CN114560924B - Selenium-containing teriparatide and fusion polypeptide for promoting osteoblast differentiation and application thereof - Google Patents
Selenium-containing teriparatide and fusion polypeptide for promoting osteoblast differentiation and application thereof Download PDFInfo
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/29—Parathyroid hormone (parathormone); Parathyroid hormone-related peptides
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- A—HUMAN NECESSITIES
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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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
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- C07K14/635—Parathyroid hormone (parathormone); Parathyroid hormone-related peptides
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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
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/76—Albumins
- C07K14/765—Serum albumin, e.g. HSA
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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
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/76—Albumins
- C07K14/77—Ovalbumin
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses selenium-containing teriparatide and fusion polypeptide for promoting osteoblast differentiation and application thereof. The parent amino acid sequence of the selenium-containing teriparatide is SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF. The selenium-containing teriparatide provided by the invention can effectively promote the proliferation and mineralization of osteoblasts, prevent and/or treat osteoporosis, relieve the pain of patients with osteoporosis, and has the characteristics of high efficiency and low toxicity, and can be further developed into medicines.
Description
Technical Field
The invention relates to the technical field of active peptides. More particularly, it relates to selenium-containing teriparatide for promoting osteoblast differentiation and application thereof.
Background
In recent years, along with the aging development of the social population of China, the occurrence rate of Osteoporosis (OP) and the total number of patients gradually increase, and the OP and the total number of patients become increasingly important health problems of human beings, and have the advantages of high treatment cost, more complications and poor survival quality of patients, and bring heavy burden to families and society. How to effectively prevent and treat osteoporosis is an important problem which is the focus of research and needs to be solved urgently by scientific researchers at present. Related researches prove that osteoblasts are in a very critical position in the pathological process of the whole disease occurrence and development of osteoporosis, not only play an irreplaceable role in the bone tissue formation process, but also can directly synthesize and secrete more cytokines, further play a decisive role in biological behaviors such as the growth, differentiation and the like of the osteoclasts, and finally effectively regulate and control the bone tissue absorption process of an organism. Osteoblasts are functional cells with potential capability of forming bone tissues, and have important clinical significance for effectively accelerating proliferation speed and promoting osteogenic differentiation process.
Teriparatide (teriparatide) is a synthetic polypeptide hormone, is a No. 1-34 amino acid fragment of human parathyroid hormone PTH, and is H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH, and is a common polypeptide medicament for clinically treating osteoporosis at present. It is the first new class of bone forming agents approved by the FDA of the U.S. food and drug administration, and this parathyroid hormone derivative can promote bone growth by increasing the activity and number of osteoblasts, whereas current conventional osteoporosis drugs generally act only on osteoclasts to slow or block bone loss. Recent clinical studies involving 1637 postmenopausal osteoporosis patients showed that 96% of patients showed a significant increase in bone (mineral) density BMD in both spine and buttocks after treatment with the drug, compared to those who had been administered calcium and vitamin D supplements alone. It has also been found that the agent reduces the risk of developing spinal fractures and other types of fractures by 65% and 53%, respectively. Another characteristic of the medicine is that the side effects are relatively small.
Selenium (Se) is a life-essential micronutrient which has received a great deal of attention and is involved in various biological processes such as antioxidant defense, thyroid hormone production and immune response through selenoprotein (selenase). Although the importance of selenium for bone metabolism is not clear, some clinical diseases such as sarcoidosis are associated with selenium deficiency. Although selenium deficiency can lead to growth retardation, it has not been determined whether such growth inhibition is associated with changes in bone metabolism. Meanwhile, various selenium-containing enzymes are expressed in bone cells, but the nutrition and physiological effects of selenium and bone health are still unknown. The benefit of the trace element selenium to human health is widely accepted, and bioactive selenium peptide is one of the important organic sources for supplementing selenium. With the increasing search for the nutritional value associated with selenium and its derivatives, various potential health benefits of selenium peptides in addition to their basic nutritional value have been increasingly discovered. The clinical anti-osteoporosis polypeptide medicine is as follows: the teriparatide is characterized in that the teriparatide is used as an active structure as a center, a methionine-containing or cysteine-containing sequence is replaced by seleno-amino acid or selenocysteine, or a certain amount of seleno-amino acid or selenocysteine is added to a polypeptide sequence, so that the artificial synthesis of the selenide is designed. The seleno-peptide has high biological safety, low antigenicity, low allergy, high solubility, etc. Therefore, searching for efficient seleno-peptide which is beneficial to osteoblast differentiation process has very important significance for developing anti-osteoporosis drugs.
Disclosure of Invention
The first object of the present invention is to provide selenium-containing teriparatide which has high activity and low toxicity and promotes mineralization of osteoblasts.
A second object of the present invention is to provide the use of selenium-containing teriparatide as described above for promoting osteoblast differentiation and for preventing and/or treating osteoporosis.
In order to achieve the above purpose, the invention adopts the following technical scheme:
according to a first object of the present invention there is provided a selenium-containing teriparatide, the amino acid sequence of which comprises one or more of the following sequences:
(1) SVSEIQL { SeM } HNLGKHLNSMERVEWLRKKLQDVHNF; wherein methionine at position 8 in the parent teriparatide sequence is replaced by selenomethionine;
(2) SVSEIQLMHNLGKHLNS { SeM } ERVEWLRKKLQDVHNF; wherein, 18-bit methionine in the parent teriparatide sequence is replaced by selenomethionine;
(3) SVSEIQL { SeM } HNLGKHLNS { SeM } ERVEWLRKKLQDVHNF; wherein, 8-position methionine and 18-position methionine in the parent teriparatide sequence are replaced by selenomethionine;
further, the present invention provides a fusion polypeptide comprising one of the selenium-containing teriparatide described above. The fusion polypeptide may be obtained by chemical binding, cleavage or physical cleavage. Such as protein complexes formed by the polypeptide with ovalbumin or bovine serum albumin.
The selenium-containing teriparatide of the present invention may be prepared by other methods known in the art, such as solid phase synthesis methods, bioengineering methods, and the like.
According to a second object of the present invention, there is provided the use of said selenium-containing teriparatide in a medicament for promoting osteoblast differentiation. Further provides the application of the selenium-containing teriparatide in preparing medicines for preventing and/or treating osteoporosis.
The invention further relates to a medicament comprising a selenium-containing teriparatide of the invention, e.g. SVSEIQL { SeM } HNLGKHLNSMERVEWLRKKLQDVHNF (replacement of methionine at position 8 in the parent teriparatide sequence with selenomethionine); SVSEIQLMHNLGKHLNS { SeM } ERVEWLRKKLQDVHNF (18 methionine replaced with selenomethionine in the parent teriparatide sequence); one or more of SVSEIQL { SeM } HNLGKHLNS { SeM } ERVEWLRKKLQDVHNF (8, 18 methionine in the parent teriparatide sequence are replaced with selenomethionine).
The medicaments of the present invention may be formulated in a variety of forms common in the art, including, but not limited to, powders, tablets (including various coated tablets, slow-or controlled-release tablets), lozenges, capsules (including soft and hard capsules), granules, pills, dispersible powders, aqueous or oily suspensions, aqueous or oily solutions, emulsions, elixirs, syrups and the like, suitable for topical use, creams, ointments, gels, aqueous or oily solutions, aqueous or oily suspensions and the like; a powder or liquid aerosol suitable for inhalation; sterile aqueous or oily injection or lyophilized powder for injection, suppository, etc. suitable for parenteral administration for intravenous, subcutaneous or intramuscular injection.
The medicament of the invention can further contain various conventional auxiliary materials and/or other active ingredients. Suitable excipients include, but are not limited to, excipients, lubricants, binders, disintegrants, water soluble polymers, inorganic salts, solvents, dissolution aids, suspending agents, isotonic agents, buffers, preservatives, antioxidants, colorants, sweeteners, acidulants, foaming agents, flavoring agents and the like.
The beneficial effects of the invention are as follows:
the selenium-containing teriparatide can effectively promote the mineralization of osteoblasts, prevent and/or treat osteoporosis, relieve the pain of patients suffering from osteoporosis, and has the characteristics of high efficiency and low toxicity.
Drawings
FIG. 1 is a graph showing comparison of proliferation rates of selenium-containing teriparatide and teriparatide in MC3T3-E1 cells of mice for 24 hours.
FIG. 2 is a graph showing comparison of proliferation rates of selenium-containing teriparatide and teriparatide in MC3T3-E1 cells of mice for 48 hours.
FIG. 3 is a graph showing comparison of proliferation rates of selenium-containing teriparatide and teriparatide in MC3T3-E1 cells of mice over 72 hours.
FIG. 4 is a graph showing comparison of 24h selenium-containing teriparatide and teriparatide activity against mouse MC3T3-E1 cell alkaline phosphatase.
FIG. 5 is a graph showing comparison of 48h selenium-containing teriparatide and teriparatide activity against mouse MC3T3-E1 cell alkaline phosphatase.
FIG. 6 is a graph showing comparison of the activity of selenium-containing teriparatide and teriparatide against mouse MC3T3-E1 cell alkaline phosphatase for 72 h.
Detailed Description
In order to more clearly illustrate the present invention, the present invention will be further described with reference to preferred embodiments and the accompanying drawings. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and that this invention is not limited to the details given herein.
EXAMPLE 1 Effect of selenium-containing teriparatide on proliferation of mouse osteoblasts MC3T3-E1
Based on the amino acid sequences of 3 selenium-containing teriparatide designed and obtained in the figures 1-3, experimental samples are obtained through a solid phase synthesis method, and osteoblast proliferation activity verification is carried out. Solid phase synthetic peptides company: jier Biochemical (Shanghai) Co., ltd.
Detection of proliferation rate of mouse osteoblast MC3T 3-E1:
osteoblasts MT3T3-E1 were selected for growth in log phase, according to 2X 10 4 Density of individual/mL cells were added to 96-well plates, 100 μl of cell suspension per well, experiment set to 5 groups, blank group: only DMEM medium containing 1% fetal bovine serum was added; positive control group: adding 0 final concentration except DMEM medium containing 1% fetal calf serum; 62.5;125;250;500ug/mL teriparatide; peptide group No. 1: adding 0 final concentration except DMEM medium containing 1% fetal calf serum; 62.5;125;250;500ug/mL of selenium-containing teriparatide No. 1; peptide group No. 2: adding final concentration 0 except for adding DMEM medium containing 1% fetal bovine serum; 62.5;125;250;500ug/mL of selenium-containing teriparatide No. 2; peptide group No. 3: adding final concentration 0 except for adding DMEM medium containing 1% fetal bovine serum; 62.5;125;250;500ug/mL of selenium-containing teriparatide No. 3. 4 compound holes are arranged in each experimental group, the proliferation rate of cells in each group is detected by MTT method after medicine is added for 24h, 48h and 72h, 20 mu L of MTT (5 g/L) is added 4h before the experiment is finished, and then the temperature is 37 ℃ and the concentration of CO is 5% 2 Incubation is performed for 4 hours under the temperature condition, after the culture solution is sucked and discarded, 0.15mL of dimethyl sulfoxide solution is added, after shaking is performed for a few minutes until crystals are completely dissolved, an enzyme-labeled instrument is used for detecting absorbance (OD value) of the crystals, detection wavelength=570 nm, and reference wavelength=630 nm. The cell proliferation rate was calculated as: proliferation rate = (a sample-a blank)/(a blank serum-a blank) ×100%.
EXAMPLE 2 Effect of selenium-containing teriparatide on mouse MT3T3-E1 cell alkaline phosphatase
Detection of mouse osteoblast MT3T3-E1 alkaline phosphatase activity:
selecting a log-phaseLong osteoblasts MT3T3-E1 according to 2X 10 4 Density of individual/mL cells were added to 96-well plates, 100 μl of cell suspension per well, experiment set to 5 groups, blank group: only DMEM medium containing 1% fetal bovine serum was added; positive control group: adding 0 final concentration except DMEM medium containing 1% fetal calf serum; 62.5;125;250;500ug/mL teriparatide; peptide group No. 1: adding 0 final concentration except DMEM medium containing 1% fetal calf serum; 62.5;125;250;500ug/mL of selenium-containing teriparatide No. 1; peptide group No. 2: adding final concentration 0 except for adding DMEM medium containing 1% fetal bovine serum; 62.5;125;250;500ug/mL of selenium-containing teriparatide No. 2; peptide group No. 3: adding final concentration 0 except for adding DMEM medium containing 1% fetal bovine serum; 62.5;125;250;500ug/mL of selenium-containing teriparatide No. 3. After 4 duplicate wells were set up for each experimental group, the culture solution was aspirated and discarded after 24h, 48h and 72h of drug intervention, thoroughly washed 2 times with PBS buffer, 100. Mu.L of cell lysate (1% Triton X-100) was added to each well, and the lysis was performed at 4℃for 30 minutes according to the instructions of the alkaline phosphatase assay kit (Biyun Tian).
EXAMPLE 3 Effect of selenium-containing teriparatide on mineralization of nodules in mouse MT3T3-E1 cells
Determination of mineralized nodules of mouse osteoblasts MT3T 3-E1:
osteoblasts MT3T3-E1 were selected for growth in log phase, according to 1X 10 5 The density of each cell per mL is added into a 6-hole plate, each hole is 2mL of cell suspension, after 24h of culture, the original culture solution is sucked and discarded, the culture solution is replaced by the culture solution without fetal bovine serum, after 24h of starved cells are attached to the cell, the culture solution without fetal bovine serum is sucked and discarded, the experiment is set as 5 groups, and the blank control group: only DMEM medium containing 1% fetal bovine serum and three osteoinductive agents (dexamethasone 10nmol, sodium beta-glycerophosphate 10mmol, ascorbic acid 5 μg/ml) were added; positive control group: in addition to DMEM medium containing 1% foetal calf serum and three osteoinductive agents (dexamethasone 10nmol, sodium beta-glycerophosphate 10mmol, ascorbic acid 5. Mu.g/mL), teriparatide was added at a final concentration of 250 ug/mL; peptide group No. 1: except for adding 1%Except for DMEM medium of fetal bovine serum and three osteogenic inducers (dexamethasone 10nmol, sodium beta-glycerophosphate 10mmol, ascorbic acid 5 μg/mL), selenium-containing teriparatide No. 1 with a final concentration of 250ug/mL is added; peptide group No. 2: except for adding DMEM medium containing 1% fetal bovine serum, no. 2 selenium-containing teriparatide with a final concentration of 250ug/mL is added; peptide group No. 3: in addition to the DMEM medium containing 1% fetal bovine serum, selenium-containing teriparatide No. 3 was added at a final concentration of 250 ug/mL. 4 multiple wells were set per experimental group at 37deg.C with 5% CO 2 After 14 and 21 days of incubation, the medium was discarded and washed twice with PBS. Then, according to the instruction of the cell calcein red staining kit, the mineralized nodules among MT3T3-E1 cells are observed and counted under an inverted microscope.
Detection of mouse osteoblast MT3T3-E1 supernatant osteocalcin:
mouse embryo osteoblast precursor cell MC3T3-E1 is inoculated into a 24-hole cell culture plate, and after the cells are attached to the wall, the culture medium is discarded after 24 hours. Experiments were set to 5 groups, blank control group: positive control group was incubated with DMEM containing 1% fetal bovine serum alone: in addition to the DMEM medium containing 1% fetal bovine serum, teriparatide was added at a final concentration of 250 ug/mL; peptide group No. 1: except for adding DMEM medium containing 1% fetal bovine serum, selenium-containing teriparatide No. 1 with the final concentration of 250ug/mL is added; peptide group No. 2: except for adding DMEM medium containing 1% fetal bovine serum, no. 2 selenium-containing teriparatide with a final concentration of 250ug/mL is added; peptide group No. 3: in addition to the DMEM medium containing 1% fetal bovine serum, selenium-containing teriparatide No. 3 was added at a final concentration of 250 ug/mL. Distributed culture for 14 days and 21 days. After the culture is finished, collecting the culture medium, and detecting the osteocalcin content of the culture medium by using a radioimmunoassay kit to obtain the osteocalcin content of the sample.
In conclusion, the selenium-containing teriparatide proved by the embodiment of the invention has better functions of promoting the proliferation of mouse osteoblasts MT3T3-E1, and the secretion and mineralization of alkaline phosphatase, and is a bioactive selenium peptide with potential of preventing/treating osteoporosis.
TABLE 1 teriparatide He Hanxi teriparatide amino acid sequence
TABLE 2 comparison of mineralized nodule counts of selenium-containing teriparatide and teriparatide on mouse embryonic osteoblasts MC3T3-E1
TABLE 3 comparison of the content of osteocalcin in mouse embryonic osteoblasts MC3T3-E1 with selenium-containing teriparatide and teriparatide
It should be understood that the foregoing examples of the present invention are provided merely for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention, and that various other changes and modifications may be made therein by one skilled in the art without departing from the spirit and scope of the present invention as defined by the appended claims.
Claims (10)
1. Selenium-containing teriparatide for promoting osteoblast differentiation, characterized in that the amino acid sequence of the selenium-containing teriparatide is selected from one of the following sequences:
(1) SVSEIQL { SeM } HNLGKHLNSMERVEWLRKKLQDVHNF; wherein methionine at position 8 in the parent teriparatide sequence is replaced by selenomethionine;
(2) SVSEIQLMHNLGKHLNS { SeM } ERVEWLRKKLQDVHNF; wherein, 18-bit methionine in the parent teriparatide sequence is replaced by selenomethionine;
(3) SVSEIQL { SeM } HNLGKHLNS { SeM } ERVEWLRKKLQDVHNF; wherein, 8-position methionine and 18-position methionine in the parent teriparatide sequence are replaced by selenomethionine;
2. a fusion polypeptide comprising any of the selenium-containing teriparatide of claim 1.
3. The fusion polypeptide of claim 2, wherein the fusion polypeptide is a protein complex formed by linking the selenium-containing teriparatide to a carrier protein.
4. A fusion polypeptide according to claim 3 wherein the carrier protein is ovalbumin or bovine serum albumin.
5. Use of selenium-containing teriparatide according to claim 1 for the preparation of a medicament for promoting osteoblast differentiation.
6. Use of selenium-containing teriparatide according to claim 1 for the preparation of a medicament for the prevention and/or treatment of osteoporosis.
7. A medicament comprising the selenium-containing teriparatide of claim 1.
8. The seleno-teriparatide-containing medicament of claim 7, comprising SVSEIQL { SeM } HNLGKHLNSMERVEWLRKKLQDVHNF, wherein methionine at position 8 in the parent teriparatide sequence is replaced with selenomethionine.
9. The selenium-containing teriparatide drug of claim 7, comprising SVSEIQLMHNLGKHLNS { SeM } ERVEWLRKKLQDVHNF, wherein methionine at position 18 in the parent teriparatide sequence is replaced with selenomethionine.
10. The seleno-teriparatide-containing medicament according to claim 7, comprising SVSEIQL { SeM } HNLGKHLNS { SeM } ER VEWLRKKLQDVHNF, wherein methionine at positions 8, 18 of the parent teriparatide sequence is replaced with selenomethionine.
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| 富硒对黄粉虫蛋白分布及其酶解多肽抗氧化活性的影响;林晏因等;现代食品科技;第33卷(第06期);第53-61页 * |
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