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WO2003020752A1 - Peptide et produits pharmaceutiques le contenant - Google Patents

Peptide et produits pharmaceutiques le contenant Download PDF

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Publication number
WO2003020752A1
WO2003020752A1 PCT/CN2002/000310 CN0200310W WO03020752A1 WO 2003020752 A1 WO2003020752 A1 WO 2003020752A1 CN 0200310 W CN0200310 W CN 0200310W WO 03020752 A1 WO03020752 A1 WO 03020752A1
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WO
WIPO (PCT)
Prior art keywords
short peptide
bone marrow
present
peptide
cells
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2002/000310
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English (en)
Chinese (zh)
Inventor
Hui Zhong
Qingjun Ma
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Bioengineering Chinese Academy of Military Medical Sciences
Original Assignee
Institute of Bioengineering Chinese Academy of Military Medical Sciences
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institute of Bioengineering Chinese Academy of Military Medical Sciences filed Critical Institute of Bioengineering Chinese Academy of Military Medical Sciences
Publication of WO2003020752A1 publication Critical patent/WO2003020752A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • 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
    • 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
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • the present invention relates to a short peptide and a medicine using the short peptide as an active ingredient.
  • Osteogenic growth peptide is composed of 14 amino acids, which is exactly the same as the C-terminal 14 amino acids of histone H4. Endogenous OGP is the translation product of histone H4 raRNA at different translation initiation sites. The level of OGP in human serum is very high and is mainly secreted by osteoblasts and fibroblasts. In the blood, most OGPs combine with ⁇ 2 -macroglobulin and 0GP-binding protein (0GPBP) to form an inactive complex (Bab et al, 1992; Greenberg et al, 1997).
  • OGP secretes OGP, and OGP functions in an autocrine and paracrine manner (Bab et al. 1993).
  • the role of OGP is mainly reflected in two aspects: one is to promote bone formation, and the other is to promote bone marrow repair and hematopoietic function. Injecting 0GP to adult rats can significantly increase bone formation and trabecular bone density. In vitro experiments confirmed that OGP can promote the proliferation of osteoblasts.
  • Alkaline phosphatase activity is an indicator of the activity of osteoblasts and some fibroblasts. The level of alkaline phosphatase in animal serum is an important indicator of bone formation.
  • 0GP can stimulate osteoblasts cultured in vitro to secrete alkaline phosphatase, and the content of alkaline phosphatase in the serum of animals injected with 0GP will also increase significantly, indicating that 0GP also promotes osteoblast activity and bone formation (Bab et al, 1992).
  • Bone marrow stromal cells contain immature osteoblasts.
  • OGP can stimulate the osteogenic activity of human bone marrow stromal cells (ie, the process of osteoblast maturation) and matrix mineralization in vitro (Robinson et al, 1995). After bone marrow injury, there is a stage of bone formation in the early stage of bone marrow regeneration.
  • 0GP may be closely related to the repair process after bone marrow injury.
  • the formed bone trabeculae are replaced by newly formed bone marrow after being absorbed by osteoclasts (Bab et al. 1992, 1994).
  • the bone formation phase of bone marrow regeneration is regulated by many factors, and 0GP is one of the important factors (Bab 1993).
  • 0GP also has tuning The function of cell proliferation and hematopoietic function of bone marrow stromal cells.
  • Injecting 0GP to mice can not only increase the number of bone marrow cells, but also induce the increase in the number of various blood cells (white blood cells, red blood cells, platelets, etc.) in mice. Change the original ratio between these cells; mice that received a lethal dose of bone marrow radiation and had a bone marrow transplant, if injected with 0GP in advance, can double the bone marrow volume and rebuild blood function a week after transplantation, increasing survival rate About 3 times (Robinson et al, 1995; Gurevitch et al. 1996).
  • Hematopoietic factors currently used clinically mainly include granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), various Interleukins and erythropoietin (EP0), etc., but these factors can only promote the increase of specific blood cell lines.
  • G-CSF granulocyte colony-stimulating factor
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • EP0 erythropoietin
  • hematopoietic stem cells to self-proliferate is regulated by the bone marrow stroma microenvironment, including the normal ratio of various blood cell numbers. Factors that can only promote the proliferation of a single type of blood cell will increase the number of single type of blood cells, which will destroy this microenvironment and cause hematopoietic stem cells to lose their ability to proliferate, thereby reducing the body's own hematopoietic potential. 0GP can comprehensively promote the balanced increase of the number of various blood cells, and will not destroy the microenvironment required for the proliferation of hematopoietic stem cells, thus ensuring that the body maintains or restores normal hematopoietic functions. Therefore, in promoting the growth and hematopoietic function of bone marrow transplants in patients, 0GP has the unparalleled superiority of the above factors (Gurevitch et al. 1996).
  • the object of the present invention is to provide a short peptide which has the characteristics and advantages of OGP, has a smaller molecular weight than 0GP, is easy to synthesize, and has a medicinal value.
  • the short peptide provided by the present invention is composed of 5 amino acid residues, and its sequence is N'-YGFGG-C.
  • the short peptide of the present invention can be obtained by a conventional chemical synthesis method or a biosynthesis method.
  • the 5-peptide of the present invention has activities of promoting bone formation, promoting bone marrow proliferation, and promoting hematopoiesis; It has the same characteristics as or even better than OGP; the production process and required equipment are simple, the molecular weight is small, and the manufacturing cost is low.
  • the short peptides of the present invention can produce drugs that promote bone formation, bone marrow proliferation, hematopoietic and anti-fatigue, especially drugs used for tumor radiotherapy chemotherapy, anemia and aplastic anemia, radiation disease and other blood diseases.
  • the above-mentioned medicine may further contain one or more pharmaceutically acceptable carriers.
  • the carrier includes a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption enhancer, a surfactant, an adsorption carrier, a lubricant, etc., which are conventional in the pharmaceutical field, and a fragrance may be added if necessary.
  • the medicament of the present invention can be made into various forms such as tablets, powders, granules, capsules, oral solutions and injection solutions.
  • the medicines in the above various dosage forms can be prepared according to the conventional methods in the pharmaceutical field.
  • the amount of the drug per day typically 10- 7 mg / kg of body weight.
  • the medicament of the present invention has the following aspects.
  • hematopoietic factors used in clinical practice mainly include rhG-CSF and rhGM-CSF. These factors mainly act on hematopoietic stem cells to differentiate them into different white blood cells, thereby reducing the recovery time of white blood cells and neutrophils. After receiving chemoradiotherapy, the patient's blood cell count fell across the board, and the above hematopoietic factors only increased the number of white blood cells. Therefore, it must be used in combination with other factors to effectively restore the patient's hematopoietic function.
  • the short peptide of the present invention alone can increase the balance of various blood cell numbers.
  • Bone marrow transplantation is a life-saving treatment for various blood tumors, aplastic anemia, severe thalassemia, and some congenital immunodeficiency or metabolic diseases.
  • the number of patients receiving bone marrow transplantation in the world has increased year by year, showing that bone marrow transplantation has become the current treatment trend. If you can reduce the time to recover from a bone marrow transplant, you can reduce your chances of getting infected and reduce your hospital stay.
  • the current clinical treatment drugs for bone marrow transplantation are also rhG-CSF and rhGM-CSF. Their role is mainly to increase the body's ability to resist infection by increasing the number of white blood cells in a short period of time.
  • the short peptides of the present invention can stimulate the growth of bone marrow transplants in a short time on the one hand, and can also promote the recovery of blood cell levels by promoting the non-directional differentiation of hematopoietic stem cells on the other hand. From the point of view of the action mechanism of the short peptide of the present invention, 0GP should be able to provide better therapeutic effects than rhG-CSF and rhGM-CSF.
  • the short peptide of the present invention can stimulate the proliferation of bone marrow cells, the amount of bone marrow extraction from the donor can be reduced.
  • the current extraction volume is 1000 ml.
  • the transplantation volume can be reduced to tens or even several ml.
  • the short peptides of the present invention can be used to treat chronic cancerous anemia, aplastic anemia, and other anemia diseases.
  • Erythropoietin EP0 has the effect of promoting erythrocyte production, which can improve the athlete's physical level in a short time. Since a very small amount of EP0 can increase the level of red blood cells, and there is also endogenous EP0 in the human body, it is very difficult to test exogenous EP0. The use of EP0 will increase blood viscosity and cause hypertension and vascular embolism, which will cause harm to the body and life of athletes. EP0 is currently listed as a banned drug.
  • the short peptide of the present invention can promote the increase of the balance of various blood cells, including red blood cells. Therefore, the short peptide of the present invention is helpful for improving the athlete's physical level and promoting physical recovery, and the amount is small.
  • Osteoporosis is a bone metabolic disease with low bone mass and degeneration of bone tissue microstructure leading to increased bone fragility and subsequent increased risk of fracture. It is one of the common diseases of the elderly. With the aging of the world's population, osteoporosis treatment drugs have developed rapidly. These drugs are mostly developed based on the bone metabolism regulators that have been discovered. There are two common types: one is to promote bone formation therapy, which mainly uses parathyroid hormone and sodium fluoride drugs. The other is anti-absorption drugs such as estrogen and calcitonin. The short peptide of the present invention has the ability to promote bone formation and increase The effect of bone density can therefore also be used in the treatment of osteoporosis.
  • the short peptide of the present invention directly acts on osteoblasts, it does not cause side effects caused by other hormone drugs. Due to the promotion effect of the short peptide of the present invention on osteogenesis and bone marrow repair, it is also a good candidate drug for promoting fracture healing.
  • Figure 1 is a histogram of the effect of different drug concentrations on the formation of red blood cell colonies
  • Figure 2 is a histogram of the effects of different drug concentrations on granulocyte macrophage colony formation.
  • Figure 3 is a histogram of the effects of different drug concentrations on colony formation of megakaryocytes.
  • Figure 4 shows the reduction of bone marrow hematopoietic cells induced by cyclophosphamide in mice by the short peptide of the present invention.
  • FIG. 5 is a histogram of the recovery of the mouse bone marrow hematopoietic cells induced by cyclophosphamide in the short peptide of the present invention in the CFU-GM / lml system.
  • FIG. 6 is a histogram of the recovery of treatment of mice bone marrow hematopoietic cells induced by cyclophosphamide with a short peptide of the present invention in a CFU-MEG / 0.2ral system
  • FIG. 7 is a histogram of the short peptide-stimulated colony formation of progenitor cells of red blood cell lines
  • FIG. 8 is a histogram of the short peptide-stimulated colony formation of explosive red blood cell lines of the present invention.
  • Figure 9 is a histogram of granule cell macrophage cell colony formation stimulated by short peptides of the present invention
  • Fig. 10 is a histogram of colony formation of megakaryocytes stimulated by short peptides of the present invention
  • Figure 11 is a histogram of CD34 + group cell expansion stimulated by short peptides of the present invention
  • Example 1 Non-specific differentiation of mouse bone marrow hematopoietic stem cells stimulated by the short peptide of the present invention in vitro
  • the granulocyte-macrophage colony culture and counting culture system is: horse serum 2 ml, 5% agar 0.4 ml, the short peptide solution of the present invention or GM-CSF 0.76 ml, mouse bone marrow nucleated cells 1 X lOVml, 1640 medium was supplemented to 7.6ml, the body After mixing system, add lml of each dish, on 37 ⁇ C0 2 incubator, 6 days in culture counted by microscopic observation under saturated humidity, greater than or equal to a 50 cell colonies.
  • Results 1, 2, 3, 1, 1 is a positive control group (EP0), 2-6 groups with a short peptide of the invention as a stimulator cell culture, followed by concentration of 10- 6 ⁇ , 10- 7 ⁇ , 1 ( ⁇ 8 ⁇ , 10- 9 ⁇ , 10- 10 ⁇ ; FIG.
  • 21 is a positive control group (GM- CSF), 2-6 groups with a short peptide of the invention as a stimulation of cell culture factor, followed by concentration of 10- 6 ⁇ , 10- 7 ⁇ , 10- 8 ⁇ , 10- 9 ⁇ , 10 '1% in FIG.
  • GM- CSF positive control group
  • 2-6 groups with a short peptide of the invention as a stimulation of cell culture factor followed by concentration of 10- 6 ⁇ , 10- 7 ⁇ , 10- 8 ⁇ , 10- 9 ⁇ , 10 '1% in FIG.
  • FIG. 31 is a positive control group (IL-11), 2-5 of the present invention with group cell culture as a short peptide stimulating factor, followed by concentration of 10- 6 ⁇ , 1 ( ⁇ 7 ⁇ , 10- 8 ⁇ , 10 ,, 10 "10 ⁇ ⁇ can be seen from the results in FIG short peptides of the invention process
  • concentration of 10- 6 ⁇ , 1 ⁇ 7 ⁇ , 10- 8 ⁇ , 10 ,, 10 "10 ⁇ ⁇ can be seen from the results in FIG short peptides of the invention process
  • the colony formation of erythrocytes, granulocytes-macrophages, and megakaryocytes is significantly increased. This indicates that the short peptide of the present invention can stimulate non-directional differentiation of mouse bone marrow hematopoietic stem cells ability.
  • Example 2 Provide the increase of various blood cells in the bone marrow of mice after chemotherapy
  • mice (20-24 g) were treated with the chemotherapy drug cyclophosphamide, which caused hematopoietic damage. Mice were injected intraperitoneally with cyclophosphamide, O. lrag / g body weight, once a day for 3 consecutive days. After 3 days of discontinuation, the number of bone marrow nucleated cells and peripheral blood whole blood indexes decreased to a minimum.
  • Treatment of the short peptide of the present invention Mice's quadriceps were injected with 100 ⁇ 1 of the short peptide aqueous solution of the present invention in each group, once a day for 5 consecutive days, and cyclophosphamide was injected intraperitoneally on the 3rd, 4th, and 5th days.
  • mice were taken from each group, and blood was collected from the posterior orbital vein. Each 0.5ml blood sample was treated with 7.5% EDTA 10 ⁇ 1 for anticoagulation. The mice in each group were tested separately. Red blood cell, white blood cell and platelet indicators.
  • mice were treated with cyclophosphamide (Cy) and phenylhydrazine (Pa), and the effect of 0GP-5 peptide on the recovery of mature blood cells in mice was observed.
  • Mice intramuscularly injected 0GP-5 peptide once a day for 5 consecutive days, and intraperitoneally injected cyclophosphamide (0.1 mg / g body weight) and phenylhydrazine (0.06 mg / g body weight) on the 3rd, 4th, and 5th days.
  • Table 1 0GP-5 peptide promotes the increase in the balance of various blood cells in peripheral blood of mice after chemotherapy
  • Example 4 Provide non-directional differentiation and proliferation of human umbilical cord blood hematopoietic stem cells
  • Umbilical cord blood hematopoietic stem cell transplantation has received increasing attention and has become an alternative method of allogeneic bone marrow transplantation. It is one of the most significant advances in the field of hematopoietic stem cell transplantation in the past decade.
  • the current in vitro expansion of umbilical cord blood hematopoietic stem cells is mainly a combination of several different hematopoietic growth factors.
  • the results of the present invention show that umbilical cord blood hematopoietic stem cells have been cultured in vitro. Different concentrations of 0GP-5 peptide were added during the course.
  • FIG. 7-11 After about one week of culture, it was found that the progenitor cell colonies of the red line, granulocyte, and macrophage cell lines all reached or exceeded the positive control.
  • the results are shown in Figure 7-11. 7, 8, 1-8 are set with a short peptide of the present invention as a cell culture stimulating factor, followed by concentration of 10- '2 -10- 5 M, 9 for the positive control group (EP 0);
  • FIG. 9, 1-8 group CSF are short peptides of this invention as a cell culture, followed by concentration of 10- 12 - 10- 5 M, 9 for the positive control group (G- CSF); in FIG.
  • each group 1-8 In order to use the short peptide of the present invention as a stimulating factor for cell culture, the concentration is 10- 12 -1 ( ⁇ 5 M, 9 groups are positive control (IL-11); in FIG. 11, the cytokines of the mixed group include IL-3 , IL- 6, IL-11, SCF, EP, OGP- 5 groups with different doses of 10— "M, 1 (T 8 M, 10" 5 M c
  • mice randomized, normal saline control group, group administered injections peptide of the present invention is a pharmaceutical active ingredient, a dose of 10- 8 g / mouse / day, 5 days, after the last administration on day 3
  • the swimming experiment and the hypoxia capacity experiment were performed.
  • the results showed that the administration group could significantly increase the hypoxia capacity of the mice at normal pressure, and could significantly extend the weight-bearing swimming time of the mice, and had anti-fatigue effects.
  • Table 1 The results are shown in Table 1.
  • the short peptides of the present invention can be widely used in the manufacture of medicines that promote bone formation, promote bone marrow proliferation, promote hematopoietic, adjuvant radiotherapy and chemotherapy, treat anemia and aplastic anemia, anti-fatigue, treat radiation diseases and other blood diseases.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Physical Education & Sports Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un type de pentapeptides et des produits pharmaceutiques le contenant en tant que principe actif. L'invention porte sur des produits pharmaceutiques contenant lesdits peptides pour accélérer l'ostéose, la myélose et l'hématogenèse. La séquence du reste d'acide aminé des peptides de l'invention est représentée par N'-YGFGG-C'. Lesdits peptides sont largement utilisés pour la préparation de produits pharmaceutiques pour l'accélération de l'ostéose, de la myélose et de l'hématogenèse, en vue de contribuer à une thérapie radicale anti-tumorale, pour le traitement de l'anémie et de l'anémie aplastique, pour la résistance à la fatigue, pour le traitement de maladies dues au rayonnement ou d'autres hémopathies.
PCT/CN2002/000310 2001-09-05 2002-05-08 Peptide et produits pharmaceutiques le contenant Ceased WO2003020752A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN01123684.1 2001-09-05
CN01123684A CN1403474A (zh) 2001-09-05 2001-09-05 一种短肽及以其为活性成份的药物

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WO2003020752A1 true WO2003020752A1 (fr) 2003-03-13

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101999662A (zh) * 2010-06-17 2011-04-06 苟春虎 治疗骨质疏松胶囊
WO2012166594A1 (fr) * 2011-05-27 2012-12-06 The University Of Akron Matières polymères bioactives réticulées par un peptide

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016002717A1 (fr) * 2014-06-30 2016-01-07 国立大学法人名古屋大学 Promoteur de l'ostéogenèse
CN111647042A (zh) * 2019-07-10 2020-09-11 中南大学湘雅二医院 骨重建调节多肽及应用
CN112646042A (zh) * 2019-10-10 2021-04-13 陕西麦科奥特科技有限公司 活性多肽化合物
CN119912524B (zh) * 2025-04-01 2025-07-04 南方医科大学第三附属医院（广东省骨科研究院） 一种用于促骨形成g5类似肽或其可药用盐

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4487764A (en) * 1981-11-25 1984-12-11 Hoechst Aktiengesellschaft New peptides and a process for their preparation
US5484770A (en) * 1988-09-16 1996-01-16 Hafslund Nycomed Bioreg As Peptide compounds which inhibit the proliferation of epidermal or epithelial stem cells
WO1998030581A1 (fr) * 1997-01-07 1998-07-16 Primamedic Ltd. Myelopeptides et leur utilisation therapeutique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4487764A (en) * 1981-11-25 1984-12-11 Hoechst Aktiengesellschaft New peptides and a process for their preparation
US5484770A (en) * 1988-09-16 1996-01-16 Hafslund Nycomed Bioreg As Peptide compounds which inhibit the proliferation of epidermal or epithelial stem cells
WO1998030581A1 (fr) * 1997-01-07 1998-07-16 Primamedic Ltd. Myelopeptides et leur utilisation therapeutique

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101999662A (zh) * 2010-06-17 2011-04-06 苟春虎 治疗骨质疏松胶囊
WO2012166594A1 (fr) * 2011-05-27 2012-12-06 The University Of Akron Matières polymères bioactives réticulées par un peptide

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