A polypeptide having usp1 inhibitory activity and its use in the preparation of a medicament for preventing and / or treating cancer

Abstract

The present application belongs to the field of polypeptide drugs, and relates to a polypeptide with ubiquitin-specific peptidase 1 (USP1) inhibitory activity and application thereof in preparation of a drug for preventing and / or treating cancer. The amino acid sequence of the polypeptide of the present application is shown as SEQ ID NO:1. The cancer is at least one of breast cancer, cervical cancer, ovarian cancer, liver cancer, lung cancer, gastric cancer, osteosarcoma, prostate cancer, glioblastoma, esophageal squamous cell carcinoma, pancreatic cancer, melanoma, renal cancer and nasopharyngeal carcinoma. The present application has the following technical effects: the polypeptide of the present application is designed to target and combine with deubiquitinating enzyme USP1, inhibit the combination of USP1 and substrate protein FANCD2, thereby blocking the deubiquitination process of FANCD2, and regulating the DNA damage repair mediated by the Fanconi anemia (FA) pathway. The polypeptide of the present application shows good in-vitro and in-vivo inhibitory activity on various human tumor cells.

Description

Technical Field

[0001] This invention belongs to the field of polypeptide drugs and relates to a polypeptide with ubiquitin-specific peptidase 1 (USP1) inhibitory activity and its application in the preparation of drugs for the prevention and / or treatment of cancer. Background Technology

[0002] Cancer, a highly prevalent and deadly disease, has become one of the major public health problems threatening human life and health, and its effective treatment remains extremely challenging. While commonly used chemotherapeutic drugs can inhibit tumor cell proliferation, they generally suffer from insufficient targeting. These drugs, while killing tumor cells, also damage normal tissues, leading to significant toxic side effects. Furthermore, long-term use can easily induce multidrug resistance in tumor cells, thus limiting the continued improvement of efficacy. Peptide drugs, composed of natural amino acids, typically possess good biocompatibility and water solubility, and relatively low immunogenicity. In addition, peptide compounds can be prepared using mature technologies such as solid-phase synthesis, facilitating sequence design, structural modification, and large-scale production, showing promising application prospects in drug development and industrialization. Because peptides can specifically bind to tumor-related molecular targets or directly act on tumor cells and their microenvironment, they demonstrate significant value in the development of anti-tumor drugs.

[0003] Ubiquitin-Specific Peptidase 1 (USP1) is a crucial regulator in DNA damage response and genome stability maintenance, participating in the deubiquitination regulation of Fanconi anemia complementation group I (FANCI) and Fanconi anemia complementation group D2 (FANCCD2) proteins in the Fanconi anemia (FA) pathway. Following DNA damage in tumor cells, FANCD2 and FANCI form a heterodimer and undergo monoubiquitination. This complex is recruited to the DNA damage site to participate in subsequent repair. USP1 removes the monoubiquitination modification on FANCD2 and FANCI, releasing them from the DNA damage site and completing the DNA damage repair process. If USP1 function is abnormal, FANCD2 and FANCI remain in a ubiquitinated state, leading to a regulatory imbalance in the Fanconi anemia (FA) pathway. This, in turn, causes abnormal DNA damage repair and increased genomic instability, potentially resulting in cell cycle arrest and / or apoptosis. Therefore, developing inhibitors targeting USP1 is of great significance for cancer treatment. However, there are currently no clinically available USP1-targeted anti-tumor drugs, especially peptide-based USP1 inhibitors with both good targeting and safety profiles, which still need to be developed. Summary of the Invention

[0004] The purpose of this invention is to overcome the shortcomings of the prior art by designing a polypeptide with USP1 inhibitory activity and its application in the preparation of drugs for the prevention and / or treatment of cancer. The polypeptide has a good inhibitory effect on a variety of cancer cells.

[0005] To solve the above-mentioned technical problems, the technical solution of the present invention is as follows: In a first aspect of the invention, a polypeptide having USP1 inhibitory activity is provided, the amino acid sequence of which is shown in SEQ ID NO: 1.

[0006] In a second aspect of the invention, a polypeptide with USP1 inhibitory activity is provided, the amino acid sequence of the polypeptide being shown in SEQ ID NO: 1, and the carboxyl group of the arginine (Arg) residue at the carboxyl terminus of the polypeptide being protected by amidation modification.

[0007] In a third aspect of the invention, the use of the polypeptide as described in the first or second aspect in the preparation of a medicament for the prevention and / or treatment of cancer is provided, wherein the cancer is at least one of breast cancer, cervical cancer, ovarian cancer, liver cancer, lung cancer, gastric cancer, osteosarcoma, prostate cancer, glioblastoma, esophageal squamous cell carcinoma, pancreatic cancer, melanoma, renal cancer, and nasopharyngeal carcinoma; the polypeptide is capable of inhibiting the proliferation of cancer cells in such cancers.

[0008] Furthermore, the cancer mentioned is breast cancer.

[0009] Furthermore, the polypeptide can be used in combination with a pharmaceutically acceptable carrier. When used as a drug, the polypeptide can be used directly or in the form of a pharmaceutical composition. The dosage form of the pharmaceutical composition is selected from injections, lyophilized powder injections, infusions, liposomes, or nanoformulations. To ensure efficacy, the polypeptide is preferably administered to the patient requiring treatment via injection, such as intravenous, intramuscular, subcutaneous, or intraperitoneal injection.

[0010] Furthermore, the polypeptide or a pharmaceutically acceptable salt thereof serves as the active pharmaceutical ingredient.

[0011] Further, the mass fraction of the active pharmaceutical ingredient is 0.1% to 99%; more preferably, the mass fraction of the active pharmaceutical ingredient is 0.1% to 20%.

[0012] Furthermore, the polypeptide can be used in combination with other drugs. The polypeptide and other drugs can be used in combination via simultaneous administration, sequential administration, or alternating administration.

[0013] The features of this invention are as follows: This invention designs and synthesizes polypeptide I targeting the tumor protein USP1, with the sequence shown in SEQ ID NO: 1. The N-terminus of the polypeptide contains a membrane-penetrating peptide sequence (amino acid sequence shown in SEQ ID NO: 3, specifically: YGRKKRRQRRR), ensuring that the polypeptide can penetrate the cell membrane and enhancing its cellular uptake capacity. To improve the stability of polypeptide I, its carboxyl-terminal amino acid is amidated, converting its free carboxyl group (–COOH) into a stable amide group (–CONH2). Finally, the polypeptide I obtained by this invention exhibits excellent inhibitory activity against various types of human cancer cells, providing an option for broad-spectrum polypeptide anticancer drugs.

[0014] Compared with existing technologies, this invention has the following advantages: This invention designs and provides a novel sequence-specific polypeptide. Experimental results show that this polypeptide has good inhibitory activity against various types of human cancer cells, and can provide candidate molecules for the development of novel polypeptide anti-tumor drugs. Meanwhile, the polypeptide described in this invention can be prepared using a relatively mature synthetic process, which is relatively simple and facilitates synthesis, purification, and subsequent structural optimization. Since its constituent amino acids are all natural amino acids, this polypeptide has certain advantages in biocompatibility and has good development and application prospects. Attached Figure Description

[0015] Figure 1 The amino acid sequence and structural formula of polypeptide I are shown.

[0016] Figure 2 The results of the designed peptides I and II on the inhibition of tumor cells are shown. Among them, A is the inhibition result of peptides I and II on HCC1500 cells; B is the inhibition result of peptides I and II on MDA-MB-453 cells; and C is the inhibition result of peptides I and II on MDA-MB-468 cells.

[0017] Figure 3 The results show the inhibitory effects of peptide I on human breast cancer cells and 13 other human cancer cells.

[0018] Figure 4 This study describes the induction effect of peptide I on the expression of γH2AX, a DNA damage marker protein, in breast cancer cells.

[0019] Figure 5 The results show the in vivo inhibition of human breast cancer xenograft tumors in nude mice by peptide I. In the figures, A represents the euthanasia of nude mice 21 days after administration, followed by tumor tissue dissection and photographic observation; B represents tumor volume measured every 2 days after administration, presented as a line graph; C represents tumor mass after treatment with the solvent group and peptides at 30 mg / kg and 10 mg / kg; D represents the body weight of nude mice measured every 2 days after administration, presented as a line graph; EF represents the anesthesia of nude mice after administration, followed by orbital blood collection to measure serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities to evaluate the hepatotoxicity of peptide I; G represents the measurement of serum creatinine levels to evaluate the nephrotoxicity of peptide I. In the figures, ns indicates no statistically significant difference between the two groups, and * indicates statistically significant differences between the two groups. P <0.05. Detailed Implementation

[0020] The technical solutions of the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, but the present invention is not limited to the following technical solutions.

[0021] The human breast cancer cells described in the following examples are SKBR3, T47D, MCF-7, HCC1500, SUM149PT, HCC1806, MDA-MB-453, BT549, HCC1937, MDA-MB-231, and MDA-MB-468. The 13 other human cancer cells are human cervical cancer cells HeLa, human ovarian cancer cells SK-OV-3, human hepatocellular carcinoma cells HCC-LM3, human large cell lung cancer cells H460, human gastric cancer cells HGC-27, human osteosarcoma cells MG-63, human prostate adenocarcinoma cells PC-3, human glioblastoma astrocytoma cells U-87 MG, human esophageal squamous cell carcinoma cells Eca-109, human pancreatic adenocarcinoma cells SW1990, human malignant melanoma cells A375, human renal cancer cells (renal rhabdomyosarcoma) G-401, and human nasopharyngeal cancer cells HNE1. The conventional cancer cells used above were all obtained from Kunming Medical University.

[0022] Unless otherwise specified, all reagents used in the embodiments of this invention are commercially available. RPMI 1640 medium, DMEM medium, and DMEM / F12 medium were purchased from Thermo Fisher Scientific, and fetal bovine serum was purchased from Lanzhou Rongye Biotechnology Co., Ltd.; phosphate-buffered saline (PBS), 0.25% trypsin (containing EDTA), and CCK8 reagent were purchased from Beyotime Biotechnology Co., Ltd.

[0023] Cell lines were cultured in RPMI 1640, DMEM, or DMEM / F12 medium containing 10% fetal bovine serum at 37°C, 5% CO2, and 90% humidity.

[0024] Example 1: Peptide Design and Synthesis The core sequence of peptide II, ASSHIQDDMHLVIRKQLS (as shown in SEQ ID NO: 4), was obtained by extracting structural information of the USP1-UAF1 protein complex. Based on the core sequence of peptide II, the binding affinity of the peptide to USP1 was optimized through amino acid mutations. Peptide I was obtained by adding a transmembrane peptide sequence to the N-terminus, and the amino acid sequence of peptide I is shown in SEQ ID NO: 1.

[0025] The synthesis process of polypeptide I is as follows: using Ramage Amide AM resin as a solid support, the polypeptide is synthesized from the carboxyl terminus (C-terminus) to the amino acid terminus (N-terminus). First, the first arginine residue at the C-terminus protected by Fmoc is loaded onto the resin, so that an amide group (–CONH2) is formed at the C-terminus of the resulting polypeptide. Subsequently, using a cyclical approach of "Fmoc deprotection-amino acid coupling-washing," leucine (Leu), glutamine (Gln), arginine (Arg), arginine (Arg), isoleucine (Ile), valine (Val), leucine (Leu), histidine (His), methionine (Met), isoleucine (Ile), valine (Val), glutamine (Gln), isoleucine (Ile), tryptophan (Trp), serine (Ser), arginine (Arg), arginine (Arg), glutamine (Gln), arginine (Arg), arginine (Arg), lysine (Lys), lysine (Lys), arginine (Arg), glycine (Gly), and tyrosine (Tyr) were linked to the polypeptide chain one by one to obtain the resin-bound target peptide chain. Finally, piperidine was used to remove the Fmoc protecting group at the N-terminus, and then the resin was treated with a lysis buffer containing trifluoroacetic acid (TFA) and triisopropylsilane (TIS) to cleave the peptide from the solid support and remove the side chain protecting groups at the same time, to obtain peptide I.

[0026] The purity of the peptide was determined by high-performance liquid chromatography (HPLC). Buffer solutions of 0.1% trifluoroacetic acid in 100% acetonitrile (Solution A) and 0.1% trifluoroacetic acid in 100% water (Solution B) were prepared. A C18 column was installed on the HPLC system, and the column was conditioned. A mixture of 5% Solution A and 95% Solution B was used to wash the column for 15 min at a flow rate of 40 mL / min. The column was then equilibrated with a 50% mixture (containing 0.1% trifluoroacetic acid) for 15 min. The synthesized peptide was then packed into the column. The peptide was eluted using a linear gradient of 5%–40% Solution A and 95%–60% Solution B for 25 min at a flow rate of 1.0 mL / min. UV detection was performed at 220 nm. The purity of the obtained peptide I was determined to be 96.42%.

[0027] Polypeptide II was synthesized using the method described above.

[0028] The polypeptides I and II synthesized using the above method were tested for antitumor activity. In the following examples, the sequence of polypeptide I is shown in SEQ ID NO: 1, and the sequence of polypeptide II is shown in SEQ ID NO: 2.

[0029] The polypeptide II sequence shown in SEQ ID NO: 2 is the core sequence of polypeptide II with a membrane-penetrating peptide sequence added to the N-terminus.

[0030] In this invention, the amino acid sequences shown in SEQ ID NO: 1-4 are all represented from left to right in the direction from amino to carboxyl.

[0031] Example 2: Test of peptide antitumor activity The inhibitory effect of peptides on cancer cell growth was evaluated using the CCK-8 (Cell Counting Kit-8) method. The CCK-8 reagent contains the water-soluble tetrazolium salt 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfonylbenzene)-2H-tetrazole monosodium salt. In the presence of intracellular dehydrogenases and electron transport systems, it can be reduced by surviving cells to a water-soluble orange-yellow formazan-like product. This product exhibits a characteristic absorption peak at 450 nm, and its absorbance value is positively correlated with the number of viable cells, making it suitable for quantitative analysis of cell number and cell viability.

[0032] Peptide I and peptide II prepared in Example 1 were dissolved in 50% PBS (phosphate-buffered saline) + 50% DMSO (dimethyl sulfoxide) to prepare concentrated solutions with concentrations of 2500, 1250, 625, 312.5, and 156.25 μM, respectively. Logarithmic growth phase breast cancer cells HCC1500, MDA-MB-468, and MDA-MB-453 were seeded into 96-well plates at 5000 cells per well and cultured at 37 °C in a 5% CO2 incubator for 24 h. Then, different concentrations of peptides were added to each well of the cell culture, with final peptide concentrations of 25, 12.5, 6.25, 3.125, and 1.5625 μM, and a final DMSO concentration of 0.5%. The same volume of solvent was added to the control group cell culture. After culturing cells in an incubator for 72 h, 10 μL of CCK8 solution was added to each well, and the cells were incubated for another 1 h. The absorbance at 450 nm was measured using a microplate reader. The percentage of absorbance in the peptide experimental group relative to the control group represents the cell viability or proliferation level. The control group was assumed to be 100%. The half-maximal inhibitory concentration (IC50) of the peptide on cell proliferation was calculated. 50 ) value, see results Figure 2 See Table 1.

[0033] according to Figure 2 As shown in Table 1, peptide I exhibited good inhibitory activity against breast cancer cells HCC1500, MDA-MB-453, and MDA-MB-468, with an IC50 value of [missing value]. 50 The concentrations were 4.07, 7.973, and 4.875 μM, respectively. Peptide II exhibited weak inhibitory activity against breast cancer cells, but the IC50 concentration was low. 50 All >20 μM.

[0034] Table 1. Half-maximal inhibitory concentrations (IC50) of peptides I and II on human breast cancer cell lines. 50 (μM)

[0035] Example 3 Evaluation of the inhibitory activity of peptide I on breast cancer cells The peptides obtained in Example 1, and peptide I with the best activity as determined in Example 2, were dissolved in 50% PBS (phosphate buffer) + 50% DMSO (dimethyl sulfoxide) solution. The peptides were then prepared into concentrated solutions with concentrations of 2500, 1250, 625, 312.5 and 156.25 μM. SKBR3, T47D, MCF-7, HCC1500, SUM149PT, HCC1806, MDA-MB-453, BT549, HCC1937, MDA-MB-231, and MDA-MB-468 breast cancer cells were seeded into 96-well plates at 3000 cells per well and cultured at 37°C with 5% CO2 for 24 h. Then, different concentrations of peptide I were added to each well of the cell culture, with final concentrations of 25, 12.5, 6.25, 3.125, and 1.5625 μM, and a final concentration of 0.5% DMSO. The control group cell culture was incubated with the same volume of solvent for 72 h. Finally, 10 μL of CCK8 solution was added to each well, and the cells were cultured for another 1 h. The absorbance at 450 nm was measured using a microplate reader. The percentage of absorbance value in the experimental group relative to that in the control group represents the cell viability or cell proliferation level, with the control group defaulting to 100%. The half-maximal inhibitory concentration (IC50) of peptide I on cell proliferation was calculated. 50 ), the results are shown Figure 3 And Table 2.

[0036] Table 2. Half-maximal inhibitory concentration (IC50) of peptide I on human breast cancer cell lines 50 (μM)

[0037] according to Figure 3 As shown in Table 2, peptide I exhibited strong inhibitory activity against breast cancer cell lines SKBR3, T47D, MCF-7, HCC1500, SUM149PT, HCC1806, MDA-MB-453, BT549, HCC1937, MDA-MB-231, and MDA-MB-468, with an IC50 concentration of [missing value]. 50The corresponding values ​​were 1.316 μM, 4.605 μM, 10.07 μM, 4.07 μM, 2.886 μM, 4.337 μM, 7.973 μM, 2.632 μM, 5.194 μM, 4.839 μM, and 4.875 μM.

[0038] Example 4: Evaluation of the inhibitory activity of peptide I against 13 other human cancer cells The human breast cancer cells from Example 3 were replaced with 13 other types of human cancer cells, and all other procedures were the same as in Example 3. Inhibitory effect and IC50 were observed. 50 The results of the values ​​are shown below. Figure 3 And Table 3.

[0039] Table 3. Half-maximal inhibitory concentration (IC50) of peptide I against 13 other human cancer cell lines 50 (μM)

[0040] according to Figure 3 As shown in Table 3, polypeptide I exhibits strong inhibitory activity against other cancer cell lines, including human cervical cancer cells (HeLa), human ovarian cancer cells (SK-OV-3), human hepatocellular carcinoma cells (HCC-LM3), human large cell lung cancer cells (H460), human gastric cancer cells (HGC-27), human osteosarcoma cells (MG-63), human prostate adenocarcinoma cells (PC-3), human glioblastoma-astrocytoma cells (U-87 MG), human esophageal squamous cell carcinoma cells (Eca-109), human pancreatic adenocarcinoma cells (SW1990), human malignant melanoma cells (A375), human renal cancer cells (rhabdoid tumor of the kidney) (G-401), and human nasopharyngeal carcinoma cells (HNE1). The IC50 values ​​are [not specified in the original text]. 50 The corresponding values ​​were 3.397 μM, 1.63 μM, 4.191 μM, 3.426 μM, 0.9281 μM, 3.245 μM, 0.3102 μM, 2.894 μM, 7.538 μM, 3.106 μM, 3.811 μM, 4.053 μM, and 1.746 μM.

[0041] Example 5: Induction of DNA damage in tumor cells by polypeptide I Peptide I was dissolved in 50% PBS (phosphate-buffered saline) + 50% DMSO (dimethyl sulfoxide) to prepare concentrated solutions with concentrations of 75, 150, 300, and 600 μM. Breast cancer cells HCC1806 and SUM149PT were seeded in 6-well plates and cultured. When the cell confluence reached approximately 50%, different concentrations of peptide I were added for treatment. The final concentrations of peptide I in HCC1806 cells were 1.5 μM, 3.0 μM, and 6.0 μM, respectively, while the final concentrations in SUM149PT cells were 0.75 μM, 1.5 μM, and 3.0 μM, respectively. After 48 hours of treatment, the culture medium was discarded, and total protein was extracted from the cells using RIPA lysis buffer. The expression level of the DNA damage marker protein γH2AX (phosphorylated histone H2AX) in the cells was detected by Western blotting, with GAPDH (glyceraldehyde-3-phosphate dehydrogenase) used as an internal control.

[0042] Results of Western blot analysis of proteins are as follows Figure 4 As shown, in breast cancer cells HCC1806 and SUM149PT, after treatment with different concentrations of peptide I for 48 hours, the expression of the DNA damage marker protein γH2AX was significantly increased compared with the untreated control group, and showed a certain concentration-dependent increasing trend, while the expression of the internal reference protein GAPDH remained basically stable. This indicates that peptide I targeting USP1 may inhibit cell proliferation by inhibiting DNA damage repair in breast cancer cells.

[0043] Example 6: Detection of in vivo antitumor activity of peptide I HCC1806 breast cancer cells in logarithmic growth phase were digested with trypsin, centrifuged to remove supernatant, resuspended in pre-cooled 1×PBS, counted, and the concentration was adjusted to 1x10⁻¹. 6 Cells / ml were collected, 75 μL of cell suspension was added to 25 μL of matrix gel and mixed well, then injected into the axilla of nude mice using a syringe. Measurements were taken one week after inoculation, when the subcutaneous tumor volume reached 50-70 mm². 3 Nude mice were randomly divided into a solvent control group, a peptide I (10 mg / kg) group, and a peptide I (30 mg / kg) group, with 5 mice in each group. Peptide I was prepared with 1% DMSO, and 100 μL was administered intraperitoneally to each mouse. The solvent control group was injected with a solvent without peptide I. Administration was once daily for 21 consecutive days. During this period, mouse body weight was measured regularly, and tumor volume was measured (tumor volume = 0.5 x length x width). 2 After drug administration, nude mice were euthanized by cervical dislocation, tumor tissue was removed, weighed, photographed, and serum was collected for liver and kidney function testing. The drug used in this example was polypeptide I.

[0044] Figure 5 This represents the inhibitory effect of peptide I on human breast cancer in vivo. Figure 5Image A in the image shows the tumor after the drug administration was completed. Figure 5 In Figure B, the tumor volume was measured every two days after drug treatment and represented by a line graph. Figure 5 The median C represents tumor mass after drug administration, expressed as a bar chart. Figure 5 According to the results from the AC study, compared with the solvent control group, the tumor volume and weight of breast cancer in nude mice were significantly lower after administration of 10 mg / kg and 30 mg / kg of peptide I. Figure 5 D represents the change in body weight of nude mice during the drug administration period, represented by a line graph; after drug administration, orbital blood was collected from mice to detect the serum alanine aminotransferase (ALT) level. Figure 5 (E) and aspartate aminotransferase (AST) Figure 5 The content of creatinine (F) was measured to evaluate the hepatotoxicity of peptide I in nude mice; serum creatinine levels were also measured. Figure 5 The content of G) was used to evaluate the nephrotoxicity of peptide I in nude mice; by Figure 5 According to the DG, the administration of peptide I did not affect the weight of nude mice, nor did it cause liver or kidney toxicity.

[0045] In summary, peptide I exhibits good in vivo anti-breast cancer activity, effectively inhibiting the growth of breast cancer cells in nude mice, and has no obvious toxicity to nude mice.

[0046] It should be noted that the embodiments described above are only for explaining the present invention and do not constitute any limitation on the present invention. The present invention has been described with reference to typical embodiments, but it should be understood that the words used therein are descriptive and explanatory terms, not limiting terms. Modifications can be made to the present invention within the scope of the claims, and revisions can be made to the present invention without departing from the scope and spirit of the present invention. Although the present invention described herein relates to specific methods, materials, and embodiments, it does not mean that the present invention is limited to the specific examples disclosed herein; on the contrary, the present invention extends to all other methods and applications having the same function.

Claims

1. A polypeptide with USP1 inhibitory activity, characterized in that, The amino acid sequence of the polypeptide is shown in SEQ ID NO:

1.

2. A polypeptide with USP1 inhibitory activity, characterized in that, The amino acid sequence of the polypeptide is shown in SEQ ID NO:1, and the last amino acid Arg of the polypeptide is protected by amidation modification.

3. The use of the polypeptide according to any one of claims 1-2 in the preparation of drugs for the prevention and / or treatment of cancer, characterized in that, The cancer mentioned is at least one of the following: breast cancer, cervical cancer, ovarian cancer, liver cancer, lung cancer, stomach cancer, osteosarcoma, prostate cancer, glioblastoma, esophageal squamous cell carcinoma, pancreatic cancer, melanoma, kidney cancer, and nasopharyngeal carcinoma.

4. The application according to claim 3, characterized in that, The cancer in question is breast cancer.

5. The application according to claim 3, characterized in that, The peptide is used in combination with a pharmaceutically acceptable carrier.

6. The application according to claim 3, characterized in that, The polypeptide or its pharmaceutically acceptable salt is used as the active pharmaceutical ingredient.

7. The application according to claim 6, characterized in that, The mass fraction of the active pharmaceutical ingredient is 0.1% to 99%.

8. The application according to claim 3, characterized in that, The peptide is used in combination with other drugs.

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