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WO2018147516A1 - Composition de prévention ou de traitement de maladies osseuses comprenant comme principe actif un peptide dérivé de la protéine de moule - Google Patents

Composition de prévention ou de traitement de maladies osseuses comprenant comme principe actif un peptide dérivé de la protéine de moule Download PDF

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Publication number
WO2018147516A1
WO2018147516A1 PCT/KR2017/008035 KR2017008035W WO2018147516A1 WO 2018147516 A1 WO2018147516 A1 WO 2018147516A1 KR 2017008035 W KR2017008035 W KR 2017008035W WO 2018147516 A1 WO2018147516 A1 WO 2018147516A1
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Prior art keywords
peptide
bone
composition
peptides
piisvywk
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Ceased
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PCT/KR2017/008035
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English (en)
Korean (ko)
Inventor
제재영
형준호
오윤옥
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Pukyong National University
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Pukyong National University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0643—Osteoclasts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/998—Proteins not provided for elsewhere

Definitions

  • the present invention relates to a composition for preventing or treating bone diseases comprising mussel protein-derived peptide as an active ingredient.
  • Osteoporosis is postmenopausal osteoporosis, which is indicated by increased bone resorption due to the activation of osteoclasts due to rapid hormonal changes following menopause, and senile osteoporosis, in which osteoblasts decrease due to aging and osteoblasts decrease. Can be classified as Since osteoporosis fractures lead to severe activity limitations and are associated with a high mortality rate of about 15-35% in hip fractures, the diagnosis and treatment of osteoporosis is important before osteoporotic fractures occur (osteoporosis diagnosis). And Treatment Guidelines 2007, 2008).
  • osteoporosis treatments include bisphosphonate-based drugs, which are deposited on the mineral component of the bone and form an ATP analog that does not hydrolyze when osteoclasts phage on the bone where the bisphosphonate is deposited. It is known to reduce the bone resorption and thereby increase the bone density by causing toxicity to cells or causing osteoclast activity and apoptosis in various ways in osteoclasts. These drugs are known to be relatively safe, but in recent years, their long-term use affects bone remodeling or bone regeneration after bone fracture due to normal bone resorption and bone formation. Concerns have been raised about the impact, and in fact, there are reports of fatigue fractures in many patients. Therefore, there is an urgent need for the discovery of new mechanisms of bone metabolism associated with the development of osteoporosis and the need for development of preventive or therapeutic agents for osteoporosis.
  • An object of the present invention to provide a peptide for promoting bone formation comprising SEQ ID NO: 1 (PIISVYWK) or SEQ ID NO: 2 (FSVVPSPK).
  • Another object of the present invention to provide a composition for the prevention or treatment of bone diseases comprising the peptide.
  • Another object of the present invention to provide a composition for promoting osteoblast differentiation comprising the peptide.
  • the present invention provides a peptide for promoting bone formation, including SEQ ID NO: 1 (PIISVYWK) or SEQ ID NO: 2 (FSVVPSPK).
  • the peptide may be derived from mussel protein.
  • the peptide may be to promote differentiation of osteoblasts.
  • the present invention also provides a composition for the prevention or treatment of bone diseases comprising the peptide.
  • the bone disease may be any one selected from the group consisting of osteoporosis, osteoarthritis, rheumatoid arthritis, osteomalacia, rickets, fibrous osteoarthritis, aplastic bone disease and metabolic bone disease.
  • composition for promoting osteoblast differentiation comprising the peptide.
  • Peptide according to the present invention is a peptide for promoting bone formation comprising SEQ ID NO: 1 (PIISVYWK) or SEQ ID NO: 2 (FSVVPSPK), the peptide has an effect of promoting the differentiation of osteoblasts can be useful for the treatment of bone diseases Can be.
  • Figure 1 shows the results of measuring the ALP activity after the treatment of the PIISVYWK and FSVVPSPK peptide ( a, b p ⁇ 0.05).
  • Figure 2 shows the results confirmed by Western blotting whether the protein expression involved in osteoblast differentiation after treatment with PIISVYWK and FSVVPSPK peptide.
  • Figure 3 shows the results confirmed by Western blotting whether the expression of MAPKs involved in osteoblast differentiation after treatment with PIISVYWK and FSVVPSPK peptide.
  • Figure 4 shows the results of confirming whether the mineral formation of osteoblasts after treatment with the PIISVYWK and FSVVPSPK peptide ( ac p ⁇ 0.05).
  • Figure 5 shows the results of activation of the BMP signaling pathway with or without the treatment of PIISVYWK and FSVVPSPK peptide and BMP antagonist.
  • Figure 6 shows the results of activation of the MAPKs signaling pathway with or without the treatment of PIISVYWK and FSVVPSPK peptide and BMP antagonist.
  • Figure 7 shows the results of activation of the BMP signaling pathway after treatment with PIISVYWK and FSVVPSPK peptides and MAPKs inhibitors.
  • Figure 8 shows the results of ALP activity after treatment with PIISVYWK and FSVVPSPK peptides and MAPKs inhibitors.
  • FIG. 9 is a graph showing the quantification of the change in bone mineral density by micro CT after the PIISVYWK (P1), FSVVPSPK (P2) peptide, and estrogen (17 ⁇ -estradiol) were administered to the osteoporosis model.
  • P1 PIISVYWK
  • FSVVPSPK P2
  • estrogen 17 ⁇ -estradiol
  • bone formation of the present invention refers to the formation of bone tissue by the deposition of lime salt on the bone tissue.
  • osteoblast is a cell having the ability to calcify bone tissue by synthesizing and secreting bone matrix and depositing inorganic salts such as calcium and magnesium ions on a substrate. It can be seen at the site of the neonatal.
  • bone formation in the advanced state is a cell that is buried in the bone tissue formed by itself become bone cells.
  • prevention means any action that inhibits or delays the development of a bone disease by the administration of the pharmaceutical composition of the present invention. Any action that improves or beneficially changes symptoms.
  • the route of administration of the pharmaceutical composition of the present invention may be administered via any general route as long as it can reach the target tissue (such as a bone defect site) or cell.
  • the pharmaceutical composition of the present invention may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, orally, pulmonary, rectally, intracellularly or indirectly, as desired.
  • the pharmaceutical compositions of the present invention may be administered by any device in which the active substance may migrate to the target cell.
  • the pharmaceutical composition of the present invention may comprise an acceptable carrier.
  • the pharmaceutical composition comprising a pharmaceutically acceptable carrier may be in various oral or parenteral formulations. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used. Solid form preparations for oral administration include tablet pills, powders, granules, capsules, and the like, which form at least one excipient such as starch, calcium carbonate, sucrose or lactose in one or more compounds. ) And gelatin.
  • Liquid preparations for oral administration include suspensions, solution solutions, emulsions, and syrups, and various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be included.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • the pharmaceutical composition of the present invention is selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, liquid solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations and suppositories. It can have either formulation.
  • the pharmaceutical composition of the present invention is administered in a therapeutically effective amount or in a pharmaceutically effective amount.
  • therapeutically effective amount or pharmacologically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, with an effective dose level representing the type of subject and its severity, age, sex, activity of the drug , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of the drug, and other factors well known in the medical arts.
  • the present invention provides a method for treating bone disease, comprising administering to a subject a pharmaceutically effective amount of said bone formation promoting peptide, or a composition comprising said peptide.
  • the present invention also provides a method for preventing bone disease, comprising administering to a subject a pharmaceutically effective amount of the bone formation promoting peptide, or a composition comprising the peptide.
  • the peptide or composition may be administered orally or parenterally when administered, and may be used in the form of a general pharmaceutical preparation. That is, the composition of the present invention may be administered in various oral and parenteral dosage forms in actual clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants that are commonly used. Is prepared using. Solid preparations for oral administration include tablets, pills, powders, granules and capsules, and the like, which may be used in the pharmaceutical composition of the present invention at least one excipient such as starch, calcium carbonate, sucrose, lactose And gelatin etc. are mixed and prepared.
  • Liquid preparations for oral administration include suspensions, solutions, emulsions and syrups, and may include various excipients such as wetting agents, sweeteners, fragrances and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol and gelatin may be used.
  • the compositions of the present invention may be via subcutaneous injection, intravenous injection or intramuscular injection during parenteral administration.
  • Dosage units may contain, for example, one, two, three or four times the individual dosage, or they may contain 1/2, 1/3 or 1/4 times.
  • the individual dosage preferably contains an amount in which the effective drug is administered at one time, which usually corresponds to all, 1/2, 1/3 or 1/4 times the daily dose.
  • the effective dose of the composition of the present invention is 0.0001 to 10 g / kg, preferably 0.0001 g to 5 g / kg, may be administered 1 to 6 times a day.
  • the subject may be a mammal, for example a human.
  • the method may be used alone or in combination with methods using surgery, hormone therapy, chemotherapy and biological response modifiers for the prevention and treatment of bone disease.
  • the present invention also provides a method for promoting osteoblast differentiation using the bone formation promoting peptide.
  • Two antioxidative peptides derived from mussel protein (PIISVYWK, 1004.57 Da: SEQ ID NO: 1; FSVVPSPK, 860.09 Da: SEQ ID NO: 2) were synthesized by Fmoc solid phase peptide synthesis (SPSS) (Peptron Inc. Seoul). Other materials used for cell culture were purchased from Gibro-BRL (Gaithersburg, MD, USA). Antibodies for protein analysis (p-Smad1 / 5, Smad1 / 5/8, Dlx5, Runx2, osterix, p-ERK, p-JNK, p-p38 and ⁇ -actin) are described in Santa Cruz Biotechnology (Santa Cruz, CA, USA). Other reagents used in this study were purchased from Sigma-Aldrich.
  • the mouse-derived mesenchymal stem cells used in the experiment were purchased from ATCC (D1 cell, CRL-12424) and incubated in DMEM medium containing 10% FBS and 1% penicillin / streptomycin at 5% CO 2 and 37 ° C. .
  • DMEM + 50 ⁇ g / mL ascorbic acid, 10 mM ⁇ -glycerolphosphate and 10 -7 M dexamethasone was exchanged every other day.
  • BMP antagonist noggin, 100 ng / mL
  • MAPKs inhibitors 10 ⁇ M SB203580, 20 ⁇ M PD98059 and 10 ⁇ M SP600125
  • the cytotoxicity of the two peptides used was measured by MTT (3- (4,5-dimethythiazol-2-yl) -2,5diphenyltetrazolium bromide).
  • MTT 3- (4,5-dimethythiazol-2-yl) -2,5diphenyltetrazolium bromide.
  • ALP activity was calculated as follows.
  • ALP activity (%) (A- A 0 ) / A 0 ⁇ 100
  • A peptide treated group
  • a 0 untreated group
  • the peptide was treated for 7 days, and then the medium was removed and washed twice in PBS. After fixing the cells for 5 minutes by treatment with 10% formalin solution, washed again in PBS, BCIP / NBT substrate solution was added to the well plate and incubated for 15 minutes at 37 °C and observed under a microscope.
  • the cells were cultured in 12-well plates and treated with peptides for 21 days. After the incubation, the cells were washed in PBS and fixed with 70% ethanol solution at 4 ° C. for 1 hour. 2% Alizarin red S (pH 4.2) solution was treated for 15 minutes at room temperature, dyed and washed 4 times with distilled water and dried completely. The mineral formation of the cells was observed under a microscope, and the absorbance was measured at 562 nm by decolorizing the Alizarin red S solution stained using 10% cetylpyridinium chloride solution for quantification. The degree of mineral formation was calculated using the following formula.
  • A peptide treated group
  • a 0 untreated group
  • mice used in the experiment were 7-week-old C57BL / 6N mice, purchased from Envigo (USA) and undergoing a 1 week accrual period.
  • OVX 12-week-old female mice
  • SEQ ID No. 1 and 2 peptides 50 ⁇ g / 25 g mice, respectively
  • PBS PBS
  • 100 ⁇ L of (Gibco) was intraperitoneally administered once a day for 2 months.
  • 4 female mice per group were subjected to subcutaneous incision only in the Sham model of osteoporosis, and 100 ⁇ L PBS was intraperitoneally administered.
  • the femur was separated from the mouse to remove muscle, washed with physiological saline, fixed in 4% formalin for 24 hours, and bone density was measured.
  • Microscopic tomography of the femur was measured using a micro-CT scanner (Inveon preclinical CT, Siemens Healthcare, USA) with a sample length of 1.9 cm, width 2 cm, photon energy of 80 keV, and a current of 500 ⁇ A.
  • a volume portion of 2 mm 3 of the same site per group was measured using Siemens Inveon Software.
  • BMP-2 / 4 stimulates the phosphorylation of Smad1 / 5 in downstream signaling systems to promote intracellular signaling, while phosphorylated Smad1 / 5 is important for producing specific proteins involved in osteoblast differentiation and formation.
  • the two types of peptides increased the expression of BMP-2 / 4 so that the downstream signaling agent Smad1 / 5 and the transcriptional regulators Dlx-5, Runx-2 and Osterix all increased the expression or activity, It was confirmed to promote differentiation of osteoblasts (FIG. 2). It was also confirmed that the expression of type I collagen, a biomarker for osteoblast differentiation, was strongly increased (FIG. 2).
  • mitogen-activated protein kinases are known to play an important role in osteoblast differentiation, and the present inventors conducted experiments to determine whether two types of peptides have an effect of activating MARKs. As a result, the phosphorylation of MARKs p-p38, p-ERK and p-JNK was increased to confirm osteoblast differentiation (Fig. 3).
  • BMPs activation of BMPs is known to be associated with increased phosphorylation of MAPKs.
  • the treatment of BMP antagonists does not change the phosphorylation of MAPKs (p-p38, p-ERK and p-JNK) by peptides. It was confirmed (Fig. 6).
  • MAPKs inhibitors SB203585 p38 inhibitors
  • PD98059 ERK inhibitors
  • SP600125 JNK inhibitors
  • the two peptides are involved in signaling pathways that affect the phosphorylation of ERK and JNK, and by activating BMPs signaling pathways, they can promote osteoblast differentiation, which is effective in the treatment of bone diseases, especially osteoporosis. It was confirmed that there is.
  • PIISVYWK (P1) and FSVVPSPK (P2) peptides were measured.
  • a micro CT photograph and a graph of bone mineral density change results are shown in FIG. 9.
  • PIISVYWK (P1) and FSVVPSPK (P2) peptides in osteoporosis-induced models showed significantly higher bone mineral density than mice injected with PBS alone, and 17 ⁇ -estradiol (Est, estrogen) used as a positive control. It showed a better degree of bone formation than). Both peptides showed higher or similar bone density than normal mice.

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Abstract

L'invention concerne un peptide de croissance ostéogénique comprenant le numéro de séquence 1 (PIISVYWK) ou le numéro de séquence 2 (FSVVPSPK); et une composition de prévention ou de traitement de maladies osseuses comprenant le peptide. Le peptide favorise la différenciation des ostéoblastes et peut ainsi s'utiliser pour le traitement d'une maladie osseuse.
PCT/KR2017/008035 2017-02-08 2017-07-26 Composition de prévention ou de traitement de maladies osseuses comprenant comme principe actif un peptide dérivé de la protéine de moule Ceased WO2018147516A1 (fr)

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Cited By (1)

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CN114031669A (zh) * 2021-12-01 2022-02-11 浙江海洋大学 厚壳贻贝抗氧化活性肽及其制备和应用

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KR20240142627A (ko) * 2023-03-21 2024-10-02 주식회사 아모라이프사이언스 골세포 분화용 세포배양기재 및 이의 제조방법
KR20250035701A (ko) 2023-09-06 2025-03-13 국립부경대학교 산학협력단 거품세포 형성 억제 및 항염증 활성 펩타이드를 유효성분으로 포함하는 죽상동맥경화증 억제용 조성물 및 억제방법

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114031669A (zh) * 2021-12-01 2022-02-11 浙江海洋大学 厚壳贻贝抗氧化活性肽及其制备和应用
CN114031669B (zh) * 2021-12-01 2023-05-02 浙江海洋大学 厚壳贻贝抗氧化活性肽及其制备和应用

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