CN117866046A - Chemotherapy drug sensitization polypeptide and application thereof - Google Patents
Chemotherapy drug sensitization polypeptide and application thereof Download PDFInfo
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- CN117866046A CN117866046A CN202311841309.9A CN202311841309A CN117866046A CN 117866046 A CN117866046 A CN 117866046A CN 202311841309 A CN202311841309 A CN 202311841309A CN 117866046 A CN117866046 A CN 117866046A
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Abstract
The invention discloses a chemotherapy drug sensitization polypeptide and application thereof, wherein the amino acid sequence of the sensitization polypeptide is shown as SEQ ID NO. 1; the sensitization polypeptide obviously reduces the interaction between RIOK1 and a substrate MYH9 thereof, and inhibits the phosphorylation of MYH9Ser1943 locus mediated by RIOK1, thereby inhibiting the activation of wnt signal channels and the generation of stem cell phenotypes and promoting the killing of chemotherapy on tumor cells; the sensitization polypeptide and the chemotherapeutic cisplatin are combined for administration, so that the killing effect of the chemotherapeutic on tumor cells can be obviously improved, and the sensitization polypeptide and the chemotherapeutic cisplatin can be used for preparing antitumor drugs or drugs for improving the sensitivity of the chemotherapeutic. In order to improve the membrane penetration effect, the invention also provides a fusion protein, which is formed by connecting the sensitization polypeptide and the cell penetration peptide, so that the cell membrane penetrability of the sensitization polypeptide is increased, and the application range of the sensitization polypeptide is enlarged.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a chemotherapy drug sensitization polypeptide and application thereof.
Background
Ovarian high grade serous adenocarcinoma (HGSOC) is the most common and most malignant pathological type of ovarian cancer, with the highest mortality rate of female reproductive system malignancy due to its hidden onset and early lack of classical signs. Because ovarian high-grade serous adenocarcinomas are easy to widely spread and plant, the platinum-based combined chemotherapy is the only effective treatment mode for reducing tumor load or eliminating residual tumor cells before and after operation at present. However, the long-term effect of platinum-containing chemotherapy is not ideal, tumor cells are extremely resistant to chemotherapy, about 70% of patients relapse within two years after receiving adjuvant chemotherapy, and as the number of times of relapse increases, the stronger the resistance of tumor cells to platinum, the shorter the platinum-free chemotherapy interval, and finally death of the patients is caused, which is one of the main reasons that the five-year prognosis of ovarian high-grade serous gonad cancer is still insufficient for 40%.
Therefore, developing effective treatments to promote sensitivity of ovarian high grade serous adenocarcinomas to platinum-containing chemotherapeutics or to reverse chemoresistance is a current clinical challenge.
Disclosure of Invention
The object of the first aspect of the present invention is to provide a polypeptide.
The object of the second aspect of the present invention is to provide a fusion protein.
In a third aspect, the present invention provides a biological material related to the above polypeptide or fusion protein.
The object of the fourth aspect of the present invention is to provide the use of the above polypeptide or fusion protein or biological material.
In a fifth aspect, the present invention provides a method for producing the fusion protein.
The object of the sixth aspect of the invention is to provide a product.
The technical scheme adopted by the invention is as follows:
in a first aspect of the present invention, there is provided a polypeptide having an amino acid sequence of any one of the following:
(a) SEQ ID NO. 1;
(b) Amino acid sequence with same or similar functions after the amino acid sequence shown in (a) is modified by substitution, deletion or addition of one or more amino acids.
In a second aspect of the invention there is provided a fusion protein comprising a polypeptide according to the first aspect of the invention.
Preferably, the fusion protein further comprises at least one of a signal peptide, a targeting peptide, a tag peptide, a fluorescent protein, a transmembrane peptide;
preferably, the transmembrane peptide is located at the N-terminus of the fusion protein.
Preferably, the amino acid sequence of the transmembrane peptide includes, but is not limited to, any of the following:
(a) SEQ ID NO. 2;
(b) Amino acid sequence with same or similar functions after the amino acid sequence shown in (a) is modified by substitution, deletion or addition of one or more amino acids.
Preferably, the amino acid sequence of the fusion protein is any one of the following:
(a) SEQ ID NO. 3;
(b) Amino acid sequence with same or similar functions after the amino acid sequence shown in (a) is modified by substitution, deletion or addition of one or more amino acids.
In a third aspect of the invention there is provided a related biomaterial of the polypeptide of the first aspect of the invention or the fusion protein of the second aspect of the invention, the related biomaterial being any of the following:
(a) A nucleic acid molecule encoding a penetrating peptide according to the first aspect of the invention or a fusion protein according to the second aspect of the invention;
(b) An expression cassette comprising the nucleic acid molecule of (a);
(c) A recombinant vector comprising the nucleic acid molecule of (a);
(d) A recombinant vector comprising the expression cassette of (b);
(e) A recombinant microorganism comprising the nucleic acid molecule of (a);
(f) A recombinant microorganism comprising the expression cassette of (b);
(g) A recombinant microorganism comprising the recombinant vector of (c);
(h) A recombinant microorganism comprising the recombinant vector of (d).
Preferably, the vector comprises a viral vector and/or a non-viral vector.
Preferably, the viral vector comprises an adeno-associated viral vector, an adenovirus vector, a lentiviral vector, a retrovirus vector, a herpesvirus vector, and/or a phage vector.
Preferably, the non-viral vector comprises a cationic polymer, a liposome, and/or a plasmid vector.
Preferably, the cells are not new animal or plant varieties.
Preferably, the cells comprise prokaryotic cells or eukaryotic cells.
Preferably, the prokaryotic cells include at least one of E.coli, B.subtilis, C.glutamicum, streptomyces, and the like.
Preferably, the eukaryotic cells include at least one of fungal cells, insect cells, mammalian cells, and the like.
Preferably, the fungal cells comprise yeast cells.
Preferably, the yeast cells include at least one of pichia pastoris, saccharomyces cerevisiae, and the like.
In a fourth aspect of the invention there is provided the use of a polypeptide according to the first aspect of the invention or a fusion protein according to the second aspect of the invention or a related biomaterial according to the third aspect of the invention in any of the following:
(a) Preparing a medicament for treating ovarian cancer;
(b) Preparing a drug for increasing sensitivity of a chemotherapeutic drug;
(c) Inhibition of MYH9Ser1943 site phosphorylation for non-therapeutic purposes;
(d) Preparing an agent for inhibiting MYH9Ser1943 locus phosphorylation;
(e) Preparing a medicament for inhibiting the stem cell phenotype of the nest cancer cells.
Preferably, the MYH9Ser1943 site phosphorylates to MYH9Ser1943 site phosphorylation in ovarian cancer cells.
Preferably, the ovarian cells are SPC25 highly expressed ovarian cells.
Wherein the chemotherapeutic drug is an ovarian cancer chemotherapeutic drug, preferably a platinum chemotherapeutic drug; platinum chemotherapeutics are alkylating agents, belong to cell cycle non-characteristic drugs, and have the action mechanism that the drugs form a Platinum-DNA adduct with DNA molecules after entering tumor cells, so that the synthesis and transcription of the DNA are blocked, thereby mediating apoptosis or cell necrosis of the tumor cells and achieving the effect of killing tumors. Platinum drugs can be classified into three generations according to their chemical modification and human pharmacokinetics, wherein Cisplatin (CDDP), the first generation of platinum drugs, is representative of "high potency" among all platinum drugs, and therefore, cisplatin is generally used as a model drug for the study of platinum chemotherapy. However, the strong drug effect brings about strong clinical toxic and side effects, and for "attenuation", the second generation platinum (carboplatin, nedaplatin) and the third generation platinum (oxaliplatin, lobaplatin) are generated, but the action mechanisms of all platinum are similar.
Tumor stem cells are a subset of cells in tumor tissue that have stem cell-like self-renewal capacity, and are capable of resisting chemotherapy in a variety of ways, including promotion of enhancement of the mechanism of repair of extracellular DNA damage of drugs, etc., and thus are considered to be one of the important causes of recurrence after tumor chemotherapy and development of tumor resistance. The chemosensitization polypeptide CBP1 can inhibit the generation of tumor stem cell phenotype in ovarian cancer, and can enhance the killing effect of the drug on tumor cells when being combined with platinum-based chemo-therapeutic drugs.
Preferably, the platinum-based chemotherapeutic drug comprises cisplatin, carboplatin, nedaplatin, lobaplatin, and the like.
In a fifth aspect of the invention there is provided a method of preparing a fusion protein according to the third aspect of the invention comprising preparing the fusion protein by FMOC solid phase synthesis.
The method comprises the following steps:
s1: synthesizing CTC Resin, and preparing Fmoc-Arg-CTC Resin;
s2: fmoc group was removed to give H 2 N-Arg-CTC Resin；
S3: condensation reaction to obtain Fmoc-Glu-Arg-CTC Resin;
s4: cycling steps S2 and S3 to prepare H 2 N-His-Leu-Tyr-Val-Ser-Pro-Trp-Gly-Gly-Ala-Tyr-Ile-Pro-Arg-Thr-Leu-Asn-Glu-Val-Lys-Asn-Tyr-Glu-Arg-CTC Resin；
S5: and adding a cutting fluid to cut to obtain the fusion protein.
Preferably, the fusion protein may be further purified to increase purity.
Preferably, the cutting fluid comprises trifluoroacetic acid, anisole sulfide, 1, 2-ethanedithiol, phenol and water.
Preferably, the mass ratio of trifluoroacetic acid, anisole, 1, 2-ethanedithiol, phenol and water is 87.5 percent, 2.5 percent and 2.5 percent.
Preferably, the time of the cutting is 2-3 hours.
In a sixth aspect of the invention there is provided a product comprising a polypeptide according to the first aspect of the invention or a fusion protein according to the second aspect of the invention or a related biomaterial according to the third aspect of the invention.
Preferably, the product comprises a medicament, an agent.
Preferably, the medicament further comprises a chemotherapeutic agent.
Preferably, the chemotherapeutic agent comprises a platinum-based chemotherapeutic agent.
Preferably, the platinum-based chemotherapeutic drug comprises cisplatin, carboplatin, nedaplatin, lobaplatin, and the like.
Preferably, the mass ratio of the fusion protein to the chemotherapeutic agent is 1:2 to 4.
Preferably, the medicament further comprises pharmaceutically acceptable excipients.
Preferably, the pharmaceutically acceptable auxiliary materials comprise at least one of solvents, wetting agents, emulsifying agents, thickening agents, excipients, suspending agents, disintegrants, fillers, lubricants or diluents.
Preferably, the dosage form of the medicament is various dosage forms conventional in the art, preferably solid, semisolid or liquid form, and can be aqueous solution, non-aqueous solution or suspension, more preferably tablet, capsule, soft capsule, granule, pill, oral liquid, dry suspension, dripping pill, dry extract, injection or infusion, transdermal agent, transdermal microneedle.
Preferably, in vitro cell experiments, the fusion protein is at a working concentration of 4 to 6uM.
Preferably, the administration dose of the fusion protein is 8-12 mg/kg of mice per time; the dosing frequency was once every two weeks.
In some embodiments of the invention, the mode of administration of the drug may be conventional in the art, including but not limited to injection or oral administration. The injection administration can be intravenous injection, intramuscular injection, intraperitoneal injection, intradermal injection or subcutaneous injection.
The term "administered dose" as used herein is an amount capable of alleviating or delaying the progression of a disease, degenerative or damaging condition. May depend on the particular disease being treated, as well as other factors including age, weight, health, severity of symptoms, route of administration, frequency of treatment, and whether additional medications are concomitantly used during the treatment.
The beneficial effects of the invention are as follows:
the invention provides a chemotherapy drug sensitization polypeptide, the amino acid sequence of which is shown as SEQ ID NO. 1; the sensitization polypeptide can competitively inhibit the combination of RIOK1 and SPC25, inhibit the phosphorylation of the substrate MYH9 by the RIOK1, thereby inhibiting the activation of wnt signal paths and the generation of stem cell phenotypes and promoting the killing of chemotherapy on tumor cells; in order to improve the membrane penetration effect, the invention also provides a fusion protein, which is formed by connecting the sensitization polypeptide and the cell penetration peptide, so that the cell membrane penetrability of the sensitization polypeptide is increased, and the application range of the sensitization polypeptide is enlarged. Therefore, the invention provides a new scientific basis for the molecular mechanism of resisting the generation of the ovarian high-grade serous adenocarcinoma chemotherapy, and verifies the effectiveness of the chemotherapy combined blocking peptide at animal level, thereby providing a new strategy for the clinical treatment of the high-grade serous ovarian cancer.
Drawings
FIG. 1 amino acid sequence of CBP1 polypeptide.
FIG. 2 shows the results of CBP1 liquid chromatography.
FIG. 3 transmembrane peptide mediates CBP1 passage through the cell membrane into tumor cells.
FIG. 4 CBP1 significantly inhibits the binding of RIOK1 to the substrate MYH9 and reduces the phosphorylation of MYH 9.
Fig. 5.Cbp1 reduced tumor cell β -catenin expression and significantly inhibited Wnt signaling pathway.
Fig. 6.Cbp1 significantly inhibited the stem cell phenotype of tumor cells and enhanced sensitivity to cisplatin chemotherapy.
FIG. 7 in vivo drug sensitivity test design in nude mice.
FIG. 8 shows the results of in vivo drug sensitivity test in nude mice.
Detailed Description
The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention.
Example 1 preparation of Polypeptides
The current research shows that the tumor organoids derived from the tissue of a tumor patient have extremely high similarity with the tissue of the source in genetics and can be stably passaged in vitro, so that the tumor organoids are widely used for screening effective medicaments and testing drug sensitivity and have better accuracy. Thus, an organoid platform for ovarian high-grade serous adenocarcinomas was first established, and activity was detected after cisplatin treatment of the organoids, and then the organoids were finally divided into two response groups, platinum-resistant and platinum-sensitive, in combination with clinical chemotherapy sensitivity of the source patient. Further analysis of the transcriptome of the two organoids revealed that SPC25 was specifically up-regulated in the platinum-tolerant group, and likewise, SPC25 was observed to have the same expression pattern in large-scale clinical tissue samples, which provides a sufficient basis for SPC25 to be likely involved in regulating chemotherapy tolerance of ovarian high-grade serous adenocarcinoma.
Further research has found that SPC25 can act as a "molecular scaffold" to bind the protein kinase RIOK1 and myosin heavy chain protein MYH9 simultaneously within the cytoplasm of tumor cells, increasing the interaction of the RIOK1 and MYH9 proteins and simultaneously promoting the phosphorylation reaction of RIOK1 on serine residue number 1943 of MYH9 protein. The phosphorylated MYH9 subcellular localization is transferred to the nucleus, and is used as a transcription stimulus to mediate the powerful activation of the downstream beta-catenin transcription, and the tumor cells are induced to generate stem cell characteristics through a classical wnt signal pathway, so that the resistance to chemotherapy is finally caused.
According to the above molecular mechanism, a blocking peptide CBP1 with cell membrane permeability was designed and synthesized against the amino acid sequence of the key binding domain of the interaction of RIOK1 and SPC25 proteins, which mimics the binding domain of RIOK1 and SPC 25. Wherein the amino acid sequence of the CBP1 polypeptide: HLYVSPWGGAYIPRTLNEVKNYER (SEQ ID NO. 3), the entire polypeptide comprising 24 amino acids, as shown in the sequence schematic of FIG. 1, wherein the amino acid sequence at the C-terminus (BP 1: AYIPRTLNEVKNYER (SEQ ID NO. 1)) is an effector sequence, capable of mimicking the binding region of the RIOK1 kinase protein and SPC25 protein, and competitively inhibiting the binding of intracellular SPC25 and RIOK 1; the amino acid sequence at the N-terminal is a cell membrane penetrating peptide (CPP: HLYVSPWGG (SEQ ID NO. 2)) which can mediate the whole polypeptide to penetrate the cell membrane and enter the cell to function.
The preparation method comprises the following steps: the in vitro synthesis of the polypeptide adopts an FMOC solid phase synthesis method widely applied at the present stage, taking CBP1 as an example, and comprises the following steps:
ctc resin synthesis: CTC Resin and Fmoc-Arg-OH are placed in a reactor, a proper amount of DCM (dichloromethane) is added to swell the Resin for 2-3 minutes, then 0.9mmol of DIPEA (N, N-diisopropylethylamine) is added to react for 2-3 hours; then after blocking the stump with 1ml of HPLC grade methanol for 30 minutes, 2 washes with DMF (dimethylformamide), methanol and DCM (dichloromethane) alternately 2 washes; finally, washing for 2 times by using DMF again to obtain Fmoc-Arg-CTC Resin for standby.
2. Removing Fmoc: adding 20% Pip/DMF (piperidine) solution 3 times of the resin volume into the reactor, bubbling nitrogen for 30 min, and washing with 2 times of DMF 5 times of the resin volume to obtain H 2 N-Arg-CTC Resin is ready for use.
3. Condensation: 3mol of Fmoc-Glu-OH amino acid is added into the reaction system, the amino acid is dissolved by proper DMF, 1.8mmol of DIPEA and 1.8mmol of HBTU condensing agent are added, after reaction for 30 minutes, the Fmoc-Glu-Arg-CTC Resin is obtained by washing with 2 times of Resin volume of DMF.
4. The cyclic reaction, namely, the steps 2 and 3 are circulated in turn, and H is finally obtained 2 N-His-Leu-Tyr-Val-Ser-Pro-Trp-Gly-Gly-Ala-Tyr-Ile-Pro-Arg-Thr-Leu-Asn-Glu-Val-Lys-Asn-Tyr-Glu-Arg-CTC Resin。
5. Cutting: after the cyclic reaction is completed, 6 times volume of cutting fluid (trifluoroacetic acid: anisole: 1, 2-ethanedithiol: phenol: water=87.5%: 5%:2.5%: 2.5%) is added into the system, and the mixture is incubated for 2 to 3 hours on a shaking table; the resin was then filtered off and the filtrate was precipitated with ice dry diethyl ether, and finally the precipitate was taken out and dried in a desiccator at room temperature for 24 hours to give crude CBP1.
6. Purifying: purifying by liquid chromatography, collecting peak liquid, sampling to determine purity, freeze drying at-80deg.C, and preserving to obtain CBP1 synthetic polypeptide sample with purity higher than 98.31% as shown in FIG. 2 liquid chromatography, which can be used for cell and in vivo animal experiments.
Effect example
1. In vitro cell experiments:
dissolving proper BP1 and CP1 polypeptide freeze-dried powder in DMSO solvent, mixing the dissolved polypeptide solution with FITC solution, carrying out coupling reaction under the action of isocyanate, respectively carrying out FITC fluorescent labels on BP1 and CBP1, adding the mixed solution into DMEM culture medium containing 10% FBS, taking ovarian cancer tumor cells OV90 in good state, culturing with the culture medium, taking out the cells after 24 hours, gently washing the cells with PBS buffer solution for 2-3 times to remove redundant FITC label polypeptide, fixing the cells with 4% paraformaldehyde for 30 minutes, removing redundant paraformaldehyde and washing the cells with PBS for 2-3 times, then incubating the cells with DAPI nuclear fluorescent dye for 15 minutes at normal temperature, removing and washing the redundant DAPI dye, observing the cells under a fluorescent microscope, and displaying that CBP1 carrying the transmembrane peptide at the N end can enter the cells through a cell membrane, but BP1 cannot enter the cells through the cell membrane (figure 3).
Further, the polypeptide lyophilized powder of CBP1, CPP, CBPcontrol was dissolved in DMSO as described above, and then added to DMEM medium containing 10% fbs and the working concentration of the polypeptide in the medium was maintained at 5uM. Then, HEK293T cells with good states are taken, exogenous SPC25-Flag, RIOK1-HA and MYH9-Myc plasmids are transiently transfected into the HEK293T cells according to the grouping shown in FIG. 4, and the culture medium is replaced by the cell culture medium containing the 5uM polypeptide for 48 hours after transfection, and the culture is continued. After 24 hours, cell lysates were collected and the competitive inhibition effect of the polypeptides was examined by CO-immunoprecipitation (CO-IP).
CO-IP experiments demonstrated that CBP1 was able to significantly inhibit the binding of SPC25 and RIOK1 to each other and significantly reduce the interaction of RIOK1 and its substrate MYH9 in HEK293T cells relative to control and transmembrane peptides at 5uM polypeptide concentrations, thereby inhibiting RIOK 1-mediated phosphorylation at MYH9Ser1943 (fig. 4).
To verify the downstream effect of CBP1, western blotting experiments were performed on the above-described cell lysates to detect β -catenin expression, and experimental results showed that CBP1 significantly inhibited β -catenin expression in tumor cells while inhibiting MYH9Ser1943 site phosphorylation compared to control group, and similarly, the dual luciferase reporter experiments also demonstrated that CBP1 was able to significantly inhibit wnt signaling activation in tumor cells (fig. 5).
Further, the results of flow cytometry experiments on tumor cells cultured by the polypeptides show that CBP1 significantly reduces the tumor cell subset proportion of the stem cell marker CD133+, which indicates that CBP1 has the effect of inhibiting the phenotype of tumor stem cells. Secondly, the polypeptide is combined with cisplatin to treat tumor cells for 12 hours for apoptosis flow detection, and the result shows that the tumor cells in the CBP1 group show higher sensitivity to cisplatin under the cisplatin treatment, which indicates that the CBP1 can promote the killing effect of cisplatin on the tumor cells (figure 6).
2. In vivo drug sensitivity experiments:
first about 1 x 10 6 Ovarian cancer tumor cells OV90 stably expressing the luciferase gene were intraperitoneally injected and inoculated into BLAB/c Nude mice, and after one week satisfactory tumor-forming mice were grouped as shown in FIG. 7, with 8 mice per group and starting administration, wherein Cisplatin (CDDP) was intraperitoneally injected at a dose of 5mg/kg each time, three times per week; CBP1 was administered by intraperitoneal injection at a dose of 10mg/kg each time, once every two weeks, during which time tumor growth was observed by a biopsy system and survival data were recorded.
The observation results are shown in fig. 8, and it can be seen from the results that the combined administration of CDDP and CBP1 can significantly improve the killing effect of chemotherapeutic drugs on tumor cells compared with the single administration of CDDP or CBP1, and the survival rate of mice in the combined administration group is significantly better than that of mice in other control groups; wherein, the CBP1 has the effect of inhibiting the tumor cells from generating stem cell phenotype, so that the tumor cells are more easily killed by CDDP and are more sensitive to chemotherapy; can be used as sensitizer of CDDP for preparing antitumor drugs.
In conclusion, in vitro and in vivo experiments prove that CBP1 can competitively inhibit the combination of RIOK1 and SPC25, inhibit the phosphorylation of RIOK1 on a substrate MYH9, inhibit the activation of wnt signaling pathway and the generation of stem cell phenotype, and promote the killing of tumor cells by chemotherapy. Therefore, the invention provides a new scientific basis for the molecular mechanism of resisting the generation of the ovarian high-grade serous adenocarcinoma chemotherapy, and verifies the effectiveness of the chemotherapy combined blocking peptide at animal level, thereby providing a new strategy for the clinical treatment of the high-grade serous ovarian cancer.
The present invention has been described in detail in the above embodiments, but the present invention is not limited to the above examples, and various changes can be made within the knowledge of those skilled in the art without departing from the spirit of the present invention. Furthermore, embodiments of the invention and features of the embodiments may be combined with each other without conflict.
Claims (10)
1. A polypeptide having an amino acid sequence of any one of:
(a) SEQ ID NO. 1;
(b) Amino acid sequence with same or similar functions after the amino acid sequence shown in (a) is modified by substitution, deletion or addition of one or more amino acids.
2. A fusion protein comprising the polypeptide of claim 1; preferably, the fusion protein further comprises at least one of a signal peptide, a targeting peptide, a tag peptide, a fluorescent protein, and a transmembrane peptide.
3. The fusion protein of claim 2, wherein the amino acid sequence of the transmembrane peptide comprises any one of the following:
(a) SEQ ID NO. 2;
(b) Amino acid sequence with same or similar functions after the amino acid sequence shown in (a) is modified by substitution, deletion or addition of one or more amino acids.
4. A fusion protein according to claim 3, wherein the amino acid sequence of the fusion protein comprises any one of the following:
(a) SEQ ID NO. 3;
(b) Amino acid sequence with same or similar functions after the amino acid sequence shown in (a) is modified by substitution, deletion or addition of one or more amino acids.
5. A related biological material of the polypeptide of claim 1 or the fusion protein of any one of claims 2 to 4, which is any one of the following:
(a) A nucleic acid molecule encoding the polypeptide of claim 1 or the fusion protein of any one of claims 2-4;
(b) An expression cassette comprising the nucleic acid molecule of (a);
(c) A recombinant vector comprising the nucleic acid molecule of (a);
(d) A recombinant vector comprising the expression cassette of (b);
(e) A recombinant microorganism comprising the nucleic acid molecule of (a);
(f) A recombinant microorganism comprising the expression cassette of (b);
(g) A recombinant microorganism comprising the recombinant vector of (c);
(h) A recombinant microorganism comprising the recombinant vector of (d).
6. A method for producing a fusion protein according to any one of claims 2 to 4, comprising producing the fusion protein by FMOC solid phase synthesis.
7. Use of the polypeptide of claim 1 or the fusion protein of any one of claims 2 to 4 or the related biological material of claim 5 in any one of the following:
(a) Preparing a medicament for treating ovarian cancer;
(b) Preparing a drug for increasing sensitivity of a chemotherapeutic drug;
(c) Inhibition of MYH9Ser1943 site phosphorylation for non-therapeutic purposes;
(d) Preparing an agent for inhibiting MYH9Ser1943 locus phosphorylation;
(e) Preparing a medicament for inhibiting the stem cell phenotype of the nest cancer cells.
8. The use according to claim 7, wherein the chemotherapeutic agent comprises a platinum-based chemotherapeutic agent; preferably, the platinum-based chemotherapeutic agent comprises cisplatin, carboplatin, nedaplatin, lobaplatin.
9. A product comprising the polypeptide of claim 1 or the fusion protein of any one of claims 2-4 or the related biological material of claim 5; preferably, the product comprises a medicament, an agent.
10. The product of claim 9, wherein the drug further comprises a chemotherapeutic drug; preferably, the chemotherapeutic agent comprises a platinum-based chemotherapeutic agent; preferably, the platinum-based chemotherapeutic agent comprises cisplatin, carboplatin, nedaplatin, lobaplatin.
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