkles on the surface of the skin, reduce the depth of the wrinkles and achieve the effect of removing the wrinkles, and can be used for treating or nursing the condition, disorder or disease caused by the muscle contraction, treating, preventing or repairing skin aging or photoaging, and can also be used in products for reducing, preventing or treating the wrinkles.
EXAMPLE 3 nematode locomotor activity experiment
3.1 reagents and materials
Peptone, naCl, caCl 2 、MgSO 4 ·7H 2 O、KH 2 PO 4 Cholesterol, agar powder, potassium hydroxide, sodium hydroxide, ethanol and double distilled water.
3.2 instruments
An in vitro microscope and an ultra-clean workbench.
3.3 subjects
OP 50 Bacteria and caenorhabditis elegans, available from Shanghai Seiyaku Biotechnology Co.
3.4 sample to be tested
Drug administration group:
acetyl hexapeptide-30 (Ac-Glu-Asp-Tyr-Tyr-Arg-Leu-NH) 2 ) The test concentrations were 50ppm and 100ppm, respectively;
peptide (4) at test concentrations of 50ppm and 100ppm, respectively.
Control group: no sample was added.
3.5 purpose of experiment
The purpose of the experiment is to evaluate whether the test sample has an antioxidation effect by taking caenorhabditis elegans as an experimental object and observing the influence of the test sample on the head swing frequency of the caenorhabditis elegans through administration, so as to determine whether the peptide can exert an anti-aging effect.
3.6 Experimental methods
Preparation of the culture medium:
LB liquid medium: accurately weighing 5g of tryptone, 2.5g of yeast powder and 5g of sodium chloride, adding 500mL of double distilled water for full dissolution, and adding a proper amount of NaOH to adjust the pH to about 7.4 for later use.
NGM medium: 1.25g of tryptone, 1.5g of sodium chloride and CaCl are accurately weighed 2 0.05g，MgSO 4 ·7H 2 O 0.123g，KH 2 PO 4 3.5g, 0.0025g of cholesterol, 0.5mL of ethanol and 8.5g of agar are dissolved in 500mL of double distilled water, and after the double distilled water is completely dissolved, a proper amount of KOH is added to adjust the pH to about 7.0 for standby.
Shaking: the pipette gun measures 10mL of LB liquid medium into a 15mL centrifuge tube, and then picks up OP 50 And (3) after the bacterial colonies are fully and uniformly mixed in the centrifuge tube, placing the centrifuge tube in a shaking table to incubate at the temperature of 37 ℃ and the rotating speed of 220rpm, and after 12-14 hours, when the bacterial colonies become turbid in the centrifuge tube, proving that the bacterial shaking is successful.
Coating: shaking the strain with LB liquid medium according to the following formula 1:100, and then dissolving a proper amount of medicines into the diluted solution to obtain bacterial solutions containing 50ppm and 100ppm of samples to be tested respectively. And adding the bacterial solutions of the samples to be detected with different concentrations into the NGM culture medium according to the volume of 20 mu L of each dish, and then uniformly coating by using a coater to finish inoculation. The control group was inoculated by adding 20. Mu.L of LB liquid medium to NGM medium, and then uniformly coating with a coater.
Placing the NGM culture medium coated with the groups into a biochemical incubator at 37 ℃ for culturing for 12 hours, taking out the culture medium, and adding 10 caenorhabditis elegans into the administration group and the control group respectively. After 24 hours, the nematodes were placed under a microscope to observe the state of caenorhabditis elegans and to count the head wobble frequency of the nematodes in different groups for 1min, wherein the head wobble of the nematodes is recorded as one time.
3.7 experimental results
Aging is a complex process of gradual decline and lesions of the viscera systems of the organism, and is also a leading factor of a plurality of neurodegenerative diseases. The caenorhabditis elegans has short life cycle, clear genetic background, high conservation of senescence-associated regulatory genes and human beings, and close correlation of head swing and senescence. As caenorhabditis elegans ages, they accumulate in large amounts of oxygen radicals in the body, and excessive oxygen radicals can cause the caenorhabditis elegans nervous system to deteriorate, thereby affecting its motor performance. The frequency of head oscillation may reflect the motor performance of the nematode, which may be used as an indicator of the basic function of the nervous system. Thus the frequency of head oscillations of caenorhabditis elegans can reflect its physical condition and the degree of aging. As the aging process progresses, the frequency of head oscillations gradually decreases. Therefore, the statistical nematode head swing frequency after administration can reflect the antioxidation protection effect of the test sample on nematodes, so as to judge the antioxidation capability and the anti-aging effect of the corresponding test sample.
The effect of the test sample on the athletic performance of the nematodes is shown in fig. 3, and the results show that compared with the control group, the acetyl hexapeptide-30 and the peptide (4) can increase the swinging times of the heads of the nematodes within the range of 100ppm, show the effect of promoting the swinging of the heads of the nematodes, and increase the swinging effect of the heads of the nematodes along with the increase of the concentration. Wherein, the technical effect of the peptide (4) of the invention is better; the peptide (4) can obviously increase the swinging times of the nematode heads at the low concentration of 50ppm, promote the nematode heads to swing, play an antioxidant role and delay nematode aging.
Therefore, the peptide has an antioxidation effect, can delay aging, has excellent anti-aging effect, and can be applied to the fields of cosmetics, medicines and the like.
Example 4
Preparation of essence containing peptide (4)
The preparation method comprises the following steps: stirring and heating the purified water to 85 ℃, and preserving heat for 30min; pre-dissolving sodium hyaluronate and xanthan gum in butanediol, adding into water, stirring and dissolving completely; stirring and cooling to 35 ℃, adding the rest ingredients, and stirring uniformly.
Example 5
Preparation of emulsions containing peptide (4)
The preparation method comprises the following steps: dissolving the peptide (4) with water to obtain a polypeptide solution; heating cetostearyl alcohol (and) cetylglucosides, jojoba oil, mineral oil, isopropyl palmitate to 85deg.C, and stirring well; obtaining phase A; dissolving glycerol, allantoin, polyacrylamide (and) C13-14 isoparaffin (and) laureth-7 with water, and heating to 85deg.C to obtain phase B; adding phase A into phase B rapidly, homogenizing at constant temperature for 3-5min, and cooling; cooling to below 60deg.C, adding antiseptic, stirring, cooling to below 45deg.C, adding polypeptide solution and essence, and stirring.
Example 6
Preparation of toner containing peptide (4)
The preparation method comprises the following steps: dissolving allantoin and glycerol with water, heating to 85deg.C, and maintaining for 30 min; dissolving PEG-7 glycerol cocoate and peptide (4) with water; the above solutions are cooled and then mixed, and the mixed solution is obtained after uniform stirring; and sequentially adding propylene glycol, preservative and essence into the mixed solution, adding water and stirring uniformly to obtain the product.
While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. It is therefore intended that the following claims be interpreted as including the preferred embodiment and all such alterations and modifications as fall within the scope of the embodiments of the invention.
Finally, it is further noted that relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Moreover, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or terminal that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or terminal. Without further limitation, an element defined by the phrase "comprising one … …" does not exclude the presence of other like elements in a process, method, article or terminal device comprising the element.
The above detailed description of the designed peptides and cosmetic or pharmaceutical compositions and uses thereof, provided by the present invention, has been presented herein with specific examples to illustrate the principles and embodiments of the invention, the above examples being provided solely to assist in the understanding of the methods of the invention and their core ideas; meanwhile, as those skilled in the art will have variations in the specific embodiments and application scope in accordance with the ideas of the present invention, the present description should not be construed as limiting the present invention in view of the above.
Claims (23)
1. A peptide of formula (I) or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof,
R 1 -Glu-Asp-Tyr-Tyr-Arg-Nle-R 2 （I）
in the formula (I) of the present invention,
R 1 is acetyl; r is R 2 is-OH or-NH 2 。
2. The peptide of formula (I) or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof according to claim 1, characterized by being selected from the following peptides (4):
（4）Ac-Glu-Asp-Tyr-Tyr-Arg-Nle-NH 2 。
3. the peptide of formula (I), or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-2, wherein the cosmetically acceptable salt or pharmaceutically acceptable salt comprises a metal salt of the peptide of formula (I), wherein the metal comprises: lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc or aluminum.
4. The peptide of formula (I) or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein the cosmetically acceptable salt or pharmaceutically acceptable salt comprises a salt of the peptide of formula (I) with an organic base comprising: ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine or piperazine.
5. The peptide of formula (I), or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-2, wherein the cosmetically acceptable salt or pharmaceutically acceptable salt comprises a salt of the peptide of formula (I) with an inorganic or organic acid, wherein the organic acid comprises: acetic acid, citric acid, lactic acid, malonic acid, maleic acid, tartaric acid, fumaric acid, benzoic acid, aspartic acid, glutamic acid, succinic acid, oleic acid, trifluoroacetic acid, oxalic acid, pamoic acid or gluconic acid; the inorganic acid includes: hydrochloric acid, sulfuric acid, boric acid or carbonic acid.
6. A cosmetic or pharmaceutical composition comprising an effective amount of a peptide of formula (I) or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 5, together with at least one excipient and optionally a cosmetically or pharmaceutically acceptable adjuvant.
7. The cosmetic or pharmaceutical composition according to claim 6, wherein the adjuvant is selected from the group consisting of: analgesic, agent that inhibits PAR-2 activity, collagen synthesis stimulator, agent that regulates PGC-1 alpha synthesis, agent that regulates PPARgamma activity, agent that increases or decreases triglyceride content of adipocytes, agent that stimulates or delays adipocyte differentiation, lipolytic or lipolysis-stimulating agent, lipolytic agent, adipogenic agent, inhibitor of acetylcholinergic receptor aggregation, agent that inhibits muscle contraction, anticholinergic agent, elastase inhibitor, matrix metalloproteinase inhibitor, melanin synthesis stimulating or inhibiting agent, whitening or decoloring agent, pigmentation-promoting agent, self-tanning agent, anti-aging agent, NO-synthase inhibitor, 5 alpha-reductase inhibitor, lysyl hydroxylase and/or prolyl hydroxylase inhibitor, antioxidant, radical scavenger and/or anti-atmospheric agent, active carbonyl scavenger anti-glycation agents, antihistamines, antivirals, antiparasitic agents, emulsifiers, emollients, organic solvents, liquid propellants, moisture retaining substances, alpha hydroxy acids, beta hydroxy acids, moisturizers, epidermohydrolases, vitamins, amino acids, proteins, pigments, dyes, biopolymers, gelling polymers, thickeners, surfactants, softeners, adhesives, preservatives, anti-wrinkle agents, agents capable of reducing or treating the lower eye bags, keratolytic agents, antifungal agents, bactericides, bacteriostats, agents that stimulate the synthesis of dermis or epidermis macromolecules and/or that inhibit or prevent their degradation, agents that stimulate elastin synthesis, agents that stimulate decorin synthesis, agents that stimulate laminin synthesis, agents that stimulate defensin synthesis, agents that stimulate cAMP synthesis, agents that stimulate HSP70 synthesis, an agent that stimulates hyaluronic acid synthesis, an agent that stimulates fibronectin synthesis, an agent that stimulates deacetylase synthesis, an agent that stimulates synthesis of lipid and stratum corneum components, ceramide, fatty acid, an agent that inhibits collagen degradation, an agent that inhibits elastin degradation, an agent that inhibits serine protease, an agent that stimulates fibroblast proliferation, an agent that stimulates keratinocyte proliferation, an agent that stimulates adipocyte proliferation, an agent that stimulates melanocyte proliferation, an agent that stimulates keratinocyte differentiation, an agent that inhibits acetylcholinesterase, a skin relaxant, an agent that stimulates glycosaminoglycan synthesis, an anti-hyperkeratosis agent, an acne lytic agent, an anti-psoriasis agent, an anti-rash agent, a DNA repair agent, a DNA protectant, a stabilizer, an antipruritic agent, an agent for treating and/or caring sensitive skin, a solidifying agent a tightening agent, a restructuring agent, an anti-stretch agent, an agent that modulates sebum production, an antiperspirant, an agent that stimulates healing, an agent that assists healing, an agent that stimulates re-epithelialization, an agent that assists re-epithelialization, a cytokine, a sedative, an anti-inflammatory agent, an anesthetic, an agent that acts on capillary circulation and/or microcirculation, an agent that stimulates angiogenesis, an agent that inhibits vascular permeability, an intravenous tension agent, an agent that acts on cellular metabolism, an agent for improving dermal-epidermal junction, an agent that induces hair growth, a hair growth inhibition or delay agent, a fragrance, a chelator, a plant extract, an essential oil, a marine extract, an agent derived from a biofermentation process, an inorganic salt, a cellular extract, a sunscreen, and an organic or inorganic photoprotectant that is effective against a and/or B uv light, or mixtures thereof.
8. Cosmetic or pharmaceutical composition according to claim 6 or 7, characterized in that the formulation of said cosmetic or pharmaceutical composition is selected from: cream, oil, balm, foam, lotion, gel, wipe, slurry, ointment, mousse, powder, stick, pen, spray, aerosol, capsule, tablet, granule, chewing gum, solution, suspension, emulsion, elixir, polysaccharide film, jelly, or gelatin.
9. The cosmetic or pharmaceutical composition according to claim 8, wherein the capsule comprises: soft capsule and hard capsule.
10. The cosmetic or pharmaceutical composition according to claim 9, wherein the capsule is a gelatin capsule.
11. The cosmetic or pharmaceutical composition according to claim 8, wherein the tablet comprises: sugar-coated tablets.
12. A cosmetically or pharmaceutically acceptable delivery system or slow release system comprising an effective amount of a peptide of formula (I) as claimed in any one of claims 1 to 5 or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a cosmetic or pharmaceutical composition as claimed in any one of claims 6 to 11;
The cosmetically or pharmaceutically acceptable delivery system or slow release system is selected from: liposomes, oleosomes, ethosomes, millimeter capsules, microcapsules, nanocapsules, nanostructured lipid carriers, sponges, cyclodextrins, lipid vesicles, micelles, millimeter spheres, microspheres, nanospheres, lipid spheres, microemulsions or nanoemulsions.
13. The cosmetically or pharmaceutically acceptable delivery system or slow release system of claim 12 wherein the cosmetically or pharmaceutically acceptable delivery system or slow release system is a liposome or microemulsion.
14. The cosmetically or pharmaceutically acceptable delivery system or slow release system of claim 13 wherein the microemulsion is a water-in-oil microemulsion having an internal structure of reverse micelles.
15. Use of a peptide of formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 6 to 11, or a pharmaceutically acceptable delivery system or slow release system according to any one of claims 12 to 14, for the preparation of a pharmaceutical composition for the treatment or care of dystonia caused by muscle contraction.
16. The use according to claim 15, wherein the dystonia is focal dystonia; such focal dystonias include, but are not limited to, facial spasms, torsional dystonias, cervical dystonias or torticollis, laryngeal dystonias or spasmodic dysphonia, oromandibular dystonia, limb dystonia, nocturnal molar, hemifacial spasms, tics, and/or strabismus.
17. The use according to claim 16, wherein the limb dystonia comprises writer's cramp, musician's cramp or foot dystonia.
18. The use according to claim 15, wherein the dystonia is segmental dystonia, multifocal dystonia or hemidystonia.
19. The use according to claim 18, wherein the segmental dystonia is meju syndrome.
20. The use according to claim 15, wherein the dystonia is dopamine-responsive dystonia.
21. Use of a peptide of formula (I) according to any one of claims 1 to 5, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a cosmetic or pharmaceutical composition according to any one of claims 6 to 11, or a cosmetically or pharmaceutically acceptable delivery system or slow release system according to any one of claims 12 to 14, for the preparation of a cosmetic or pharmaceutical composition for the treatment, prevention or repair of skin ageing, wherein the treatment, prevention or repair of skin ageing is reduction, prevention or treatment of facial wrinkles.
22. Use of a peptide of formula (I) according to any one of claims 1 to 5 or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a cosmetic or pharmaceutical composition according to any one of claims 6 to 11, or a cosmetically or pharmaceutically acceptable delivery system or slow release system according to any one of claims 12 to 14, for the preparation of a cosmetic or pharmaceutical composition for use in antioxidative.
23. Use of a peptide of formula (I) according to any one of claims 1 to 5 or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a cosmetic or pharmaceutical composition according to any one of claims 6 to 11, or a cosmetically or pharmaceutically acceptable delivery system or slow release system according to any one of claims 12 to 14, for the preparation of a cosmetic or pharmaceutical composition for delaying ageing.
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