WO2023184332A1 - 一种靶向卵巢多肽及其应用 - Google Patents
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Classifications
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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
- A61K38/10—Peptides having 12 to 20 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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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
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
Definitions
- the invention discloses a polypeptide that can target the ovary and its derivatives and applications, and belongs to the field of biomedicine.
- the use of the polypeptide in preparing ovary-targeted drugs or detection reagents is specifically disclosed; its derivatives are also disclosed, and the derivatives are products obtained by modifying the terminal or side chain of the polypeptide.
- This type of peptide molecules can specifically target ovarian tissue, providing a method for the treatment of ovarian diseases, and can also treat diseases caused by metabolic disorders and aging-related diseases.
- Ovarian diseases mainly include premature ovarian failure, ovarian insufficiency, and polycystic ovary syndrome.
- ovarian diseases mainly include premature ovarian failure, ovarian insufficiency, and polycystic ovary syndrome.
- the incidence of ovarian diseases has been on the rise, which leads to loss of fertility and low estrogen status. It has become a factor that cannot be ignored affecting female reproductive health and social stability. It is a disease that seriously affects women's physical and mental health.
- the time that an oocyte is available for fertilization after maturation is very limited.
- the optimal time for fertilization and development in mice is within 12 hours after ovulation, while in humans it is within 4-12 hours after ovulation or egg retrieval. Over time, mature oocytes enter the aging stage and eventually degenerate.
- ovarian diseases In assisted reproductive intervention, inhibiting post-ovulatory aging in mammals can improve and increase fertilization rates and fertility rates.
- the causes of ovarian diseases are complex, the pathogenesis is unknown, and the incidence rate is increasing year by year.
- ovarian diseases are mainly treated clinically with hormone replacement therapy. Although the effects are quick, long-term use of hormones can cause significant side effects.
- Hormones can regulate the body's metabolic process, maintain the dynamic balance of physical and chemical factors in the body's internal environment, and regulate the body's growth, development, reproduction and aging functions. Hormones can also enhance the body's resistance and adaptability to harmful stimuli. Hormone disorders can cause overall endocrine disorders in the body, leading to the occurrence of metabolic diseases such as obesity, diabetes, fatty liver, osteoporosis, etc. In addition, hormonal disorders can cause premature loss of fertility and other aging phenotypes such as inflammation, arteriosclerosis, etc. in the reproductive system. A large amount of research literature and clinical data show that hormone disorders can lead to the occurrence of breast cancer, ovarian cancer, endometrial cancer and other diseases.
- Metabolic disorder is a state of the body, which is a pathological and uncoordinated supply and demand imbalance in the body's digestion, absorption, and excretion of substances.
- the main manifestation is glycolipid disorder, which can lead to a series of metabolic diseases, such as diabetes, hypertension, hyperlipidemia, etc.
- Diabetes is a group of metabolic diseases characterized by chronic hyperglycemia caused by multiple causes and is caused by defects in insulin secretion and/or utilization.
- Long-term carbohydrate, fat, and protein metabolism disorders can cause damage to multiple systems, leading to chronic progressive lesions, functional decline, and failure of the eyes, kidneys, nerves, heart, blood vessels, and other tissues and organs.
- Acute and severe metabolic disorders such as diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome, may occur when the condition is severe or under stress.
- Metformin, sulfonylureas, and thiazolidinediones (two or three) can be used alone or in combination, and can be used in combination with insulin.
- the present invention has discovered the following sequence polypeptides, which can specifically target the ovaries and can treat ovarian diseases, metabolic disorders and diseases caused by aging.
- polypeptide sequence comprising the sequence represented by formula M1-Za-M2 or the sequence represented by Za, wherein:
- M1 and M2 each independently have single or multiple amino acid polypeptide segments or do not exist;
- Za is His-Val-Gln-X1-Ile-Ser-X2-X3-Gly-X4-Ser-Pro-X5-Ser-X6-Pro-Val-Leu
- X1 is Ala or Ser
- X2 is Ile or Met
- X3 is Gln or Ser or Gly
- X4 is Gln or Thr or Ser
- X5 is Ala or Pro or Leu
- X6 is Glu or Gln.
- Za is selected from one of
- M1 does not exist, and M2 is F, or neither M1 nor M2 exists.
- the derivatives are products obtained by conventional modifications on the amino acid side chain groups, amino terminus and carboxyl terminus of the polypeptide, or are connected to the polypeptide for use in polypeptides or proteins.
- the product obtained from the detected or purified tag; the conventional modifications include fluorescent group modification, phosphorylation modification, cyclization modification of disulfide bond, biotin labeling modification, photosensitizer, azide modification, PEG modification, and formazan modification.
- the tags are His 6 , GST, EGFP, MBP, Nus, HA, IgG, FLAG, c-Myc or ProfinityeXact.
- Another aspect of the present invention provides a polynucleotide encoding the above-mentioned polypeptide or a derivative thereof.
- Yet another aspect of the present invention provides a vector comprising the above polynucleotide.
- Yet another aspect of the present invention provides a host cell transfected with the above vector.
- Another aspect of the present invention provides the use of the polypeptide of the present invention or a derivative thereof in the preparation of an ovary-targeting detection reagent, an ovary-targeting drug, or an ovary-targeting tool.
- the tools are selected from carriers, preparations or kits, such as carriers or preparations that achieve targeting effects by coupling the polypeptides of the present invention or derivatives thereof, such as liposomes, nanoparticles, etc.
- the present invention provides an ovarian-targeted detection reagent, which contains the polypeptide of the present invention or a derivative thereof.
- Another aspect of the present invention provides the use of the polypeptide or derivatives thereof in the preparation of medicaments for treating or preventing ovarian-derived diseases.
- Yet another aspect of the present invention provides a method for treating or preventing ovarian-derived diseases, the method comprising administering to a subject a therapeutically effective amount of the polypeptide of the present invention or a derivative thereof.
- Another aspect of the present invention provides a medicine for treating or preventing ovarian diseases, which contains the polypeptide of the present invention or a derivative thereof.
- the ovarian-derived diseases are selected from the group consisting of premature ovarian failure, polycystic ovary syndrome, functional irregular menstruation, menopausal syndrome, ovarian insufficiency, and infertility caused by follicle quality, quantity, or ovulation difficulties.
- premature ovarian failure is caused by genetic factors, chemotherapy or radiotherapy, immunosuppressants, pelvic surgery, viral infection, exposure to heavy metals, organic solvents, pesticides, Caused by plasticizers and industrial chemicals.
- the treatment or prevention of ovarian-derived diseases includes increasing ovarian weight, reducing the decline in ovarian weight, reducing ovarian atrophy, increasing the number of primordial follicles, primary follicles, and secondary follicles, extending the fertilization window period, improving post-ovulatory aging, and improving fertility. rate; treat or improve the symptoms of the following diseases, or inhibit the progression of the disease: premature ovarian failure, polycystic ovary syndrome, functional irregular menstruation, menopausal syndrome, and ovarian insufficiency.
- Another aspect of the present invention provides the use of the polypeptide or derivatives thereof in the preparation of drugs for treating metabolic disorders caused by hyperlipidemia in Kaohsiung.
- Yet another aspect of the present invention provides a method for treating or preventing metabolic disorders caused by hyperandrogen and hyperlipidemia, the method comprising administering to a subject a therapeutically effective amount of the polypeptide of the present invention or a derivative thereof.
- Another aspect of the present invention provides a drug for treating or preventing metabolic disorders caused by hyperlipidemia, and the drug for treating or preventing metabolic disorders caused by hyperlipidemia includes the polypeptide of the present invention or its derivatives.
- the metabolic disorder caused by hyperandrogen and hyperlipidemia is a metabolic abnormality caused by polycystic ovary syndrome, hyperandrogen hyperlipidemia, hyperandrogenism, hyperandrogenemia or hyperandrogen hyperlipidemia with hyperandrogen characteristics. , methods for diabetes, insulin resistance, hyperlipidemia, and obesity, the method comprising administering to a subject a therapeutically effective amount of the polypeptide of the present invention or a derivative thereof.
- Another aspect of the present invention provides the use of the polypeptide or derivatives thereof in the preparation of drugs for treating or preventing glucose and lipid metabolism disorders.
- Yet another aspect of the present invention provides a method for treating or preventing glucose and lipid metabolism disorders, the method comprising administering to a subject a therapeutically effective amount of the polypeptide of the present invention or a derivative thereof.
- Another aspect of the present invention provides a drug for treating or preventing glucose and lipid metabolism disorders, which contains the polypeptide of the present invention or a derivative thereof.
- glucose and lipid metabolism disorder is caused by leptin receptor deficiency.
- the glucose and lipid metabolism disorder is selected from fatty liver, diabetes, insulin resistance, hyperlipidemia, and obesity.
- Another aspect of the present invention provides the use of the polypeptide or derivatives thereof in the preparation of drugs for treating or preventing hair loss.
- Yet another aspect of the present invention provides a method for treating or preventing hair loss, the method comprising administering to a subject a therapeutically effective amount of the polypeptide of the present invention or a derivative thereof.
- Another aspect of the present invention provides a drug for treating or preventing hair loss, which contains the polypeptide of the present invention or a derivative thereof.
- the hair loss is caused by aging.
- Another aspect of the present invention is the use of the polypeptide of the present invention as an antibody produced by an antigen.
- Another aspect of the present invention provides the use of the polypeptide or derivatives thereof in preparing tools for culturing cells and tissues.
- the cells and tissues include ovary, uterus, bone, brain, heart, liver, spleen, lung, kidney, bone, and fat at various stages of development.
- the tools include culture fluid, additives, detection reagents, and organoids.
- the polypeptide drug of the present invention has the advantages of precise targeting and high selectivity, and also shows the characteristics of a series of small molecule drugs, such as rapid tissue permeability, low risk of immune response activation, and easy production.
- Peptide drugs are usually eliminated by the kidneys, avoiding the potential hepatotoxicity of small molecule drugs and antibody drugs. Based on the specific and strong binding of peptide drugs to their targets, peptide drugs can use lower dosages to avoid major side effects.
- the present invention proves that the ovary-targeting polypeptide of the present invention can accurately and specifically target the ovaries, has a therapeutic effect on ovarian-derived diseases, and can treat impaired glucose tolerance and insulin resistance caused by metabolic disorders caused by high fat and high cholesterol in Kaohsiung. and hair loss due to aging.
- Figure 1 is a diagram showing the results of the ovarian-targeting polypeptide of the present invention specifically targeting the ovary in Example 1.
- Figure 2 is a graph showing the results of changes in weight of different groups of mice after treatment in Example 2.
- the left picture shows the weight values of mice corresponding to different groups, and the right picture shows the weight changes of mice in different groups.
- Figure 3 is a graph showing the results of ovarian weight reduction after treatment in different groups of mice in Example 2.
- the left picture shows the ovarian weight values of mice in different groups, and the right picture shows the ovary weight changes of mice in different groups.
- Figure 4 shows the follicle count and histomorphological results of different groups in Example 2.
- the upper part is a staining picture of ovarian tissue, and the lower part is a photo of ovarian tissue morphology.
- Figure 5 shows the counting results of follicles at different stages in the ovary in Example 2.
- Figure 6 is a graph showing the pregnancy incidence results of different groups of mice in Example 2.
- Figure 7 shows that the targeted polypeptide in Example 2 inhibits the fragmentation and degeneration of oocytes caused by aging in the aging model of oocytes after maturation, and improves the status of in vitro fertilization by improving the hardening of the zona pellucida.
- Figure A shows the degradation and fragmentation rates of the control group, aging group, scrambled peptide aging group and targeted peptide group after 12 hours of aging.
- Picture B shows the hardening levels of the zona pellucida in the control group, aging group and targeted peptide group after 12 hours of aging.
- Picture C shows the in vitro fertilization rates of the control group, aging group and targeted peptide group after 12 hours of in vitro aging.
- Figure 8 shows the intraperitoneal glucose tolerance test results of different groups in the high-fat high-fat-induced polycystic ovary syndrome (PCOS) mouse pathological model in Example 3.
- PCOS polycystic ovary syndrome
- Figure 9 shows the intraperitoneal insulin tolerance test results of different groups in the high-fat high-fat-induced polycystic ovary syndrome (PCOS) mouse pathological model in Example 3.
- PCOS polycystic ovary syndrome
- Figure 10 shows the results of liver lipid droplet accumulation in different groups of db/db transgenic mice in Example 4.
- Figure 11 shows the results of different groups treating hair loss caused by aging in Example 4.
- Figure 12 is a comparison of polypeptide sequences from different species.
- subject means, but are not limited to, humans, mice, rats, apes, chickens, cattle, zebrafish, bony fish, carp, tilapia, large yellow croaker, and crucian carp. Also covered are tissues, cells and their progeny of biological entities obtained in vivo or cultured in vitro.
- administration includes oral administration, topical contact, administration as a suppository, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration to a subject.
- Administration is by any route, including parenteral and transmucosal (eg, buccal, sublingual, transpalatal, transgingival, nasal, transvaginal, transrectal, or transdermal).
- Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial.
- Other delivery modes include, but are not limited to, the use of liposome formulations, intravenous infusion, transdermal patches, etc.
- treatment refers to a method used to obtain beneficial or desired results including, but not limited to, therapeutic benefits.
- Therapeutic benefit means any treatment-related improvement in one or more diseases, conditions, or symptoms being treated, or any treatment-related effect on one or more diseases, conditions, or symptoms being treated.
- prevention refers to methods used to obtain beneficial or desired results including, but not limited to, preventive benefits.
- the composition may be administered to a subject at risk of developing a particular disease, condition, or symptom, or to a subject who reports one or more physiological symptoms of a disease, even if the disease, condition, or symptom It may not show up yet.
- therapeutically effective amount refers to an amount of a peptide or composition sufficient to achieve a beneficial or desired result.
- the therapeutically effective amount may vary depending on one or more of the following: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. Determined.
- the specific amount may vary depending on one or more of the following: the specific agent selected, the target cell type, the location of the target cells in the subject, the dosing regimen to be followed, whether it is administered in combination with other compounds, and the timing of administration. and the physical delivery systems that carry it.
- polypeptide of the present invention is as shown in SEQ ID No. 1-SEQ ID No. 10.
- the polypeptide of the present invention can be synthesized by polypeptide synthesis methods known in the art.
- the peptides are all isolated peptides.
- SEQ ID No. 1-10 are derived from mice, humans, rats, cattle, zebrafish, teleost, carp, tilapia, large yellow croaker, and crucian carp. See Figure 12 for details.
- SEQ ID No.1-10 of the present invention are homologous polypeptide sequences from different species, which have extremely similar backbone sequence structures. Compared with SEQ ID NO.1 respectively, the difference does not exceed the substitution of 6 amino acids, so it can It is presumed that these sequences have similar biological functions and should also be included in the scope of the present invention.
- the present application also relates to a medicament or pharmaceutical composition
- a medicament or pharmaceutical composition comprising at least one peptide of the invention as described above or one of its pharmaceutically acceptable salts or solvates, and at least one pharmaceutically acceptable carrier.
- At least one peptide of the invention is present as active ingredient in the medicament or pharmaceutical composition of the invention.
- compositions or medicaments of the invention are in a form suitable for administration to a mammal.
- compositions or medicaments of the invention may be administered, for example, orally, parenterally, intravenously, rectally, transdermally, topically or by inhalation.
- the composition according to the invention is administered by the intravenous or subcutaneous route.
- pharmaceutically acceptable carriers for compositions of the invention are suitably selected from the group consisting of injectable carrier liquids, such as sterile water for injection; and aqueous solutions, such as saline.
- the medicament or pharmaceutical composition of the invention may contain at least one peptide of the invention as the sole active ingredient, or may also contain at least one other active ingredient, as long as the other active ingredients do not interfere with the biological activity of the peptide according to the invention.
- the pharmaceutical composition or medicament according to the present invention may further comprise at least one antioxidant, dispersant, emulsifier, antifoaming agent, flavoring agent, preservative, solubilizer and/or coloring agent, as long as this/these other substances do not Hindering the biological properties of the peptides according to the invention.
- Sterile compositions of the invention for parenteral administration may especially be aqueous or non-aqueous solutions, suspensions or emulsions.
- Solvents or vehicles that may be used include water, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, injectable organic esters such as ethyl oleate, or other suitable organic solvents.
- These compositions may also contain adjuvants, in particular wetting agents, tonicity agents, emulsifiers, dispersing agents and stabilizing agents.
- Sterilization can be carried out in several ways, for example by sterile filtration, by incorporating a sterilizing agent into the composition, by irradiation or by heating. They may also be prepared in the form of sterile solid compositions which may be dissolved in sterile water or any other injectable sterile medium at the time of use.
- compositions for topical administration may be, for example, nasal drops or aerosols.
- the peptides of the invention used are converted into solutions, suspensions or emulsions using substances conventionally used for this purpose, such as solubilizers, emulsifiers or other excipients.
- Suitable solvents include, for example: water, physiological saline or alcohols, such as ethanol, propanol, glycerin, and sugar solutions (such as glucose or mannitol solutions), or mixtures of the above solvents.
- composition of the invention, the medicament of the invention, or the peptide of the invention or one of the pharmaceutically acceptable salts or solvates thereof is administered to the subject parenterally, and particularly transmutationally. Dermally, intravenously, subcutaneously or intramuscularly, especially intravenously or subcutaneously.
- the modified product is selected from a product modified by a fluorescent group, a product modified by phosphorylation, a product modified by cyclization based on a disulfide bond, a product modified by biotin labeling, or a product modified by biotin labeling.
- Products modified with photosensitizers, azide modifications, PEG modifications, methylation modifications, fluorescence quenching group modifications, or protein coupling Products obtained by modification, or products modified by small molecule compounds;
- the modified polypeptide Peptide (shown in SEQ ID No. 1) is connected to a fluorescent group to make the polypeptide fluorescent.
- mice were divided into four groups, namely Peptide group, PBS group, Flu group, and SCR group.
- the polypeptide Peptide (Peptide group), PBS (PBS group), a single fluorescent material (Flu group), and a scrambled polypeptide connected to a fluorescent material (SCR group) connected to a fluorescent group were injected through the tail vein injection.
- the amount is 0.325mM, and each mouse is injected with 100 ⁇ L.
- a small animal imager is used to observe the fluorescence brightness of each organ of the mouse.
- the polypeptide of the present invention has a specific ovarian targeting effect, and since the polypeptide of the present invention is shorter, it can be expected from the experimental results that the polypeptide of the present invention can be further developed through coupling tags or fluorescent preparations It can be used as an ovarian detection reagent, and by coupling with other active ingredients, or as a targeting ingredient in pharmaceutical preparations, the targeting and bioavailability of drugs for treating ovarian diseases can be further improved.
- CTX cyclophosphamide
- mice in the Peptide+CTX group were also injected with Peptide the day before the first injection of cyclophosphamide.
- the injection dose was 750 nM/g, daily injection, and continuous injection. Three weeks.
- mice in the CTRL group were injected at the same dose and interval as the mice in the CTX group, with the only difference being that cyclophosphamide was replaced with PBS.
- mice in the Peptide group were treated with the same method as the mice in the Peptide+CTX group, except that cyclophosphamide was replaced with PBS.
- mice Female mice were injected with 5IU PMSG subcutaneously and 48 hours later with 5IU hCG intraperitoneally for superovulation. They were randomly divided into control group, Aging group and Aging+Peptide group.
- the oocytes were collected, hyaluronidase was used to remove cumulus cells, and the oocytes were randomly divided into Aging group and Aging+Peptide group, and cultured and aged in M16 culture medium.
- the control group was freshly obtained mature eggs at 0 hours.
- the aging time of the Aging group was 12 hours, and the Aging+Peptide group was aged for 12 hours in M16 containing Peptide (1ug/ML).
- mice in the experimental group showed a downward trend, indicating that the ovaries of mice given cyclophosphamide showed atrophy, consistent with the characteristics of premature ovarian failure.
- mice were given cyclophosphamide and treated with Peptide, the weight of the ovaries of the mice did not show a significant decrease compared with the control group. There was no difference between the Peptide injection group alone and the control group. The above results show that Peptide can improve ovarian atrophy, and Peptide alone has no toxicity.
- PCOS polycystic ovary syndrome
- Polycystic ovary syndrome is both a reproductive disease and an endocrine disease, mainly because ovarian dysfunction leads to a decrease in estrogen and a significant increase in androgen, leading to endocrine disorders.
- Endocrine disorders mainly manifest as acne, obesity, insulin resistance, and diabetes. It can be seen from the result figures 8 and 9 that after treatment with Peptide peptide, the metabolic disorder caused by high fat in Kaohsiung has been significantly improved, mainly reflected in the improvement of glucose tolerance and insulin tolerance.
- db/db mice Three-month-old db/db transgenic mice were selected for experiments.
- db/db mice are leptin receptor gene-deficient mice. Its phenotypes include obesity, diabetes, fatty liver, etc. It is a classic model for studying glucose and lipid metabolism disorders.
- the db/db mice were divided into two groups. One group was injected with Peptide at a dose of 750 nM/g daily, and the other group was injected with an equal amount of PBS daily for one month. The results are shown in Figure 10. The accumulation of lipid droplets in the liver of the Peptide group was significantly reduced compared with the control group.
- leptin After leptin enters the blood circulation, it will participate in the regulation of sugar, fat and energy metabolism, prompting the body to reduce food intake and inhibit the synthesis of fat cells, thereby reducing weight and improving diabetes and fatty liver caused by metabolic disorders. It works after binding to the leptin receptor. When the receptor is knocked out, leptin cannot work. It can be seen from the results that the polypeptide Peptide can significantly improve the symptoms of fatty liver in db/db transgenic mice, which shows that the polypeptide can treat diseases caused by glucose and lipid metabolism disorders.
- mice over eight months old were selected. These mice had severe hair loss. These mice with hair loss caused by aging were randomly divided into two groups. One group was injected with Peptide peptide at a dose of 750 nM/g, and the other group was injected daily. One group was injected with the same amount of PBS daily, and observed after one month of continuous treatment. The experimental results are shown in Figure 11. The hair of the mice in the Peptide group began to grow, while the hair loss in the PBS group was more severe. This result indicates that Peptide can treat hair loss caused by aging.
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Abstract
提供一种多肽及其衍生物，序列由式M1-Za-M2表示；其中：M1、M2各自独立地单个或多个氨基酸多肽区段或者不存在；Za为His-Val-Gln-X1-Ile-Ser-X2-X3-Gly-X4-Ser-Pro-X5-Ser-X6-Pro-Val-Leu；用于治疗或预防卵巢源疾病、高雄高脂导致的代谢紊乱、糖脂代谢紊乱、毛发脱落。
Description
本发明公开了一种可靶向卵巢的多肽及其衍生物和应用，属于生物医药领域。具体公开了多肽在制备卵巢靶向药物或检测试剂中的用途；还公开了其衍生物，所述的衍生物为多肽经过末端或侧链的修饰后所得到的产物。该类多肽分子可特异性靶向卵巢组织内，为卵巢疾病治疗提供了一种方法，还可以治疗代谢紊乱引起的疾病和衰老相关疾病。
卵巢疾病主要包括卵巢早衰、卵巢功能不全、多囊卵巢综合征。近年来卵巢疾病发病率呈上升趋势，其导致生育力丧失及低雌激素状态，成为影响女性生殖健康和社会稳定不可忽视的因素，是严重影响女性身心健康的疾病。此外，卵母细胞成熟后可受精的时间非常有限。例如，小鼠最佳受精和发育的时间是排卵后不12小时内，而人类在排卵或取卵后4-12小时内。随时间推移，成熟的卵母细胞进入老化阶段，最终退化。在辅助生殖干预中，抑制哺乳动物排卵后老化可改善与提高受精率与生育率。卵巢疾病病因复杂，发病机制不明，发病率逐年上升。目前，卵巢疾病临床上主要采用激素替代疗法治疗。虽然见效快，但长期使用激素会出现明显的毒副作用。
激素可以调节机体的新陈代谢过程，保持机体内环境理化因素的动态平衡，调节机体的生长、发育、生殖和衰老功能，激素还能增强机体对有害刺激的抵抗和适应能力。激素紊乱会引起机体整体的内分泌紊乱从而导致代谢性疾病的发生如过度肥胖、糖尿病、脂肪肝、骨质疏松等。此外，激素紊乱会导致生殖系统导致生殖力过早的丧失及其他衰老表型如炎症反应、动脉硬化等。大量的研究文献研究及临床数据表明激素紊乱会导致乳腺癌、卵巢癌、子宫内膜癌等疾病的发生。
代谢紊乱是身体的一种状态，是机体对物质的消化、吸收、排泄出现病理性，不协调的供需不平衡的状态。主要表现为糖脂紊乱，会导致一系列的代谢疾病，比如糖尿病、高血压、高血脂等。糖尿病是一组由多病因引起的以慢性高血糖为特征的代谢性疾病，是由于胰岛素分泌和(或)利用缺陷所引起。长期碳水化合物、脂肪、蛋白质代谢紊乱，可引起多系统损害，导致眼、肾、神经、心脏、血管等组织器官出现慢性进行性病变、功能减退及衰竭。病情严重或应激时，可发生急性严重代谢紊乱，如糖尿病酮症酸中毒、高渗高血糖综合征。可单用或联合应用二甲双胍、磺脲类、噻唑烷二酮类药物(两种或三种)，并可与胰岛素合用。
随着年龄的增长身体随之出现许多衰老症状，而且病因复杂。脱发是出现早中年人群中的普遍现象，也是年龄增长的结果。脱发不仅影响美观，而且给人的情绪带来不良影响。动脉硬化、骨流失、退行性疾病，脏器功能减退等都是伴随衰老的疾病。目前，针对年龄相关的衰老性症状还没有很好的方法克服，越来越多的资金倾向于衰老相关疾病的研究，但是目前还没有很好的药物问世。
发明内容
本发明发现了以下序列多肽，这些多肽能特异性靶向卵巢并且可以治疗卵巢疾病、代谢紊乱及衰老引起的疾病。
本发明一个方面提供了一种多肽，所述多肽序列包含式M1-Za-M2所示的序列或Za所示的序列，其中：
M1、M2各自独立地单个或多个氨基酸多肽区段或者不存在；
Za为His-Val-Gln-X1-Ile-Ser-X2-X3-Gly-X4-Ser-Pro-X5-Ser-X6-Pro-Val-Leu
X1为Ala或Ser，
X2为Ile或Met，
X3为Gln或Ser或Gly，
X4为Gln或Thr或Ser，
X5为Ala或Pro或Leu，
X6为Glu或Gln。
进一步地，其中Za选自其中之一
进一步地，其中所述M1不存在，且M2为F，或者M1和M2均不存在。
本发明再一个方面提供了上述多肽的衍生物，所述衍生物为所述多肽氨基酸侧链基团上、氨基端、羧基端进行常规修饰得到的产物，或者为多肽上连接用于多肽或蛋白检测或纯化的标签所得到的产物；所述的常规修饰为荧光基团修饰、磷酸化修饰、二硫键的环化修饰、经过生物素标记修饰、光敏剂、叠氮修饰、PEG修饰、甲基化修饰、荧光淬灭基团修饰、蛋白 偶联修饰、小分子化合物修饰、氨基化修饰、酰胺化修饰、羟基化修饰、羧基化修饰、羰基化修饰、烷基化修饰、乙酰化修饰、酯化修饰、糖基化修饰；
所述的标签为His
6、GST、EGFP、MBP、Nus、HA、IgG、FLAG、c-Myc或ProfinityeXact。
本发明再一个方面提供了一种多聚核苷酸，其编码上述多肽或其衍生物。
本发明再一个方面提供了一种载体，其包含了上述多聚核苷酸。
本发明再一个方面提供了一种宿主细胞，其转染了上述载体。
本发明再一个方面提供了本发明所述多肽或其衍生物在制备靶向卵巢的检测试剂、靶向卵巢的药物或靶向卵巢的工具中的用途。
进一步地，所述工具选自载体、制剂或试剂盒，例如通过偶联本发明所述多肽或其衍生物实现靶向效果的载体或者制剂，如脂质体、纳米粒等。
本发明再一个方面提供了一种靶向卵巢的检测试剂，所述试剂中包含本发明所述的多肽或其衍生物。
本发明再一个方面提供了本发明所述的多肽或其衍生物在制备治疗或预防卵巢源疾病的药物中的用途。
本发明再一个方面提供了一种治疗或预防卵巢源疾病的方法，所述方法包含向受试者施用治疗有效量的本发明所述多肽或其衍生物。
本发明再一个方面提供了一种治疗或预防卵巢源疾病的药物，所述治疗或预防卵巢源疾病的药物中包含本发明所述的多肽或其衍生物。
进一步地，所述卵巢源疾病选自卵巢早衰、多囊卵巢综合征、功能性月经不调、绝经期综合征、卵巢功能不全、因卵泡质量、数量或排卵困难导致的不孕不育。
进一步地，所述卵巢早衰为由遗传因素导致的、化疗或放疗导致的、由免疫抑制剂导致的、由盆腔手术导致的、由病毒感染导致的、由接触重金属、有机溶剂、杀虫剂、塑化剂、工业化学制剂导致的。
进一步地，所述治疗或预防卵巢源疾病为提高卵巢重量、降低卵巢重量下降幅度、减少卵巢萎缩、提高原始卵泡、初级卵泡、次级卵泡数量、延长受精窗口期、改善排卵后老化和提高生育率；治疗或改善下述疾病的症状，或抑制疾病进展：卵巢早衰、多囊卵巢综合征、功能性月经不调、绝经期综合征、卵巢功能不全。
本发明再一个方面提供了本发明所述的多肽或其衍生物在制备治疗高雄高脂导致的代谢紊乱药物中的应用。
本发明再一个方面提供了一种治疗或预防高雄高脂导致的代谢紊乱的方法，所述方法包 含向受试者施用治疗有效量的本发明所述的多肽或其衍生物。
本发明再一个方面提供了一种治疗或预防高雄高脂导致的代谢紊乱的药物，所述治疗或预防高雄高脂导致的代谢紊乱的药物中包含本发明所述的多肽或其衍生物。
进一步地，所述高雄高脂导致的代谢紊乱是由于具有高雄激素特征的多囊卵巢综合征、高雄高脂血症、高雄激素血症、高雄激素血症或高雄高脂血症导致的代谢异常、糖尿病、胰岛素抵抗、高脂血症、肥胖症的方法，所述方法包含给与受试者治疗有效量的本发明所述的多肽或其衍生物。
本发明再一个方面提供了本发明所述的多肽或其衍生物在制备治疗或预防糖脂代谢紊乱药物中的应用。
本发明再一个方面提供了一种治疗或预防糖脂代谢紊乱的方法，所述方法包含向受试者施用治疗有效量的本发明所述的多肽或其衍生物
本发明再一个方面提供了一种治疗或预防糖脂代谢紊乱的药物，所述治疗或预防糖脂代谢紊乱的药物中包含本发明所述的多肽或其衍生物。
进一步地，所述的糖脂代谢紊乱是由于瘦素受体缺乏导致的。
进一步地，所述糖脂代谢紊乱选自脂肪肝、糖尿病、胰岛素抵抗、高脂血症、肥胖症。
本发明再一个方面提供了本发明所述的多肽或其衍生物在制备治疗或预防毛发脱落的药物中的应用。
本发明再一个方面提供了一种治疗或预防毛发脱落的方法，所述方法包含向受试者施用治疗有效量的本发明所述的多肽或其衍生物。
本发明再一个方面提供了一种治疗或预防毛发脱落的药物，所述治疗或预防毛发脱落的药物中包含本发明所述的多肽或其衍生物。
进一步地，所述的毛发脱落是由于衰老引发的毛发脱落。
本发明再一个方面本发明的所述的多肽作为抗原产生的抗体的用途。
本发明再一个方面提供了本发明所述的多肽或其衍生物在制备培养细胞及组织的工具中的应用。
进一步地，所述细胞及组织包括各个发育阶段的卵巢、子宫、骨、脑、心、肝脾、肺、肾、骨、脂肪。
进一步地，所述工具例如培养液、添加剂、检测试剂、类器官。
本发明的多肽类药物具精确寻靶和高选择性的优点，同时也显示出一系列小分子药物所具有的特点，例如快速的组织渗透性，较低的免疫应答激活风险，便于生产。多肽类药物通 常经由肾脏消除，避开了小分子药物和抗体药物潜在的肝脏毒性。基于多肽类药物与靶点的特异性的强结合作用，多肽类药物可以使用较低的给药剂量，避免出现主要的副作用。
本发明经过多项实验，证明本发明的靶向卵巢多肽可以精准特异的靶向卵巢，对卵巢源疾病有治疗作用，并且可以治疗高雄高脂引起的代谢紊乱引起的糖耐量受损及胰岛素抵抗和因衰老导致的脱发。
图1为实施例1中本发明靶向卵巢的多肽特异性靶向卵巢的结果图。
图2为实施例2中不同组小鼠经过处理后重变化的结果图。左图为不同组别对应的小鼠体重值，右图为不同组别小鼠的体重变化值。
图3为实施例2中不同组小鼠经过处理后卵巢重量降低的结果图。左图为不同组别对应的小鼠卵巢重量值，右图为不同组别小鼠的卵巢重量变化值。
图4为实施例2中不同组别卵泡计数及组织形态学结果图，上列为卵巢组织染色图，下列为卵巢组织形态照片。
图5为实施例2中卵巢中不同阶段卵泡的计数结果。
图6为实施例2中不同组别小鼠妊娠发生率结果图。
图7为实施例2中靶向多肽在卵母细胞成熟后老化模型中，抑制老化所导致的卵母细胞碎裂与退化、通过改善透明带硬化提高体外受精状态。图A是对照组、老化组、乱序多肽老化组和靶向多肽组老化12小时后退化与碎裂率。图B是对照组、老化组和靶向多肽组老化12小时透明带硬化水平。图C是对照组、老化组和靶向多肽组体外老化12小时后的体外受精率。
图8为实施例3中不同组别在高雄高脂诱导的多囊卵巢综合征(PCOS)的小鼠病理模型中腹膜内葡萄糖耐量测试结果。
图9为实施例3中不同组别在高雄高脂诱导的多囊卵巢综合征(PCOS)的小鼠病理模型中腹膜内胰岛素耐量测试结果。
图10为实施例4中不同组别在db/db转基因小鼠的肝脏脂滴积累结果。
图11为实施例4中不同组别治疗衰老引起的脱毛现象的结果。
图12为来自不同物种的多肽序列比较。
为了使本发明的上述目的、特征和优点能够更加明显易懂，下面对本发明的具体实施方 式做详细的说明，但不能理解为对本发明的可实施范围的限定。
除非另外特别指出，否则本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的含义相同的含义。此外，与本文描述的方法或材料类似或等同的任何方法或材料可用于实施本发明。出于本发明的目的，定义了以下术语。
术语“受试者”、“个体”和“患者”在本文中可互换使用以指脊椎动物，优选哺乳动物。哺乳动物包括但不限于人类、小鼠、大鼠、猿猴、鸡、牛、斑马鱼、硬骨鱼、鲤鱼、罗非鱼、大黄鱼、鲫鱼。还涵盖了在体内获得或在体外培养的生物实体的组织、细胞及其后代。
如本文所用，术语“施用”包括经口施用、局部接触、作为栓剂施用、静脉内、腹膜内、肌内、病灶内、鞘内、鼻内或皮下施用给受试者。施用是通过任何途径，包括肠胃外和经粘膜(如，经颊、舌下、经腭、经牙龈、经鼻、经阴道、经直肠或经皮)。肠胃外施用包括如，静脉内、肌内、动脉内、皮内、皮下、腹膜内、心室内和颅内。其他的递送模式包括但不限于使用脂质体制剂、静脉内输注、经皮贴剂等。
术语“治疗”是指用于获得包括但不限于治疗性益处在内的有益或期望结果的方法。治疗性益处意指治疗中的一种或多种疾病、病况或症状的任何治疗相关的改善，或对治疗中的一种或多种疾病、病况或症状的任何治疗相关的作用。“预防”是指用于获得包括但不限于预防性益处在内的有益或期望结果的方法。对于预防性益处，组合物可以施用给具有发展特定疾病、病况或症状风险的受试者，或施用给报告疾病的一种或多种生理症状的受试者，即使所述疾病、病况或症状可能尚未表现出来。
术语“治疗有效量”是指肽或组合物的足以实现有益或所需结果的量。治疗有效量可以取决于以下一个或多个而变化：被治疗的受试者和疾病状况、受试者的体重和年龄、疾病状况的严重程度、施用方式等，其可以由本领域普通技术人员容易地确定。具体的量可以取决于以下一个或多个而变化：所选择的特定药剂、靶细胞类型、受试者体内靶细胞的位置、要遵循的给药方案、是否与其他化合物联合施用、施用的时间以及携带它的实体递送系统。
多肽
一方面本发明的多肽如SEQ ID No.1-SEQ ID No.10所示，本发明的多肽能够通过本领域已知的多肽合成方法合成。
在本发明中，所述的肽均为分离的肽。
上述多肽中SEQ ID No.1-10来源于小鼠、人类、大鼠、牛、斑马鱼、硬骨鱼、鲤鱼、罗非鱼、大黄鱼、鲫鱼，详见图12。本发明SEQ ID No.1-10是来自不同物种的同源性多肽序列，其具有及其相似的骨架序列结构，分别与SEQ ID NO.1对比，差异不超过6个氨基酸的替换，因此可以推定这些序列具有类似的生物学功能，也应当包含在本发明的范围内。
组合物和药物
本申请还涉及药物或药物组合物，其包含至少一种如上所述的本发明的肽或其药学上可接受的盐或溶剂化物之一，以及至少一种药学上可接受的载体。
至少一种本发明的肽作为活性成分存在于本发明的药物或药物组合物中。
本发明的组合物或药物呈适于哺乳动物给予的形式。
本发明的组合物或药物可以例如口服、肠胃外、静脉内、直肠、透皮、局部或通过吸入来给予。具体地，根据本发明的组合物通过静脉内或皮下途径来给予。
根据具体的实施方案，本发明组合物的药学上可接受的载体合适地选自可注射的载体液体，如无菌注射用水；和水性溶液，如盐水。
本发明的药物或药物组合物可以包含至少一种本发明的肽作为唯一活性成分，或者还可以包含至少一种其他活性成分，只要所述其他活性成分不妨碍根据本发明的肽的生物活性。
根据本发明的药物组合物或药物可以进一步包含至少一种抗氧化剂、分散剂、乳化剂、消泡剂、调味剂、防腐剂、增溶剂和/或着色剂，只要这种/这些其他物质不妨碍根据本发明的肽的生物特性。
用于肠胃外给予的本发明的无菌组合物尤其可以是水性或非水性溶液、悬浮液或乳液。可以使用的溶剂或媒介物包括水、丙二醇、聚乙二醇、植物油特别是橄榄油、可注射的有机酯例如油酸乙酯、或其他合适的有机溶剂。这些组合物还可以包含佐剂，特别是湿润剂、张度剂、乳化剂、分散剂和稳定剂。可以以几种方式，例如通过无菌过滤、通过将灭菌剂掺入组合物中、通过辐照或通过加热进行灭菌。它们也可以以无菌固体组合物的形式制备，所述组合物可以在使用时溶解在无菌水或任何其他可注射的无菌介质中。
用于局部给予的组合物可以是例如滴鼻剂或气雾剂。
对于皮下、肌内或静脉内给予，将所用的本发明的肽用常规用于此目的的物质如增溶剂、乳化剂或其他赋形剂转化为溶液、悬浮液或乳液。合适的溶剂，例如：水、生理盐水或醇，例如乙醇、丙醇、甘油，以及糖溶液(如葡萄糖或甘露醇溶液)，或上述各种溶剂的混合物。
在特定的实施方案中，将本发明的组合物、本发明的药物、或本发明的肽或其药学上可接受的盐或溶剂化物之一通过肠胃外途径给予受试者，并且特别是透皮、静脉内、皮下或肌内，特别是静脉内或皮下给予。
应用
实施例1靶向性研究
所述修饰所得产物选自经过荧光基团修饰得到的产物，或经过磷酸化修饰得到的产物，或基于二硫键的环化修饰得到的产物，或经过生物素标记修饰得到的产物，或经过光敏剂修饰得到的产物，或叠氮修饰得到的产物，或经过PEG修饰得到的产物，或经过甲基化修饰得到的产物，或经过荧光淬灭基团修饰得到的产物，或经过蛋白偶联修饰得到的产物，或经过小分子化合物修饰得到的产物；
将修饰的所述多肽Peptide(SEQ ID No.1所示)与荧光基团连接，使所述多肽带有荧光。
将小鼠分为四组，分别为Peptide组、PBS组、Flu组、SCR组。通过尾静脉注射的方式分别注射连接荧光基团的所述多肽Peptide(Peptide组)、PBS(PBS组)、单独的荧光材料(Flu组)及连接荧光材料的乱序多肽(SCR组)，注射量为0.325mM，每只小鼠注射100μL，经小鼠体内代谢一段时间后，利用小动物成像仪观察小鼠各个器官的荧光亮度。
结果见图1，实验结果显示，注射连接了荧光基团的Peptide的小鼠卵巢与其他组别比较呈现强荧光，而其他组织并未观察到强荧光反应，且其他对照组PBS组、Flu组、SCR组在卵巢部位也并未观察到强荧光反应，说明Peptide可以特异性靶向卵巢。
通过上述实验结果，意外地发现本发明的多肽具有特异性的靶向卵巢的效果，且由于本发明多肽较短，通过该实验结果可以预期本发明的多肽通过偶联标签或荧光制剂可以进一步开发成为卵巢检测试剂，而通过偶联其他活性成分，或者作为药物制剂中的靶向成分，能够进一步提高针对卵巢疾病治疗药物的靶向性和生物利用度。
实施例2对卵巢早衰的治疗实验
建立卵巢早衰模型：选取8周小鼠，将小鼠分为4组实验组CTX组(环磷酰胺组)、实验组Peptide+CTX组、对照组CTRL组以及对照组Peptide组。
CTX组小鼠第一天注射75mg/kg的环磷酰胺(cyclophosphamide,CTX)，然后每隔一天注射30mg/mL环磷酰胺持续3个周。
Peptide+CTX组小鼠除按照CTX组小鼠的剂量和间隔注射环磷酰胺外，在第一次注射环磷酰胺的前一天开始注射Peptide，注射剂量为750nM/g，每日注射，连续注射三周。
CTRL组(PBS组)小鼠按照CTX组小鼠的剂量和间隔注射，区别仅在于将环磷酰胺替换为PBS。
Peptide组小鼠采用Peptide+CTX组小鼠相同方法，区别仅在于将环磷酰胺替换为PBS。
雌性小鼠皮下注射5IU PMSG，48小时后腹腔内注射5IU hCG进行超数排卵。随机分为对照组、Aging组与Aging+Peptide组。
14小时后收集卵母细胞，使用透明质酸酶去除卵丘细胞，随机分为Aging组与Aging+Peptide组，并于M16培养液中培养老化。对照组为新鲜取得的成熟卵子0小时。
Aging组老化时间12小时，Aging+Peptide组在含Peptide(1ug/ML)的M16中老化12小时。
在实验过程中检查小鼠各项指标。
1)体重和卵巢重量研究
称量各组小鼠用药前及用药三周后体重以及解剖后的卵巢重量。结果参见图2，图3。
与对照组相比实验组小鼠体重和卵巢重量具有下降趋势，说明给与环磷酰胺小鼠的卵巢出现萎缩，符合卵巢早衰特征。
给与环磷酰胺小鼠经Peptide治疗后，小鼠卵巢的重量与对照组相比并未出现显著的卵巢重量下降。而单独注射Peptide组与对照组相比没有差异，以上结果说明Peptide可以改善卵巢萎缩，且单独使用Peptide没有毒性。
2)卵泡计数及组织形态学分析
小鼠卵巢以4％多聚甲醛固定，脱水后进行石蜡包埋并切5μm厚度切片并用苏木精和伊红对卵巢组织染色并观察。实验结果参见图4，5，与实验组相比卵巢早衰造模组小鼠卵巢的原始卵泡显著减少，切片面积明显变小。而经Peptide治疗后的卵巢早衰造模组的原始卵泡数量减少趋势得到明显缓解，卵巢切片面积变小趋势得到改善。而单独注射Peptide组与对照组相比没有差异。
3)评估CTX处理与Peptide联合处理对生育力的影响
在最后一次治疗后的8周，雌性小鼠与正常且已证明有生育能力的雄性小鼠交配，然后每7周再次交配，共进行3轮连续交配。统计每组的每次妊娠的幼仔数。测量结果如图显示，CTX降低了小鼠生殖能力，但经Peptide治疗后挽救了生育能力。虽然给予CTX的剂量没有使小鼠绝育，但CTX处理小鼠的妊娠发生率低于对照组，但与Peptide共同治疗使妊娠发生 率有所恢复，单独使用Peptide组与对照组PBS组相比没有差别，结果见图6。
4)实验结果见图7，通过三组对比，Peptide可抑制卵母细胞排卵后体外老化所导致的碎裂与退化(A)。Peptide可以通过改善卵母细胞体外老化所导致的透明带硬化(B)，进而提高卵母细胞体外老化所导致的受精率低下。
实施例3对改善代谢紊乱引起的血糖升高的治疗实验
建立高雄高脂诱导的多囊卵巢综合征(PCOS)的小鼠病理模型，具体实验过程如下：C57雌性小鼠(21日龄)实验组每天皮下注射DHEA(6mg/100g体重，100μL小鼠，芝麻油加95％乙醇)，连续20天，高脂喂养(DHEA+HFD)，其中一部分同时注射Peptide(DHEA+HFD+Peptide)。对照组每天注射0.09mL芝麻油和0.01mL95％乙醇，连续注射20d，普通饲料喂养，注射生理盐水(CTRL)。实验结束后检测腹腔注射糖耐量和胰岛素耐量。多囊卵巢综合征既是生殖疾病也是内分泌疾病，主要因为卵巢功能紊乱导致雌激素减少和雄激素显著升高，从而导致内分泌紊乱。内分泌紊乱主要表现为痤疮、肥胖、胰岛素抵抗以及糖尿病等。从结果图8、9可以看出，给予Peptide多肽治疗后，高雄高脂引起的代谢紊乱得到了显著的改善，主要表现在糖耐量及胰岛素耐量的改善。
实施例4
选取3月龄db/db转基因小鼠进行实验，db/db小鼠为瘦素受体基因缺陷鼠。其表型有肥胖、糖尿病、脂肪肝等，是研究糖脂代谢紊乱的经典模型。将db/db小鼠分为两组，一组每天注射Peptide，注射剂量为750nM/g，每日注射，另一组注射等量PBS，每日注射，连续注射一个月。结果如图10所示，Peptide组肝中的脂滴积累与对照组相比显著减少。瘦素进入血液循环后会参与糖、脂肪及能量代谢的调节，促使机体减少摄食并抑制脂肪细胞的合成，进而使体重减轻并改善代谢紊乱引起的糖尿病、脂肪肝等。它与瘦素受体结合后发挥作用，受体敲除后瘦素便不能发挥作用。从结果可以看出，所述多肽Peptide可以明显改善db/db转基因小鼠的脂肪肝症状，这说明所述多肽可以治疗糖脂代谢紊乱引起的疾病。
实施例5对脱毛的治疗实验
选取八月龄以上的C57雌鼠，这些小鼠具有严重的脱毛现象，将这些衰老引起的脱毛小鼠随机分成两组，一组注射Peptide多肽，注射剂量为750nM/g，每日注射，另一组注射等量PBS，每日注射，连续治疗一个月后观察，实验结果见图11，Peptide组小鼠毛发开始生长，而PBS组则脱毛更加严重。此结果表示Peptide可以治疗衰老引起的脱毛现象。
Claims (11)
- 一种多肽，其特征在于，所述多肽序列包含式M1-Za-M2所示的序列或Za所示的序列，其中：M1、M2各自独立地单个或多个氨基酸多肽区段或者不存在；Za为His-Val-Gln-X1-Ile-Ser-X2-X3-Gly-X4-Ser-Pro-X5-Ser-X6-Pro-Val-LeuX1为Ala或Ser，X2为Ile或Met，X3为Gln或Ser或Gly，X4为Gln或Thr或Ser，X5为Ala或Pro或Leu，X6为Glu或Gln；优选地，其中Za选自其中之一HVQAIS IQGQSPASEP VL SEQ ID No.1HVQSIS MSGTSPPSEP VL SEQ ID No.3HVQSIS MGGSSPPSQP VL SEQ ID No.5HVQSIS MGGSSPPSEP VL SEQ ID No.7HVQSIS MSGTSPLSEP VL SEQ ID No.9；优选地，其中所述M1不存在，且M2为F，或者M1和M2均不存在。
- 权利要求1所述多肽的衍生物，其特征在于，所述衍生物为权利要求1所述多肽的氨基酸侧链基团上、氨基端、羧基端进行常规修饰得到的产物；或者为权利要求1所述多肽上连接用于多肽或蛋白检测或纯化的标签所得到的产物；所述的常规修饰为荧光基团修饰、磷酸化修饰、二硫键的环化修饰、经过生物素标记修饰、光敏剂、叠氮修饰、PEG修饰、甲基化修饰、荧光淬灭基团修饰、蛋白偶联修饰、小分子化合物修饰、氨基化修饰、酰胺化修饰、羟基化修饰、羧基化修饰、羰基化修饰、烷基化修饰、乙酰化修饰、酯化修饰、糖基化修饰所述的标签为His 6、GST、EGFP、MBP、Nus、HA、IgG、FLAG、c-Myc或ProfinityeXact。
- 一种多聚核苷酸，其特征在于，其编码权利要求1所述的多肽或权利要求2所述的衍生物。
- 一种载体，其特征在于，其包含了权利要求3所述的多聚核苷酸。
- 一种宿主细胞，其特征在于，其转染了权利要求4所述的载体。
- 权利要求1所述的多肽或权利要求3所述的衍生物在制备靶向卵巢的检测试剂、靶向卵巢的药物或靶向卵巢的工具中的用途；优选地，工具选自载体、制剂或试剂盒。
- 权利要求1所述的多肽、权利要求2所述的衍生物在制备治疗或预防卵巢源疾病、高雄高脂导致的代谢紊乱、糖脂代谢紊乱、毛发脱落的药物中的用途；优选地，所述卵巢源疾病选自卵巢早衰、多囊卵巢综合征、功能性月经不调、卵巢早衰或绝经期综合征、卵巢功能不全；优选地，所述治疗或预防卵巢源疾病为提高卵巢重量、降低卵巢重量下降幅度、减少卵巢萎缩、提高原始卵泡、初级卵泡、次级卵泡数量、延长受精窗口期、改善排卵后老化和提高受精率和生育率；治疗或改善下述疾病的症状，或抑制疾病进展：卵巢早衰、多囊卵巢综合征、功能性月经不调、卵巢早衰或绝经期综合征、卵巢功能不全；优选地，高雄高脂导致的代谢紊乱为高雄高脂血症、高雄激素血症、多囊卵巢综合征、高雄激素血症或高雄高脂血症导致的代谢异常、糖尿病、胰岛素抵抗、高脂血症、肥胖症；优选地，所述的糖脂代谢紊乱是由于瘦素受体缺乏导致的；优选地，所述糖脂代谢紊乱选自脂肪肝、糖尿病、胰岛素抵抗、高脂血症、肥胖症；优选地，所述的毛发脱落是由于衰老引发的毛发脱落。
- 一种药物，其特征在于，所述药物中包含治疗有效量的权利要求1所述的多肽和或权利要求2所述的衍生物；所述药物具有靶向卵巢的作用、治疗或预防卵巢源疾病、治疗或预防高雄高脂导致的代谢紊乱、治疗或预防糖脂代谢紊乱、治疗或预防毛发脱落的用途。
- 一种治疗或预防卵巢源疾病、治疗或预防高雄高脂导致的代谢紊乱、治疗或预防糖脂代谢紊乱、或者治疗或预防毛发脱落的的方法，所述方法包括给与受试者治疗有效量的权利要求1所述的多肽、权利要求2所述的衍生物。
- 权利要求1所述的多肽和或权利要求2所述的衍生物作为抗原产生的抗体的用途，或者在制备检测试剂盒中的用途。
- 权利要求1所述的多肽和或权利要求2所述的衍生物在制备培养细胞及组织的工具中的应用；优选地，进一步地所述细胞及组织包括各个发育阶段的卵巢、子宫、骨、脑、心、肝脾、肺、肾、骨、脂肪。
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Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104673802A (zh) * | 2015-03-12 | 2015-06-03 | 山东大学第二医院 | 一种编码irisin蛋白的核酸分子以及利用该核酸分子高效表达irisin蛋白的方法 |
| CN104725500A (zh) * | 2015-03-11 | 2015-06-24 | 广州健坤生物科技有限公司 | 一种具有鸢尾素结构域类似功能的蛋白、包含该蛋白的组合物及其用途 |
| CN104725478A (zh) * | 2013-12-18 | 2015-06-24 | 苏州宝时得电动工具有限公司 | 多肽化合物、多肽化合物与siRNA的组装体及其应用 |
| CN105440112A (zh) * | 2015-12-07 | 2016-03-30 | 国家纳米科学中心 | 多肽-白蛋白偶联药物、其制备方法及应用 |
| CN106349356A (zh) * | 2016-08-31 | 2017-01-25 | 广州健坤生物科技有限公司 | 一种具有鸢尾素功能结构的蛋白及其应用 |
| CN106589066A (zh) * | 2016-11-03 | 2017-04-26 | 陕西师范大学 | 人卵巢癌细胞特异性结合的多肽及其应用 |
| CN107496908A (zh) * | 2017-09-04 | 2017-12-22 | 南京医科大学 | 鸢尾素在制备抗炎药物中的应用 |
| CN108285480A (zh) * | 2018-02-02 | 2018-07-17 | 南华大学 | 十二肽及其在制备治疗和/或诊断宫颈癌的产品中的应用 |
| CN108285479A (zh) * | 2018-02-02 | 2018-07-17 | 南华大学 | 七肽及其在制备治疗和/或诊断宫颈癌的产品中的应用 |
| CN108409836A (zh) * | 2018-01-08 | 2018-08-17 | 中国医科大学 | 一种多肽及其用途 |
| CN110684100A (zh) * | 2019-09-04 | 2020-01-14 | 山东大学第二医院 | 一种分泌型fndc5蛋白及其制备方法和应用 |
-
2022
- 2022-03-31 WO PCT/CN2022/084389 patent/WO2023184332A1/zh unknown
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104725478A (zh) * | 2013-12-18 | 2015-06-24 | 苏州宝时得电动工具有限公司 | 多肽化合物、多肽化合物与siRNA的组装体及其应用 |
| CN104725500A (zh) * | 2015-03-11 | 2015-06-24 | 广州健坤生物科技有限公司 | 一种具有鸢尾素结构域类似功能的蛋白、包含该蛋白的组合物及其用途 |
| CN104673802A (zh) * | 2015-03-12 | 2015-06-03 | 山东大学第二医院 | 一种编码irisin蛋白的核酸分子以及利用该核酸分子高效表达irisin蛋白的方法 |
| CN105440112A (zh) * | 2015-12-07 | 2016-03-30 | 国家纳米科学中心 | 多肽-白蛋白偶联药物、其制备方法及应用 |
| CN106349356A (zh) * | 2016-08-31 | 2017-01-25 | 广州健坤生物科技有限公司 | 一种具有鸢尾素功能结构的蛋白及其应用 |
| CN106589066A (zh) * | 2016-11-03 | 2017-04-26 | 陕西师范大学 | 人卵巢癌细胞特异性结合的多肽及其应用 |
| CN107496908A (zh) * | 2017-09-04 | 2017-12-22 | 南京医科大学 | 鸢尾素在制备抗炎药物中的应用 |
| CN108409836A (zh) * | 2018-01-08 | 2018-08-17 | 中国医科大学 | 一种多肽及其用途 |
| CN108285480A (zh) * | 2018-02-02 | 2018-07-17 | 南华大学 | 十二肽及其在制备治疗和/或诊断宫颈癌的产品中的应用 |
| CN108285479A (zh) * | 2018-02-02 | 2018-07-17 | 南华大学 | 七肽及其在制备治疗和/或诊断宫颈癌的产品中的应用 |
| CN110684100A (zh) * | 2019-09-04 | 2020-01-14 | 山东大学第二医院 | 一种分泌型fndc5蛋白及其制备方法和应用 |
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