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WO2024149215A1 - Peptide conçu, composition et utilisation de celui-ci - Google Patents

Peptide conçu, composition et utilisation de celui-ci Download PDF

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Publication number
WO2024149215A1
WO2024149215A1 PCT/CN2024/071249 CN2024071249W WO2024149215A1 WO 2024149215 A1 WO2024149215 A1 WO 2024149215A1 CN 2024071249 W CN2024071249 W CN 2024071249W WO 2024149215 A1 WO2024149215 A1 WO 2024149215A1
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WIPO (PCT)
Prior art keywords
agents
acceptable salt
acid
stimulate
tyr
Prior art date
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Ceased
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PCT/CN2024/071249
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English (en)
Chinese (zh)
Inventor
丁文锋
肖玉
赵文豪
孙新林
陈雪
观富宜
彭晏
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Shenzhen Winkey Technology Co Ltd
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Shenzhen Winkey Technology Co Ltd
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Publication of WO2024149215A1 publication Critical patent/WO2024149215A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/08—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using activating agents
    • 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
    • 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the technical field of medicine and cosmetics, in particular to a peptide having the effects of anti-oxidation, anti-aging and inhibiting muscle contraction, and a composition containing the peptide and the use thereof.
  • the skin is affected by aging or adverse external environmental stimuli.
  • the elastic fibers and collagen fibers in the dermis are weakened.
  • the body's nerve activity is excessive, which leads to repeated contraction of facial muscles and the formation of wrinkles or expression lines in specific areas, thus showing signs of aging such as sagging, decreased elasticity, and wrinkles.
  • uncontrolled oxygen free radicals also play an important role in the aging process of the skin. Under the influence of harmful stimuli, when reactive oxygen is overproduced or metabolic disorders occur and exceed the clearance capacity of the endogenous antioxidant defense system, it will also directly or indirectly cause cellular oxidative damage, thereby accelerating skin aging.
  • the human body contains a variety of endogenous antioxidant enzymes and low-molecular antioxidants, which can capture free radicals that harm the human body, so that the production and elimination of free radicals in the body are in a dynamic balance, so that the body is not harmed.
  • the activity of antioxidant enzymes such as superoxide dismutase in the human body decreases, and the ability to remove oxygen free radicals in the body decreases.
  • Excessive concentrations of oxygen free radicals act on nucleic acids, proteins, cell membranes, etc., causing irreversible damage, thereby leading to physiological disorders and even pathological changes in the body, and accelerating skin aging. Therefore, excessive oxygen free radicals in the body are a major threat to human aging.
  • the most obvious sign of human skin aging is the formation of facial wrinkles.
  • the receptors on the muscle fibers receive neurotransmitters released from the synaptic vesicles, it will cause muscle contraction. Frequent muscle contraction will lead to wrinkle formation. Therefore, inhibiting muscle contraction can improve wrinkles on the surface of the skin. Inhibiting muscle contraction can be achieved by inhibiting the release of acetylcholine or preventing acetylcholine from binding to its receptors. It is known that the Agrin-LRP4-MuSK signaling pathway mediates the clustering of acetylcholine receptors and plays a prominent role in establishing and maintaining the normal function of neuromuscular junctions.
  • Abnormalities in the Agrin-LRP4-MuSK signaling pathway interfere with the clustering of acetylcholine receptors, leading to disorders of the neuromuscular junction, thereby inhibiting muscle contraction. Therefore, interfering with acetylcholine clustering is of great significance in inhibiting muscle contraction, which can reduce the formation of wrinkles and delay skin aging.
  • the purpose of the present invention is to provide a peptide having antioxidant, anti-aging and muscle contraction inhibiting effects, and a cosmetic composition or pharmaceutical composition containing the peptide.
  • a cosmetic composition or pharmaceutical composition containing the peptide By interfering with the clustering of acetylcholine receptors, acetylcholine is prevented from binding to its receptors, thereby inhibiting muscle contraction, improving wrinkles on the skin surface, reducing wrinkle depth, and achieving wrinkle removal effects.
  • the peptide can be used in the field of cosmetics or medicine to treat, prevent or repair skin aging or photoaging, and treat or care for conditions, disorders or diseases caused by muscle contraction; it also has an antioxidant effect and can delay aging.
  • the present invention provides a peptide represented by formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, R 1 -Glu-Asp-Tyr-Tyr-Arg-Nle-R 2 (I)
  • R 1 is selected from: H, or R 3 -CO-, wherein R 3 is selected from: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl;
  • R 2 is selected from: -NR 4 R 5 or -OR 4 , wherein each R 4 and R 5 are independently selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl;
  • the alkyl group refers to a saturated aliphatic straight or branched chain 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); and may be 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 2-24 carbon atoms (optionally having 2-16 carbon atoms; optionally having 2-14 carbon atoms; optionally having 2-12 carbon atoms; optionally having 2, 3, 4, 5, or 6 carbon atoms); the alkenyl group has one or more carbon-carbon double bonds, optionally having 1, 2 or 3 conjugated or non-conjugated carbon-carbon double bonds; the alkenyl group is bonded to the rest of the molecule through a single bond; and can be selected from: vinyl, oleyl, or linoleyl;
  • R 1 is selected from: H, acetyl, tert-butyryl, hexanoyl, 2-methylhexanoyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl or linoleoyl;
  • R 4 and R 5 are independently selected from: H, methyl, ethyl, hexyl, dodecyl or hexadecyl;
  • R 1 is selected from H, acetyl, lauroyl, myristoyl or palmitoyl;
  • R 4 is H and R 5 is selected from: H, methyl, ethyl, hexyl, dodecyl or hexadecyl;
  • R 1 is H or acetyl
  • R 2 is -OH or -NH 2 .
  • the peptide represented by formula (I), or its stereoisomer, or its mixture of stereoisomers, or its cosmetically acceptable salt, or its pharmaceutically acceptable salt is selected from the following peptides (1)-(8):
  • the peptides of formula (I) of the present invention may exist as stereoisomers or mixtures of stereoisomers; for example, the amino acids contained therein may have L-, D-configurations, or may be racemic independently of one another. 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 a pure isomer, i.e., an enantiomer or a diastereomer.
  • -Glu- is selected from -L-Glu-, -D-Glu-, or a mixture of the two, and is racemic or non-racemic.
  • the preparation method described in this document enables a person of ordinary skill in the art to obtain each stereoisomer of the peptide of the present invention by selecting amino acids with the correct configuration.
  • the present invention also includes all suitable isotopic variants of the peptides shown in formula (I).
  • Isotopic variants of these peptides of the present invention are understood here to mean compounds in which at least one atom in the peptide of the present invention is replaced by another atom of the same atomic number, but the atomic mass of the other atom is different from the atomic mass usually or mainly present in nature.
  • isotopes that can be incorporated into the peptides of the present invention are those of hydrogen, carbon, nitrogen or oxygen, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 O or 18 O.
  • isotopic variants of the peptides of the present invention may be useful, for example, for examining the mechanism of action or the distribution of the active compound in vivo; compounds labeled with 3 H or 14 C isotopes are particularly suitable for this purpose due to their relatively simple preparability and detectability.
  • an isotope e.g., deuterium
  • Isotopic variants of the peptides of the present invention can be prepared by methods known to those skilled in the art, such as by the methods further described below and in the examples, by using the respective isotopic modifications of the reagents and/or starting materials.
  • the present invention also includes prodrugs of the peptides of the present invention.
  • prodrug herein means such compounds: which themselves may be biologically active or inactive, but during their residence time in the body, they react (e.g., metabolize or hydrolyze) to generate the peptides of the present invention.
  • cosmetically acceptable salt or pharmaceutically acceptable salt refers to a salt approved for use in animals, and more specifically in humans, including metal salts of the peptide shown in formula (I), the metal including, but not limited to: lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc or aluminum, etc.; including salts formed by the peptide shown in formula (I) and organic bases, the organic bases including, but not limited to: ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine or piperazine, etc.; including salts formed by the peptide shown in formula (I) and inorganic acids or organic acids, the 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
  • the synthesis of the peptide represented by formula (I) of the present invention, or its stereoisomers or its cosmetically acceptable salts, or its pharmaceutically acceptable salts can be carried out according to conventional methods known in the prior art, such as solid phase synthesis, liquid phase synthesis or a combination of solid phase and liquid phase, and can also be prepared by biotechnological methods aimed at producing the desired sequence, or by controlled hydrolysis of proteins having animal, fungal, or plant origin.
  • a method for obtaining a peptide represented by formula (I) comprises the following steps:
  • the C-terminus is bound to a solid support and the method is carried out 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 polymer support; eliminating the group protecting the N-terminus; and repeating this sequence as many times as required in order to thereby obtain a peptide of the desired length, followed by cleavage of the synthesized peptide from the initial polymer support.
  • the functional groups of the amino acid side chains remain fully protected with temporary or permanent protecting groups throughout the synthesis and can be deprotected simultaneously or orthogonally to the process of cleavage of the peptide from the polymer support.
  • solid phase synthesis can be performed by a convergent strategy of coupling the dipeptide or tripeptide to a polymer support or to a dipeptide or amino acid previously bound to a polymer support.
  • the functional groups at the terminals may be modified by deprotecting the N-terminus and C-terminus and/or cleaving the peptide from the polymer support in an undefined order using standard conditions and methods known in the art.
  • the optional modification of the N-terminus and C-terminus may be performed on the peptide of formula (I) bound to the polymer support, or after the peptide has been cleaved from the polymer support.
  • Another aspect of the present invention provides a cosmetic or pharmaceutical composition, comprising an effective amount of the peptide represented by the above formula (I), or its stereoisomer, or a mixture of its stereoisomers, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and at least one excipient and optionally a cosmetically or pharmaceutically acceptable adjuvant.
  • the adjuvant is selected from: an agent that inhibits acetylcholine receptor clustering, other agents that inhibit TRPV1 activity, analgesics, agents that inhibit PAR-2 activity, collagen synthesis stimulators, agents that regulate PGC-1 ⁇ synthesis, agents that regulate PPAR ⁇ activity, agents that increase or decrease the triglyceride content of adipocytes, agents that stimulate or delay adipocyte differentiation, lipolytic agents or agents that stimulate lipolysis, 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 agents or depigmenting agents, pigmentation promoting agents, self-tanning agents, anti-aging agents, NO-synthase inhibitors, 5 ⁇ -reductase inhibitors, inhibitors of lysyl hydroxylase and/or prolyl
  • agents free radical scavengers and/or anti-atmospheric pollution agents, active carbonyl scavengers, anti-glycation agents, antihistamines, antivirals, antiparasitic agents, emulsifiers, emollients, organic solvents, liquid propellants, skin conditioning agents, moisture retaining substances, alpha hydroxy acids, beta hydroxy acids, moisturizers, epidermal hydrolases, vitamins, amino acids, proteins, pigments, dyes, biopolymers, gelling polymers, thickeners, surfactants, softeners, adhesives, preservatives, anti-wrinkle agents, agents capable of reducing or treating bags under the eyes, keratolytic agents, antimicrobial agents, antifungal agents, antifungal agents, bactericidal agents, antibacterial agents, agents that stimulate the synthesis of dermal or epidermal macromolecules and/or can inhibit or prevent their degradation, agents that stimulate elastin synthesis, agents that stimulate decorin synthesis, agents that stimulate
  • the formulation of the cosmetic or pharmaceutical composition is selected from the group consisting of: cream, oil, balm, foam, lotion, gel, liniment, slurry, ointment, mousse, powder, stick, pen, spray, aerosol, capsule, tablet, granule, chewing gum, solution, suspension, emulsion, elixir, polysaccharide film, jelly or gelatin;
  • the capsule includes: a soft capsule, a hard capsule, and optionally a gelatin capsule;
  • the tablet includes: a sugar-coated tablet.
  • the peptides of the present invention have variable solubility in water, depending on the nature of their sequence or any possible modifications at the N-terminus and/or C-terminus.
  • the peptides of the present invention can therefore be incorporated into the composition via an aqueous solution, and those that are insoluble in water can 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, and their dosage, will depend on many factors, including the age, condition of the patient, severity of the disorder or disease, route and frequency of administration, and the specific nature of the peptide to be used.
  • Cosmetically or pharmaceutically effective amount means a non-toxic but sufficient amount of one or more peptides of the present invention to provide the desired effect.
  • the peptides of the present invention are used in cosmetic or pharmaceutical compositions of the present invention at cosmetically or pharmaceutically effective concentrations to obtain the desired effect; in a preferred form, between 0.00000001% (by weight) and 20% (by weight), preferably between 0.000001% (by weight) and 15% (by weight), more preferably between 0.0001% (by weight) and 10% (by weight), and even more preferably between 0.0001% (by weight) and 5% (by weight), relative to the total weight of the composition.
  • Another aspect of the present invention provides a cosmetically or pharmaceutically acceptable delivery system or sustained-release system to achieve better penetration of the active ingredient and/or improve its pharmacokinetic and pharmacodynamic properties, which comprises an effective amount of the peptide represented by the above formula (I), or its stereoisomers, or a mixture of stereoisomers, or its cosmetically acceptable salt, or its pharmaceutically acceptable salt, or the above cosmetic or pharmaceutical composition.
  • delivery system refers to a diluent, adjuvant, excipient or carrier used together with the peptide of the present invention, which is selected from: water, oil or surfactant, including those of petroleum origin, animal origin, plant origin, or synthetic origin, such as and not limited to peanut oil, soybean oil, mineral oil, sesame oil, castor oil, polysorbate, sorbitan ester, ether sulfate, sulfate, betaine, glucosides, maltosides, fatty alcohols, nonoxynol ether, poloxamer, polyoxyethylene, polyethylene glycol, dextrose, glycerol, digitonin and the like.
  • a diluent, adjuvant, excipient or carrier used together with the peptide of the present invention, which is selected from: water, oil or surfactant, including those of petroleum origin, animal origin, plant origin, or synthetic origin, such as and not limited to peanut oil, soybean oil, mineral oil, sesame oil, castor
  • sustained release is used in its conventional sense to refer to a delivery system that provides for gradual release of a compound over a period of time, and preferably, but not necessarily, with a relatively constant level of compound released over the entire period of time.
  • Examples of delivery systems or sustained release systems are liposomes, oleosomes, nonionic surfactant liposome vesicles, ethosomes, millicapsules, microcapsules, nanocapsules, nanostructured lipid carriers, sponges, cyclodextrins, lipid vesicles, micelles, millispheres, microspheres, nanospheres, lipid spheres, microemulsions, nanoemulsions, milliparticles, microparticles or nanoparticles.
  • Preferred delivery systems or sustained release systems are liposomes and microemulsions, more preferably water-in-oil microemulsions with an internal structure of reverse micelles.
  • Sustained release system can be prepared by methods known in the prior art, and can be given, for example, in the following manner: by topical or transdermal administration, including adhesive patch, non-adhesive patch, closure patch, and microelectronic patch; or by systemic administration, for example and not limited to, oral or parenteral route, including nose, rectum, subcutaneous implantation or injection or directly implanted or injected into a specific body part, and preferably these peptides of the present invention of a relatively constant amount should be released.
  • topical or transdermal administration including adhesive patch, non-adhesive patch, closure patch, and microelectronic patch
  • systemic administration for example and not limited to, oral or parenteral route, including nose, rectum, subcutaneous implantation or injection or directly implanted or injected into a specific body part, and preferably these peptides of the present invention of a relatively constant amount should be released.
  • the amount of the peptide included in the sustained release system will depend on the release kinetics and duration of the position, peptide of the present invention, and the condition to be treated and/or the property of nursing, illness and/or disease, at which the composition will be given, for example.
  • Another aspect of the present invention provides a use of the peptide represented by formula (I) above, or its stereoisomer, or a mixture of its stereoisomers, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or the cosmetic or pharmaceutical composition above, or the cosmetically or pharmaceutically acceptable delivery system or sustained-release system above in the preparation of a cosmetic composition or pharmaceutical composition for treating or caring for a condition, disorder or disease caused by muscle contraction;
  • the disorder or disease is dystonia
  • the dystonia is focal dystonia; the dystonia includes, but is not limited to, facial spasm, torsion dystonia, cervical dystonia or torticollis, laryngeal dystonia or spasmodic dysphonia, oromandibular dystonia, limb dystonia such as writer's cramp or musician's cramp or foot dystonia, nocturnal bruxism, hemifacial spasm, tics and/or strabismus, segmental dystonia, Meige's syndrome, multifocal dystonia, hemidystonia, dopamine-responsive dystonia and Sekawa dystonia.
  • Another aspect of the present invention provides a use of the peptide represented by the above formula (I), or its stereoisomer, or a mixture of its stereoisomers, or a cosmetically acceptable salt, or a pharmaceutically acceptable salt, or the above cosmetic or pharmaceutical composition, or the above cosmetically or pharmaceutically acceptable delivery system or sustained-release system in the preparation of a cosmetic composition or pharmaceutical composition for treating, preventing or repairing skin aging or photoaging, wherein the treatment, prevention or repair of skin aging or photoaging is the reduction, prevention or treatment of facial wrinkles.
  • Another aspect of the present invention provides a peptide represented by the above formula (I), or its stereoisomer, or a mixture of its stereoisomers, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or the above cosmetic or pharmaceutical composition, or the above cosmetically or pharmaceutically acceptable delivery system or sustained-release system in the preparation of an antioxidant cosmetic composition or pharmaceutical composition.
  • Another aspect of the present invention provides a peptide represented by the above formula (I), or its stereoisomer, or a mixture of its stereoisomers, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or the above cosmetic or pharmaceutical composition, or the above cosmetically or pharmaceutically acceptable delivery system or sustained-release system in the preparation of a cosmetic composition or pharmaceutical composition for delaying aging.
  • the term “skin” is understood to mean the multiple layers that make it up, from the uppermost layer or stratum corneum to the lowermost layer or subcutaneous tissue, both ends are included. These layers are composed of different types of cells, such as keratinocytes, fibroblasts, melanocytes, and/or adipocytes, etc. In the present invention, the term “skin” includes the scalp.
  • treatment refers to administering a peptide according to the invention to alleviate or eliminate a disease or condition, or to reduce or eliminate one or more symptoms associated with the disease or condition.
  • treatment also encompasses the ability to alleviate or eliminate the physiological consequences of the disease or condition.
  • the term "care” includes the prevention of diseases and/or conditions.
  • prevent refers to the ability of the peptides of the present invention to prevent, delay, or hinder the onset or development of a disease or condition before it occurs.
  • repair refers to the ability of the peptides of the present invention to improve, alleviate or restore a disease or condition to its original state after it occurs.
  • aging refers to the changes that the skin undergoes with age (natural aging) or through exposure to sunlight (photoaging) or to environmental pollutants, such as chemical dirt or pollutants, tobacco smoke, etc., and includes all changes that are outwardly visible and/or perceptible by touch, such as and not limited to: the development of discontinuities in the skin (such as wrinkles, fine lines, expression lines, stretch lines, stripes, grooves, unevenness or roughness, increase in pore size, loss of moisture, loss of elasticity, loss of firmness, loss of smoothness, loss of deformation recovery ability, loss of resilience), sagging of the skin (such as sagging cheeks, bags under the eyes, or the appearance of a double chin, etc.), changes in skin color (such as scarring, redness, bags under the eyes, or the appearance of areas of hyperpigmentation such as age spots or freckles, etc.), abnormal differentiation, hyperkeratinization, elastosis, keratosis, hair loss, orange peel skin, loss of collagen structure, and
  • photoaging refers to the premature aging of the skin due to long-term exposure to ultraviolet radiation, which presents the same physiological characteristics as natural aging, such as but not limited to: loosening, sagging, color changes or irregular pigmentation, abnormalities and/or excessive keratinization.
  • Glu represents NH2 - CH ( CH2CH2COOH )-COOH
  • Glu- represents NH2 - CH( CH2CH2COOH )-CO-
  • -Glu represents -NH-CH( CH2CH2COOH ) -COOH
  • -Glu- represents -NH-CH( CH2CH2COOH )-CO-.
  • the hyphen representing a peptide bond eliminates the OH from the 1-carboxyl group of an amino acid (represented here in conventional non-ionized form) when located on the right side of the symbol, and eliminates the H from the 2 -amino group of an amino acid when located on the left side of the symbol; both modifications can be applied to the same symbol (see Table 1).
  • the peptide of the present invention is obtained through artificial design, is easy to synthesize, and is safe and non-irritating to the human body.
  • the peptide of the present invention can inhibit muscle contraction, improve wrinkles on the skin surface, reduce wrinkle depth, and achieve wrinkle removal effect. It can be used in the cosmetics or medical fields to treat, prevent or repair skin aging or photoaging, and treat or care for conditions, disorders or diseases caused by muscle contraction.
  • the peptide of the present invention has an antioxidant effect, can reduce the damage of free radicals to the body, thereby delaying aging, has anti-aging effects, and can be applied to the fields of cosmetics, medicine, etc.
  • Figure 1 is a mass spectrum of peptide (4) Ac-Glu-Asp-Tyr-Tyr-Arg- Nle - NH2 (molecular formula C41H58N10O13 ), the mass-to-charge ratio (m/ z ) of the [M+H] + quasi-molecular ion peak is 899.5229, and the molecular weight measured by mass spectrometry is 898.52.
  • FIG. 2 is a graph showing the effect of the test sample on muscle contraction.
  • FIG. 3 is a graph showing the effects of the test samples on the locomotor behavior of nematodes.
  • Amide Resin A starting resin for peptide synthesis (cross-linking degree 1%, substitution degree 1.72mmol/g, particle size 100-200 mesh);
  • Fmoc-Linker 4-[(2,4-dimethoxyphenyl)(Fmoc-amino)methyl]phenoxyacetic acid; 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:
  • the activated Fmoc-Linker was added to the swollen resin and reacted for 2.5 h. The reaction solution was removed, the resin was washed, and the solvent was removed.
  • Fmoc-Linker-Amide Resin was de-Fmoced twice with 20% piperidine/DMF, each time for 10 min, and the sample was taken for K test, which showed dark blue color. The resin was washed with DMF 7 times and the solvent was removed.
  • the N-terminal Fmoc group was deprotected and 10.0 g of activated Fmoc-Arg(Pbf)-OH was coupled to the peptidyl resin in the presence of 3.71 g HOBt and 2.892 g DIC using DMF as solvent for 2 h. The resins were then washed and the deprotection of the Fmoc group was repeated for the next amino acid coupling.
  • the N-terminal Fmoc group of the peptidyl resin was deprotected by using 20% piperidine/DMF for two times, each time for 10 min, and the sample was taken for K test, and the color was dark blue. The resin was washed with DMF for 6 times, and the solvent was removed.
  • the filtered sample was injected for purification, and the fractions were collected, concentrated and lyophilized to obtain peptide (4) Ac-Glu-Asp-Tyr-Tyr-Arg-Nle-NH 2 with a purity of 98.5%.
  • the molecular weights of the peptides obtained were determined by ESI-MS.
  • the test results of peptide (4) are shown in FIG1 .
  • the mass spectrometry result was 898.52.
  • HW-400S constant temperature smooth muscle tank HW-400S constant temperature smooth muscle tank, BL-420E biofunction experimental system, tension transducer, and other instruments are conventional experimental instruments.
  • Acetylcholine, chloral hydrate Acetylcholine, chloral hydrate.
  • Acetyl hexapeptide-30 (Ac-Glu-Asp-Tyr-Tyr-Arg-Leu-NH 2 ), tested at concentrations of 100 ppm and 200 ppm;
  • Peptide (4) tested at concentrations of 100 ppm and 200 ppm.
  • the purpose of this experiment is to use rat ileal smooth muscle as the experimental subject, observe the effect of the test sample on the rhythm of the ileal smooth muscle after acetylcholine stimulation, evaluate the effect of the test sample on muscle contraction, and thus determine whether the peptide of the present invention can inhibit muscle contraction.
  • the experimental rats were fasted but not watered for 12 hours before the experiment. 10% chloral hydrate was injected intraperitoneally at a dose of 0.1mL/25g. After the rats were anesthetized, the abdominal cavity was cut open to expose the enlarged cecum. A section of ileum was taken out from the ileocecal intestine and washed in benchtop solution that had been oxygenated for 10 minutes. Several 4cm long sections of ileum were cut and incubated in benchtop solution at 4°C for later use; the two ends of the ileum were partially ligated with cotton thread and tied to form a ring.
  • HW-400S constant temperature smooth muscle tank and BL-420E biofunction experimental system connect the tension transducer to channel 1, adjust the incubation temperature to 37°C, preheat the instrument for 0.5h, and ventilate for more than 10min. Fix one end of the intestinal segment to the inlet bracket with cotton thread, and connect the other end to the tension transducer. Adjust the position and height of the transducer appropriately, place the isolated intestinal segment in the center of the smooth muscle tank, and start recording intestinal activity.
  • acetylcholine at a final concentration of 0.1-0.4 ⁇ g/mL until the muscle activity shows a high and stable waveform, and act for 5 minutes as the initial control; after 5 minutes of equilibrium, add the samples to be tested.
  • acetylcholine at a final concentration of 0.1-0.4 ⁇ g/mL until the muscle activity shows a high and stable waveform, and act for 5 minutes as the initial control; after 5 minutes of equilibrium, add the samples to be tested.
  • acetylcholine at a final concentration of 0.1-0.4 ⁇ g/mL until the muscle activity shows a high and stable waveform, and act for 5 minutes as the initial control; after 5 minutes of equilibrium, add the samples to be tested.
  • a test drug is changed, a new ileum segment is replaced, and the instrument records the relevant data, and the ileum smooth muscle contraction inhibition rate is calculated according to the following formula.
  • Ileal smooth muscle contraction inhibition rate (contractile force after acetylcholine administration - contractile force after test sample administration) / contractile force after acetylcholine administration ⁇ 100%
  • Skin muscle relaxation is an important manifestation of aging, and inhibiting the contraction of facial expression muscles can improve wrinkles.
  • Acetylcholine as a neurotransmitter, can directly excite the acetylcholine receptors of the postsynaptic membrane, triggering a signal cascade reaction and causing muscle contraction.
  • Muscle contraction can be inhibited by inhibiting the release of acetylcholine from the presynaptic membrane or preventing acetylcholine from binding to its receptor.
  • the peptide of the present invention inhibits muscle contraction by inhibiting the binding of acetylcholine to its receptor.
  • Table 2 and Figure 2 The results of the ileum smooth muscle contraction inhibition rate of the test sample are shown in Table 2 and Figure 2 below.
  • the peptide of the present invention has a significant effect of inhibiting muscle contraction, can improve wrinkles on the skin surface, reduce the depth of wrinkles, and achieve the effect of removing wrinkles. Therefore, it can be used to treat or care for conditions, disorders or diseases caused by muscle contraction, treat, prevent or repair skin aging or photoaging, and can also be used in products that reduce, prevent or treat wrinkles.
  • Peptone NaCl, CaCl 2 , MgSO 4 ⁇ 7H 2 O, KH 2 PO 4 , cholesterol, agar powder, potassium hydroxide, sodium hydroxide, ethanol, double distilled water.
  • OP50 bacteria and Caenorhabditis elegans were purchased from Shanghai Yuanye Biotechnology Co., Ltd.
  • Acetyl hexapeptide-30 (Ac-Glu-Asp-Tyr-Tyr-Arg-Leu-NH 2 ), tested at concentrations of 50 ppm and 100 ppm;
  • Peptide (4) was tested at concentrations of 50 ppm and 100 ppm.
  • Control group no sample was added.
  • the purpose of this experiment is to evaluate whether the test sample has an antioxidant effect by using Caenorhabditis elegans as the experimental subject, administering the test sample to observe the effect of the test sample on the head swing frequency of Caenorhabditis elegans, and thereby determine whether the peptide of the present invention can exert an anti-aging effect.
  • LB liquid culture medium Accurately weigh 5 g of tryptone, 2.5 g of yeast powder, and 5 g of sodium chloride, add 500 mL of double distilled water to fully dissolve, then add appropriate amount of NaOH to adjust the pH to about 7.4 and set aside.
  • NGM medium Accurately weigh 1.25 g of tryptone, 1.5 g of sodium chloride, 0.05 g of CaCl 2 , 0.123 g of MgSO 4 ⁇ 7H 2 O, 3.5 g of KH 2 PO 4 , 0.0025 g of cholesterol, 0.5 mL of ethanol, and 8.5 g of agar, and dissolve them in 500 mL of double distilled water. After they are completely dissolved, add an appropriate amount of KOH to adjust the pH to about 7.0 and set aside.
  • the NGM medium that had been coated and grouped was placed in a 37°C biochemical incubator for 12 hours, and then the medium was taken out, and 10 Caenorhabditis elegans were added to the treatment group and the control group, respectively. After 24 hours, the nematodes were placed under a microscope to observe the state of the Caenorhabditis elegans and the head swing frequency of the nematodes in different groups was counted for 1 minute, where each left and right head swing was counted as one time.
  • Aging is a complex process in which various organ systems of the body gradually decline and become diseased, and it is also the leading factor in many neurodegenerative diseases.
  • Caenorhabditis elegans has a short life cycle and a clear genetic background. Its aging-related regulatory genes are highly conserved with those of humans, and its head swing is closely related to aging. As Caenorhabditis elegans gradually ages, a large amount of oxygen free radicals accumulate in its body. Excessive oxygen free radicals will cause the basic functions of the nervous system of Caenorhabditis elegans to decline, thereby affecting its motor behavior ability.
  • the head swing frequency can reflect the motor behavior ability of nematodes, and motor behavior ability can be used as an indicator to measure the basic functions of the nervous system. Therefore, the head swing frequency of Caenorhabditis elegans can reflect its body condition and degree of aging. As the aging process intensifies, its head swing frequency will gradually decrease. Therefore, counting the head swing frequency of nematodes after administration can reflect the antioxidant protection of the test sample on nematodes, and then judge the antioxidant capacity and anti-aging efficacy of the corresponding test sample.
  • the peptide of the present invention has an antioxidant effect, can delay aging, shows excellent anti-aging effect, and can be applied to the fields of cosmetics, medicine, etc.
  • Preparation method Stir and heat purified water to 85°C and keep warm for 30 minutes; pre-dissolve sodium hyaluronate and xanthan gum in butylene glycol, add to water, and stir to dissolve completely; stir and cool to 35°C, add remaining ingredients, and stir evenly.
  • Preparation method dissolve the peptide (4) in water to obtain a polypeptide solution; heat cetearyl alcohol (and) cetearyl glucoside, jojoba oil, mineral oil, and isopropyl palmitate to 85°C and stir evenly to obtain phase A; dissolve glycerol, allantoin, polyacrylamide (and) C13-14 isoparaffin (and) laureth-7 in water and heat to 85°C to obtain phase B; quickly add phase A to phase B, homogenize at a constant temperature for 3-5 minutes, and cool; add a preservative when cooled to below 60°C and stir evenly, add the polypeptide solution and flavor when cooled to below 45°C and stir evenly to obtain the product.
  • Preparation method dissolve allantoin and glycerin in water, heat to 85°C, and keep warm for 30 minutes; dissolve PEG-7 glyceryl cocoate and peptide (4) in water; mix the above solutions after cooling, stir evenly to obtain a mixed solution; add propylene glycol, preservatives, and flavors to the above mixed solution in sequence, add water and stir evenly to obtain the mixed solution.

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Abstract

L'invention concerne un peptide de formule (I) R1-Glu-Asp-Tyr-Tyr-Arg-Nle-R2, ou un stéréoisomère du peptide, ou un mélange du stéréoisomère du peptide, ou un sel du peptide, ou une composition de celui-ci, et son utilisation dans la préparation d'une composition pour l'antioxydation, le retardement du vieillissement, le traitement ou le soin d'affections, de troubles ou de maladies provoqués par la contraction musculaire, et le traitement, la prévention ou la réparation du vieillissement ou du photovieillissement de la peau.
PCT/CN2024/071249 2023-01-10 2024-01-09 Peptide conçu, composition et utilisation de celui-ci Ceased WO2024149215A1 (fr)

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