US20140179619A1 - Polypeptide, nucleotide sequence thereof, and method for using the same for preventing dna synthesis and inhibiting cell proliferation - Google Patents

Polypeptide, nucleotide sequence thereof, and method for using the same for preventing dna synthesis and inhibiting cell proliferation Download PDF

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US20140179619A1
US20140179619A1 US14/187,354 US201414187354A US2014179619A1 US 20140179619 A1 US20140179619 A1 US 20140179619A1 US 201414187354 A US201414187354 A US 201414187354A US 2014179619 A1 US2014179619 A1 US 2014179619A1
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cells
polypeptide
ptd
cell proliferation
dna
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Junbo HU
Xianmin XIA
Guihua Wang
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Wuhan Yicheng Biotech Inc
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Wuhan Yicheng Biotech Inc
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Assigned to WUHAN YICHENG BIOTECH. INC. reassignment WUHAN YICHENG BIOTECH. INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HU, Junbo, WANG, GUIHUA, XIA, XIANMIN
Publication of US20140179619A1 publication Critical patent/US20140179619A1/en
Priority to US15/071,178 priority Critical patent/US9498510B2/en
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/10—Fusion polypeptide containing a localisation/targetting motif containing a tag for extracellular membrane crossing, e.g. TAT or VP22
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/60—Fusion polypeptide containing spectroscopic/fluorescent detection, e.g. green fluorescent protein [GFP]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/10—Screening for compounds of potential therapeutic value involving cells

Definitions

  • the invention relates to a polypeptide, a nucleotide sequence thereof, and a method for using the same for preventing DNA synthesis and inhibiting cell proliferation.
  • the protein BCR-ABL expressed in many leukemia cells which has relatively strong protein kinase activity and plays an important role in the occurrence and development of leukemia.
  • Glivec is used in treatment for leukamia.
  • PCNA proliferating cell nuclear antigen
  • the polypeptide in the invention has the biological function of preventing PCNA from binding DNA polymerase thereby inhibiting cell division, and can effectively inhibit the growth of tumors in animals.
  • a polypeptide preventing DNA synthesis and inhibiting cell proliferation the polypeptide being represented by SEQ. ID NO. 1: methionine-proline-tyrosine-serine-threonine-glutamic acid-leucine-isoleucine-phenylalanine -tyrosine-isoleucine-glutamic acid-methionine-asparaginic acid-proline.
  • a method for treatment of a tumor in a patient comprising administering to the patient a therapeutically-effective amount of the polypeptide.
  • the invention also provides an isolated polynucleotide comprising a nucleotide sequence encoding the polypeptide, the nucleotide sequence comprising a double stranded DNA comprising a first single strand represented by SEQ. ID. NO. 3 and a second single strand represented by SEQ. ID. NO. 4.
  • a method for treatment of a tumor in a patient comprising administering to the patient a therapeutically-effective amount of the isolated nucleotide.
  • the invention also provides a fused polypeptide PTD-P15 represented by SEQ. ID. NO. 2: arginine-asparaginic acid-leucine-tyrosine-asparaginic acid-asparaginic acid-asparaginic acid-lysine-asparaginic acid-arginine-methionine-proline-tyrosine-serine-threonine-glutamic acid-leucine-isoleucine-phenylalanine-tyrosine-isoleucine-glutamic acid-methionine-asparaginic acid-proline.
  • the invention also provides a method for treatment of a tumor in a patient comprising administering to the patient a therapeutically-effective amount of the fused polypeptide PTD-P15.
  • the amino acid sequence of the polypeptide is represented by SEQ. ID. NO. 1: methionine-proline-tyrosine-serine-threonine-glutamic acid-leucine-isoleucine-phenylalanine-tyrosine-isoleucine-glutamic acid-methionine-asparaginic acid-proline; hereinafter the polypeptide is called as P15.
  • P15 methionine-proline-tyrosine-serine-threonine-glutamic acid-leucine-isoleucine-phenylalanine-tyrosine-isoleucine-glutamic acid-methionine-asparaginic acid-proline
  • P15 methionine-proline-tyrosine-serine-threonine-glutamic acid-leucine-isoleucine-phenylalanine-tyrosine-isoleucine-glutamic acid-methionine-asparaginic acid-
  • the key to testify the above model is to introduce P15 into cells and observe the impact of P15 on cell division.
  • a DNA construction which codes the fused protein comprising P15 and green fluorescent protein (GFP), thereafter transferred the construction into cultured human cells, and then observed the change of expressed fuse protein P15-GFP in cell cycle.
  • GFP green fluorescent protein
  • a fused polypeptide PTD-P15 comprising a polypeptide fragment and P15 having the ability to penetrate cytomembrane.
  • the amino acid sequence of PTD is represented by SEQ. ID. NO.
  • the experiment results show that, when P15 is expressed in several kinds of cultured cell lines with growth and division abilities or PTD-P15 is added in, P15 will inhibit the ability of PCNA to bind DNA polymerase, causing a significant reduction in the observational index regarding DNA synthesis and other several ones testifying cell proliferation, which proves that P15 has the ability to inhibit cell proliferation; and the injection of PTD-P15 can inhibit cell proliferation and the growth of tumor in animal model.
  • P15 has the ability to block PCNA from binding DNA polymerase, thus the DNA replication facilitated by DNA polymerase is inhibited, resulting in cell cycle arrest. This provides a new method and approach to design and screen new drugs for treatment of tumor and another disease resulting from abnormal cell proliferation. Simultaneously, PTD-P15 can effectively inhibit tumor growth. This proves that P15 still has the biological effect to inhibit cell proliferation even after penetrating cytomembrane, and also shows that polypeptides or molecules with the ability to penetrate cytomembrane can be used in helping P15 with biological activity to penetrate cytomembrane.
  • P15 has low toxic and side effects and weak antigenicity, and according to the experimental results, it is found that, without obvious impact on apoptosis, P15 has no obvious lethal effect on normal cells. When PTD-P15 is added into cultured cells or applied to animals, no obvious toxicity is observed.
  • PTD-P15 With small molecular weight, PTD-P15 can be chemically synthesized, and is convenient for direct large-scale application in clinic. And also, we can inject P15 into cells using other methods (e.g. the use of plasmid or virus vectors) to treat tumor resulting from abnormal cell proliferation.
  • FIG. 1 shows PTD-P15 blocks PCNA from binding DNA polymerase.
  • HT29 rectal cancer cells from patients were cultivated in culture dishes, into which the control polypeptide or different amounts of PTD-P15 were added. After a night of cultivation, cells were collected, and the amount of DNA polymerase bound by PCNA in cells was tested with co-imunoprecipitation. Results show that, the addition of PTD-P15 can reduce the DNA polymerase bound by PCNA, because the amount of DNA polymerase bound by PCNA is closely related with DNA replication. Thus, it is shown that, PTD-P15 can lower the speed of DNA replication. So long as the ability of PCNA to bind DNA polymerase is blocked, the function of the polymerase to facilitate DNA replication is inhibited, and cell division is blocked.
  • FIGS. 2A , 2 B, 2 C and 2 D show different cell cycles inhibited by PTD-P15.
  • HT29 rectal cancer cells from patients were cultivated in culture dishes, into which the control polypeptide or different amounts of PTD-P15 were added. After 24-hours of cultivation, cells were collected, and the percentage of cells in different cell cycles is tested. Results show that, PTD-P15 can increase amounts of cells in phase G 0 /G 1 , while decrease the amount of cells in phase S and G 2 /M, which shows that PTD-P15 can inhibit cell cycle.
  • Vector pEGFP-N 1 was purchased from American Clontech (Cat No. 6085-1).
  • the plasmid including cDNA that can code GFP was digested with EcoRI-BamHI (purchased from American Promega, Cat No. R6011, R6021), and then the digested plasmid was separated and purified in agarose gel for future coupled reaction.
  • the reagent kit used for DNA fragment recovery was purchased from German Qiagen (Cat No. 28704).
  • the cDNA coding P15 was from double stranded DNA by means of artificial synthesis, comprising:
  • Single strand 1 represented by SEQ. ID. NO. 3: 5′TTTTGAATTCATGCCCTATTCGACAGAACTGATATTTTATATTGAAAT GGATCCTGGATCC; and Single strand 2 represented by SEQ. ID. NO. 4: 5′TTTTGGATCCAGGATCCATTTCAATATAAAATATCTGTTCTGTCGAAT AGGGCATGAATTC.
  • the prepared plasmid was purified on a large scale (the reagent kit used for large-scale purification purchased from German Qiagen, Cat No. A7270) for future experiments.
  • This plasmid expressed one fused protein consisted of P15 and GFP respectively in eukaryotic cells.
  • the expressed P15 was connected to the end N of GFP and the fused protein was called as P15-GFP.
  • the reagent kit for transfection was purchased from American Invitrogen (Cat No. 11668). The transfection experiment was finished according to instructions provided by the manufacturer.
  • Cells COS7 were cultured in a DMEM of beef serum with a mass concentration of 10%. After transfected for 48 hours, the Cells COS7 were washed twice with PBS. Next lysate was added for cell lysis. After DNA was damaged with ultrasonic wave, appropriate amounts of 2-mercaptoethanol and bromophennol blue were added. After disposed in boiling water for 5 minutes and stored on ice, sample was taken out and added into SDS-polyacrylamide gel with a mass concentration of 12% for electrophoresis. The separated protein was transferred to nylon membrane, through which the generation of fused protein was tested with anti-GFP antibody (purchased from American Invitrogen, Cat No. R970), and the results proved the expression of P15-GFP in cells.
  • anti-GFP antibody purchased from American Invitrogen, Cat No. R970
  • NIH/3T3 fibroblast and eptithlial cells, purchased from American ATCC, Cat No. CRL-1658
  • MCF-7 breast cancer cell line, purchased from American ATCC, Cat No. HTB-22.
  • SBF fetal beef serum
  • Plasmid used for experiment pEGFP-P15 (to express fused protein P15-GFP); control plasmid: pEGFP-N1
  • the mixture stayed for 15 minutes at room temperature. Then the mixture was first introduced into cells (with a cell density of about 50%) cultured in DMEM without serum for 5 hours of cultivation at 37° C. and next into SBF with a mass concentration of 10% for 48 hours of cultivation. Under fluorescence microscope, it was easy to distinguish the cells that express fused GFP and single fluorescent proteins and the ones that do not express these proteins. In addition, by the use of FCM, it was easy to separate and purify the positive fluorescent protein cells.
  • the symbolic indicators to test cell proliferation such as cell cycle were used to study and testify the impact of P15 on cell proliferation, while in these experiments, only the cells that express fluorescent proteins were used as control group.
  • DNA synthesis is the symbol of cell proliferation.
  • P15 also strongly inhibited the synthesis of DNA (shown in Table 2).
  • P15 cannot freely penetrate cell membrane.
  • PTD-P15 represented by SEQ. ID. NO.
  • control polypeptide represented by SEQ. ID. NO. 6 asparaginic acid-arginine-arginine-asparaginic acid-leucine-tyrosine-asparaginic acid-asparaginic acid-asparaginic acid-lysine-asparaginic acid-arginine-methionine-alanine-glycine-threonine-methionine.
  • PTD-N15 blocks PCNA binding DNA polymerase.
  • Human rectal cancer cells HT29 were cultured in culture dishes, into which the control polypeptide or different amounts of PTD-P15 were added. After a night of culture, cells were collected, and the amount of DNA polymerase bound by PCNA in cells was tested with co-immunoprecipitation. The results show that, the addition of PTD-P15 CAN reduce the DNA polymerase bound by PCNA, because the amount of DNA polymerase bound by PCNA is closely related with DNA replication. In this connection we can say that, PTD-P 15 can lower the speed of DNA replication. So long as PCNA is blocked from binding DNA polymerase, the function of the polymerase to facilitate DNA replication is inhibited, and cell division is blocked (as shown in FIG. 1 ).
  • PTD-P15 The impact of PTD-P15 on cell proliferation was tested with human HeLa cell line (Hela cells purchased from American ATCC, Cat No. HTB-22). Hela cells were cultured in 10 cm cell culture dishes containing a DMEM of 10% fetal beef serum (SBF) with a mass concentration of 10% at 37° C. under an air culture condition of 5% C0 2 (volume)/95% air (volume). When the cells were cultured till to the logarithmic phase, PTD-P15 in different concentrations (respectively 8, 30 and 50 mcg/mL) were added, while control polypeptide (blank control group) was added in other cultured cells for control. After 24-hours of culture, cells were collected and FCM was adopted for cell cycle analysis. The experimental results show that: PTD-P15 can inhibit cell proliferation, increase amounts of cells in phase G 0 /G 1 while has no obvious impact on cell apoptosis, as shown in FIGS. 2A , 2 B, 2 C and 2 D.
  • mice After 5 ⁇ 10 6 human rectal cancer cells HT29 injected into the subcutaneous tissue of mice, the mice were randomly divided into two groups. After one day from the injection of the tumor cells, several 1 mg of PTD-P15 were injected into the mice in the treatment group via caudal vein, and the injection of the same amount was repeated every other day for five times. The injection times and time of 1 mg of control polypeptide were as the same as those for the treatment group. After ten days from the injection of tumor cells, the mice were killed, from which tumors were taken out for weight measurement. The results show that: compared with the control group, the weight of the tumors in the mice treated with PTD-P15 was reduced by 57%.
  • mice After 5 ⁇ 10 6 human granulocytic leukemia cells K562 injected into the subcutaneous tissue of mice, the mice were randomly divided into five groups. Mice in each group were respectively injected with 1 mg of blank solution, 1 mg of control polypeptide, 1 mg of PTD-P15, 10 mcg of Glivec and the solution comprising 1 mg of PTD-P15+10 mcg of Glivec, and the injection of the same amounts was repeated every other day for 7 times. After two weeks, the mice were killed, from which the tumors grown in the subcutaneous tissue of the mice were taken out and weighed. The results show that, compared with the control group, the injection of PTD-P15 can obviously reduce the weight of the tumors produced by K562 by 34%.
  • Glivec is a medicine used for leukemia in clinic at present, and in the present, the injection of Glivec also reduced the weight of tumors by 48%.
  • the combination of PTD-P15 and Glivec there was greater reduction in the weight of tumors than that of the tumors produced providing that only one of the two drugs was injected individually, and the reduction could be 69% when compared with the control polypeptide control. This proves that, the combination of PTD-P15 and Glivec has better tumor treatment effect than individual injection of them has, as shown in Table 3.

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CN102321158B (zh) * 2011-08-23 2013-03-27 常州德健生物科技有限公司 阻止细胞dna合成抑制细胞增殖的多肽及用途
CN104043102B (zh) * 2014-03-28 2017-04-19 武汉益承生物科技股份有限公司 一种多肽在制备治疗核因子‑κB异常活化疾病药物中的用途
CN106818746B (zh) * 2016-12-16 2019-08-20 湖北工业大学 N15多肽在制备蓝藻抑制剂中的用途
CN106729609B (zh) * 2016-12-16 2021-04-09 湖北工业大学 N15多肽在制备细菌抑制剂中的用途
CN107050421A (zh) * 2016-12-16 2017-08-18 湖北工业大学 N15多肽在制备真菌抑制剂中的用途
CN106729610B (zh) * 2016-12-16 2021-01-29 湖北工业大学 N15多肽在抑制金黄色葡萄球菌抑制剂中的用途
CN111956781B (zh) * 2019-05-20 2023-11-17 益承康泰(厦门)生物科技有限公司 一种多肽在治疗眼部炎症药物中的应用
CN110882228A (zh) * 2019-11-29 2020-03-17 南京禾瀚医药科技有限公司 一种伊匹乌肽肠溶制剂
CN111803619A (zh) * 2020-07-26 2020-10-23 武汉益承生物科技有限公司 多肽在制备创伤治疗药物中的用途

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