WO2009115007A1 - Utilisation du polypeptide tat-n25 dans le traitement de la dermatose relative à la croissance cellulaire anormale et du psoriasis - Google Patents

Utilisation du polypeptide tat-n25 dans le traitement de la dermatose relative à la croissance cellulaire anormale et du psoriasis Download PDF

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Publication number
WO2009115007A1
WO2009115007A1 PCT/CN2009/070653 CN2009070653W WO2009115007A1 WO 2009115007 A1 WO2009115007 A1 WO 2009115007A1 CN 2009070653 W CN2009070653 W CN 2009070653W WO 2009115007 A1 WO2009115007 A1 WO 2009115007A1
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WIPO (PCT)
Prior art keywords
polypeptide
tat
psoriasis
cell
drug
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PCT/CN2009/070653
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English (en)
Chinese (zh)
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夏献民
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Xia Xianmin
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Publication of WO2009115007A1 publication Critical patent/WO2009115007A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics

Definitions

  • TAT-N25 polypeptide in the treatment of abnormal cell growth diseases such as psoriasis
  • the invention relates to a use of a fusion polypeptide in the treatment of abnormal cell growth diseases such as psoriasis, and belongs to the field of medical bioengineering. Background technique
  • Psoriasis commonly known as “psoriasis” is one of the most common and refractory skin diseases in dermatology. According to the clinical and pathological features of psoriasis, it can be generally divided into six types: vulgaris, arthritis, pustular, palmoplantar pustulosis, erythrodermic, and continuous acral dermatitis. Because the disease is stubborn and difficult to treat, it is listed as an important research topic in the field of dermatology in the world today.
  • the etiology of psoriasis is unknown.
  • the main pathological features are abnormal proliferation and parakeratosis of epidermal cells.
  • the specific pathological features are as follows: 1. Excessive proliferation and differentiation of epidermal keratinocytes; 2. Microvascular dilation of the dermis; 3. Inflammation reaction.
  • cytotoxic anticancer drugs such as white blood, ethylenimine, bismorpholine, cyclophosphamide, dexamethasone, prednisone, betamethasone and other hormonal drugs, immunosuppressants and epidermal cells
  • the differentiation promoting agent is treated with retinoic acid and the like. Because the above drugs and various preparations thereof can only act on a single pathological change of psoriasis and have serious damage to the liver, kidney and immune function of the body; some patients have certain short-term effects after use, but stop the drug. After the disease rebounded to aggravate the worsening side effects, many patients have been deeply affected.
  • the object of the present invention is to provide a fusion polypeptide comprising: a polypeptide which inhibits cell growth, promotes cell differentiation, a polypeptide or a molecule which penetrates a cell membrane, and a polypeptide which penetrates a cell membrane. Or the molecule carries a polypeptide that inhibits cell growth into the cell. It has been proved by experiments that this fusion polypeptide has the ability to inhibit epidermal cell growth and promote epidermal cell differentiation. In addition, the fusion polypeptide can effectively inhibit the pathological changes of patients with psoriasis and achieve significant therapeutic effects.
  • the fusion polypeptide has been disclosed in patent application 200710051286.6, and the fusion polypeptide comprises: a polypeptide that inhibits cell growth, promotes cell differentiation, and a polypeptide or molecule that penetrates the cell membrane, and the polypeptide that inhibits cell growth and the polypeptide or molecule that penetrates the cell membrane are chemically linked.
  • the polypeptide that inhibits cell growth and the polypeptide that penetrates the cell membrane are expressed in the cell as a fusion polypeptide.
  • the polypeptide that inhibits cell growth of the fusion polypeptide is linked to a tagged protein that purifies the fusion polypeptide.
  • the polypeptide which inhibits cell growth and promotes cell differentiation is a ⁇ -25 polypeptide consisting of 25 amino acid residues at the amino terminus of the phosphatidylinositol-3-kinase regulatory subunit p55PIK, the sequence of which is: methionine-aspartate Acid-arginine-aspartate-aspartate-alanine-aspartate-tryptophan-arginine-glutamate-valine-methionine-methionine -proline-tyrosine-serine-threonine-glutamate-leucine-isoleucine-phenylalanine-tyrosine-isoleucine-glutamate-methionine (MDRDDADWREVMMPYSTELIFYIEM), or one of the polypeptides obtained by consecutively or intermittently deleting
  • the polypeptide that penetrates the cell membrane is a polypeptide derived from HIV virus prion protein, and its sequence is: tyrosine-glycine-arginine-lysine-lysine-arginine-arginine-glutamine-spermine Acid-arginine-arginine (YGRKKRRQRRR).
  • the role of the ⁇ polypeptide in the ⁇ 25 fusion polypeptide is to help the ⁇ 25 polypeptide enter the cell and exert the pharmacological effect of ⁇ 25.
  • other polypeptides are known, such as the TDT polypeptide from X protein, which has a sequence of xxxxx and similar functions to help the polypeptide penetrate the cell membrane.
  • Other molecules such as polylysine, some liposomes can also help N25 or other peptides penetrate the cell membrane. I'm expecting the above molecules and ⁇ 24 to form new compounds by covalent or non-covalent associations should also have similar efficacy to ⁇ - ⁇ 25.
  • the tagged protein used to purify the fusion polypeptide is an oligohistidine tag in which the number of histidines is Any number from 5-10.
  • N25 polypeptide that inhibits cell growth and a TAT polypeptide or molecule that penetrates the cell membrane by chemical covalent linkage to a fusion polypeptide (TAT-N25 polypeptide) for the treatment of diseases caused by psoriasis and other abnormalities of skin cell proliferation and differentiation.
  • a TAT-N25 polypeptide drug for treating dysplasia-related skin diseases and psoriasis a polypeptide ointment prepared by formulating a TAT-N25 polypeptide and a pharmaceutically acceptable agent.
  • TI ⁇ N25 polypeptide ointment characterized by: by weight percent: stearyl alcohol: 3%; glyceryl monostearate: 6%; glycerol: 10%; liquid paraffin: 10%; white petrolatum: 3%; Ethanolamine: 0.1%; sodium dodecyl gramide: 0.2%; hydroxyphenylethyl ester: 0.1%; TAT-N25 polypeptide: 0.2%; water: 60%; urea: 7.4%.
  • the fusion polypeptide drug should include an internal and external drug containing or using the fusion polypeptide in combination with a pharmaceutically acceptable agent.
  • N25 polypeptides can also be covalently or non-covalently linked to other peptides or other molecules that help N25 enter the cell membrane to form new drugs for treating cell growth abnormalities associated with skin diseases and psoriasis.
  • Fusion polypeptide drugs for the treatment of related skin diseases skin inflammation, immunological diseases of cell abnormalities in the context of polygenic inheritance, use of epidermal hyperproliferation and differentiation abnormalities and diseases associated with abnormal cell growth such as psoriasis, and application of the drug by different means The route to treat these diseases.
  • TAT-N25 peptide ointment for the treatment of psoriasis is:
  • the method of using the peptide ointment is extremely convenient: the ointment is smeared on the patient's skin for 3 times, and the course of treatment is 10 days to 1 month.
  • the invention Compared with the prior art, the invention has the advantages of high cure rate, small safety side effects and the like, and provides an ideal medicine for patients with psoriasis. detailed description
  • the TAT-N25 polypeptide demonstrates its effectiveness in the treatment of psoriasis in the following experiments, including but not limited to the following experiments:
  • Example 1 TAT-N25 polypeptide inhibits keratinocyte growth and DNA synthesis
  • HACAT cells were cultured in 10 cm cell culture medium in a cell culture medium (DMEM) containing 10% fetal calf serum at 37 ° C, 5% CO 2 /95% air culture, and the cells were cultured to logarithmic growth phase.
  • DMEM cell culture medium
  • the polypeptide was added to a final concentration of 15 ⁇ g/ml, and the blank group and the urea group were cultured for control, and the cells were cultured for 24 hours, and the cell cycle distribution of these cells was analyzed by flow cytometry.
  • the TAT-N25 polypeptide stock solution is dissolved in 6M urea, and the 6M urea refers to 6 moles of urea per liter of water.
  • the following tubes are called 6M urea.
  • the results showed that the expression of TAT-N25 fusion polypeptide had no significant effect on apoptosis at this dose, and increased the number of G0/G1 phase cells. The effect is shown in Table 1 below. Table 1: Effect of TAT-N25 on cell cycle
  • TAT-N25 polypeptide inhibits vaginal epithelial cell layer proliferation in mice
  • mice Female mice were pre-injected with estrogens such as diethylstilbestrol for 7 days to place them in the estrogen physiological cycle.
  • 0.2 (wt)% of TAT-N25 polypeptide ointment was administered vaginally for 7 days, and colchicine was intraperitoneally injected after the last administration to terminate cell division.
  • the vaginal tissue of the mice was taken, fixed, stained, and the mitotic index of the vaginal epithelial cells was observed.
  • TAT-N25 polypeptide ointment is: Percent by weight: stearyl alcohol: 3%; glyceryl monostearate: 6%; glycerol: 10%; liquid paraffin: 10%; white petrolatum: 3% Triethanolamine: 0.1%; sodium lauryl sulfate: 0.2%; hydroxyethyl ester: 0.1%; TAT-N25 polypeptide: 0.2%; water: 60%; urea: 7.4%.
  • TAT-N25 inhibits mitosis of vaginal epithelial cells
  • Example 3 Effect of TAT-N25 polypeptide on the production of epidermal cells in mouse tail scales. Mice were taken. 0.2 (wt)% TAT-N25 polypeptide ointment was directly applied to the tail for 7 days, 3 times a day, and the tail root was taken. Skin, fixation, staining, measurement of rat tail epidermal thickness and particle formation.
  • TAT-N25 polypeptide ointment has a role in promoting the formation of the rat tail particle layer.
  • Table 4 TAT-N25 polypeptide promotes granule formation in rat tail cells
  • TAT-N25 polypeptide inhibits inflammatory factor secretion
  • TAT-N25 polypeptide culture solution The concentration of 30 ⁇ g/ml TAT-N25 polypeptide culture solution was incubated for 1 day in 1 liter, and the contents of IL-1, 6, 8, TNF- and IFN- in the culture solution were determined.
  • TAT-N25 polypeptide inhibits the secretion of inflammatory factors by lymphocytes.
  • TAT-N25 peptide ointment 0.2 0% of TAT-N25 peptide ointment was applied to the skin of patients with psoriasis 3 times a day. The results are shown in Table 5, indicating that TAT-N25 peptide has obvious effects in treating psoriasis.
  • Table 5 Summary of results of TAT-N25 peptide ointment for patients with psoriasis

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne l'utilisation du polypeptide TAT-N25 dans le traitement de la dermatose relative à la croissance cellulaire anormale et du psoriasis.
PCT/CN2009/070653 2008-03-21 2009-03-05 Utilisation du polypeptide tat-n25 dans le traitement de la dermatose relative à la croissance cellulaire anormale et du psoriasis WO2009115007A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2008100471131A CN101244258B (zh) 2008-03-21 2008-03-21 Tat-n25多肽在制备治疗银屑病药物的用途
CN200810047113.1 2008-03-21

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WO2009115007A1 true WO2009115007A1 (fr) 2009-09-24

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111956781A (zh) * 2019-05-20 2020-11-20 武汉益承生物科技有限公司 一种多肽在治疗眼部炎症药物中的应用

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101244258B (zh) * 2008-03-21 2010-10-20 夏献民 Tat-n25多肽在制备治疗银屑病药物的用途
CN102321158B (zh) * 2011-08-23 2013-03-27 常州德健生物科技有限公司 阻止细胞dna合成抑制细胞增殖的多肽及用途
CN110124054B (zh) * 2019-06-21 2022-02-18 天津科技大学 一种层层自组装的靶向纳米粒子的制备方法和应用
CN116466095B (zh) * 2023-06-15 2023-09-01 朗肽生物制药股份有限公司 一种多肽及其应用

Citations (2)

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CN101016340A (zh) * 2007-01-18 2007-08-15 夏献民 融合多肽及其在肿瘤与细胞生长异常相关的疾病治疗中的用途
CN101244258A (zh) * 2008-03-21 2008-08-20 夏献民 Tat-n25多肽在治疗银屑病等细胞生长异常皮肤病中的用途

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CN101016340A (zh) * 2007-01-18 2007-08-15 夏献民 融合多肽及其在肿瘤与细胞生长异常相关的疾病治疗中的用途
CN101244258A (zh) * 2008-03-21 2008-08-20 夏献民 Tat-n25多肽在治疗银屑病等细胞生长异常皮肤病中的用途

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SUN, X. ET AL.: "The N-terminal 24 amino acid of the 55 gamma regulatory subunit of phosphoinositide 3-kinase inhibit the proliferation of gastric carcinoma cells.", TUMOR, vol. 25, no. 1, 2005, pages 24 - 27 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111956781A (zh) * 2019-05-20 2020-11-20 武汉益承生物科技有限公司 一种多肽在治疗眼部炎症药物中的应用
CN111956781B (zh) * 2019-05-20 2023-11-17 益承康泰(厦门)生物科技有限公司 一种多肽在治疗眼部炎症药物中的应用

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