Polypeptides, pharmaceutical compositions, pharmaceutical combinations and uses thereof

Abstract

The application provides a polypeptide, a pharmaceutical composition, a drug combination and application thereof, and belongs to the technical field of biological medicine. The polypeptide contains an amino acid sequence: Phi1XPhi2XXPhi3, wherein Phi1, Phi2 and Phi3 are hydrophobic amino acids, and X is any amino acid. The polypeptide prepared by the application can be combined with an NTF2L domain on a G3BPs protein, thereby affecting the normal function of the G3BPs protein and application in related diseases.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to a polypeptide, a pharmaceutical composition, a pharmaceutical combination, and their applications. Background Technology

[0002] G3BPs (Ras-GTPase-activating protein-binding proteins) are RNA-binding proteins that play a crucial role in RNA processing, degradation, and the formation of stress granules (SGs). There are two homologous proteins of G3BPs: G3BP1 and G3BP2. Given the high degree of redundancy in their structure and function, the function of "G3BP1" in the following text will encompass that of G3BP2.

[0003] G3BP1 is overexpressed in various human tumors, promoting cancer cells to enter the DNA synthesis phase (S phase) and accelerating cell growth. It plays a crucial role in cancer cell proliferation, differentiation, and apoptosis, and is closely related to cancer cell drug resistance. G3BP1 also participates in multiple carcinogenesis-related signal transduction pathways, including NF-κB, ERK, p53, and Ras. Furthermore, G3BP1 is involved in the infection process of various viruses; some viruses target G3BP1 to inhibit cellular responses, and interactions between viral proteins or RNA and host G3BP1 proteins can disrupt the cell's innate immune response. Dysfunction of G3BP1 in neurodegenerative diseases can lead to abnormal solidification of SGs and co-aggregation with disease proteins, thereby driving neurotoxicity. In conclusion, G3BP1 is a promising new target for the treatment of cancer, viral infections, and neurodegenerative diseases, and designing a substance that can inhibit G3BP1 has broad application prospects. Summary of the Invention

[0004] In view of this, in order to at least partially solve the aforementioned technical problems, the present invention provides a polypeptide, a pharmaceutical composition, a pharmaceutical combination, and its application.

[0005] According to one aspect of the present invention, a polypeptide is provided, comprising the amino acid sequence: Φ1XΦ2XXΦ3, wherein Φ1, Φ2, and Φ3 are hydrophobic amino acids, and X is any amino acid.

[0006] According to one embodiment of the present invention, the hydrophobic amino acid is selected from any one of tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, proline, and valine.

[0007] According to one embodiment of the present invention, the above-mentioned amino acid sequence is FNLGEL or YEYGRM.

[0008] According to another aspect of the present invention, a pharmaceutical composition comprising the above-described polypeptide is provided.

[0009] According to another aspect of the present invention, the use of the above-described polypeptide in the preparation of a medicament for inhibiting G3BPs is provided.

[0010] According to one embodiment of the present invention, the drug for inhibiting G3BPs is a drug for reducing the resistance of tumor cells to anti-tumor drugs, a drug for treating viral infections, or a drug for treating neurodegenerative diseases.

[0011] According to one embodiment of the present invention, the aforementioned tumors include any one of lung cancer, breast cancer, colorectal cancer, prostate cancer, stomach cancer, liver cancer, pancreatic cancer, cervical cancer, skin cancer, osteosarcoma, liposarcoma, leiomyosarcoma, leukemia, lymphoma, multiple myeloma, glioma, meningioma, testicular cancer, endometrial cancer, cervical cancer, ovarian cancer, melanoma, thyroid cancer, kidney cancer, or bladder cancer.

[0012] According to one embodiment of the present invention, the above-mentioned antitumor drugs include any one or a combination of sorafenib, 5-fluorouracil, paclitaxel, anthracyclines, platinum drugs, oxaliplatin, bortezomib, docetaxel or cabazitaxel.

[0013] According to one embodiment of the present invention, the above-mentioned anthracycline drug may be epirubicin and doxorubicin.

[0014] Based on the above technical solution, the polypeptide containing the Φ1XΦ2XXΦ3 motif provided by the present invention, when used in combination with different anti-tumor drugs, can improve the sensitivity of various tumor cells to anti-tumor drugs, thereby reducing the drug resistance of tumor cells.

[0015] Therefore, according to another aspect of the present invention, a pharmaceutical combination is provided comprising the above-described polypeptide and an antitumor drug.

[0016] According to one embodiment of the present invention, the above-mentioned antitumor drugs include any one or a combination of sorafenib, 5-fluorouracil, paclitaxel, anthracyclines, platinum drugs, oxaliplatin, bortezomib, docetaxel or cabazitaxel.

[0017] According to one embodiment of the present invention, the above-mentioned anthracycline drug may be epirubicin and doxorubicin.

[0018] The polypeptide containing the Φ1XΦ2XXΦ3 sequence of the present invention can bind to the NTF2L domain on the G3BPs protein, thereby affecting the normal function of the G3BPs protein. Therefore, it can be used for the treatment of related diseases. When used in combination with different anti-tumor drugs, it can improve the efficacy and reduce the survival rate of tumor cells. Attached Figure Description

[0019] Figure 1This is a schematic diagram of the binding of a polypeptide containing the sequence FNLGEL or YEYGRM to the hydrophobic pocket in G3BP1 NTF2L, where A represents the binding of a polypeptide containing the sequence FNLGEL to the hydrophobic pocket, and B represents the binding of a polypeptide containing the sequence YEYGRM to the hydrophobic pocket.

[0020] Figure 2 The half-maximal inhibitory concentration (IC50) of GBM1 and GBM2 in combination with sorafenib in hepatocellular carcinoma cells (Huh7) is given. 50 ) Test result image;

[0021] Figure 3 IC50 of GBM1 and GBM2 in combination with paclitaxel in breast cancer cells (MDA-MB-231) 50 Test result image;

[0022] Figure 4 IC50 of GBM1 and GBM2 in combination with epirubicin in MDA-MB-231 50 Test result image;

[0023] Figure 5 IC50 of GBM1 and GBM2 in combination with cisplatin in lung cancer cells (H1299) 50 Test result image;

[0024] Figure 6 IC50 of GBM1 and GBM2 in combination with paclitaxel in gastric cancer cells (HGC27) 50 Test result image;

[0025] Figure 7 IC50 of GBM1 and GBM2 in combination with paclitaxel in osteosarcoma cells (U2OS) 50 Detection results image. Detailed Implementation

[0026] Hereinafter, embodiments of the present invention will be described with reference to the accompanying drawings. However, it should be understood that these descriptions are merely exemplary and are not intended to limit the scope of the invention.

[0027] In this application, single-letter or three-letter abbreviations of amino acids commonly used in the art are used to express the amino acid sequences of polypeptides or proteins. For example, the sequence FNLGEL refers to phenylalanine-asparagine-leucine-glycine-glutamic acid-leucine; the sequence YEYGRM refers to tyrosine-glutamic acid-tyrosine-glycine-arginine-methionine.

[0028] In realizing the concept of this invention, it was discovered that multiple proteins, including Caprin-1, SARS-CoV-2 N protein, and SFV nsP3, collectively recognize and bind to the NTF2L domain of the G3BP1 protein, inhibiting some functions of G3BP1. Therefore, targeting the G3BP1 NTF2L domain and designing peptides that bind to this key pocket as G3BP1 binding peptides shows significant research potential in the treatment of diseases such as cancer, viral infections, and neurodegenerative diseases, providing a new strategy for related drug development.

[0029] Figure 1 This diagram illustrates the binding of a peptide containing the FNLGEL or YEYGRM sequence to the hydrophobic pocket in G3BP1 NTF2L, where A represents the binding of a peptide containing the FNLGEL sequence to the hydrophobic pocket, and B represents the binding of a peptide containing the YEYGRM sequence to the hydrophobic pocket.

[0030] Based on the crystal structure of G3BP1 NTF2L, this invention designs a polypeptide containing Φ1×Φ2×Φ3 motifs (where Φ1, Φ2, and Φ3 represent hydrophobic amino acids such as tyrosine [Tyr], tryptophan [Trp], phenylalanine [Phe], methionine [Met], leucine [Leu], isoleucine [Ile], proline [Pro], and valine [Val]), which can bind to G3BP1 NTF2L and act as an inhibitor of G3BP1. Figure 1 As shown, the hydrophobic pockets formed by Val-11, Phe-15, Phe-33, Leu-114, Phe-124, and Val-126 on G3BP1 NTF2L (referred to as hydrophobic pocket one) bind Φ1 and Φ2, while the hydrophobic pocket formed by Leu22, Met29, and Phe33 (referred to as hydrophobic pocket two) binds Φ3. Therefore, these two hydrophobic pockets are specific for peptide binding, and occupation of these two hydrophobic pockets can influence the role of G3BP1 in some diseases.

[0031] Because G3BP1 is involved in the infection process of various viruses and can drive neurotoxicity in neurodegenerative diseases, it is a potential new target for viral infections and neurodegenerative diseases. The aforementioned neurodegenerative diseases cover both acute and chronic categories. Chronic types, with a longer course and slower progression, mainly include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Acute types, with a rapid onset and rapid progression, include cerebral ischemia (CI), brain injury (BI), and epilepsy.

[0032] The polypeptides containing the Φ1XΦ2XXΦ3 motifs of the present invention can be prepared using polypeptide preparation methods commonly used in the art, such as chemical synthesis.

[0033] The polypeptide containing the Φ1XΦ2XXΦ3 motif of the present invention can be prepared as a drug as an active ingredient. Alternatively, preferably, the polypeptide containing the Φ1XΦ2XXΦ3 motif can be conjugated with a substance that promotes membrane penetration; or the polypeptide containing the Φ1XΦ2XXΦ3 motif can be co-linked with a cell-penetrating peptide into an expression vector; or the polypeptide containing the Φ1XΦ2XXΦ3 motif can be expressed using an expression vector with membrane-penetrating capability. The above operations can endow the polypeptide containing the Φ1XΦ2XXΦ3 motif with cell membrane penetration ability, thus solving the bottleneck of polypeptide drug delivery.

[0034] Specifically, a polypeptide containing the Φ1XΦ2XXΦ3 motif can be conjugated to a human immunodeficiency virus (HIV)-1 transcription activator-derived transmembrane peptide (TAT transmembrane peptide, with the sequence GRKKRRQRRR). For example, a polypeptide containing the sequence FNLGEL or YEYGRM can be conjugated to the aforementioned transmembrane peptide using conventional methods in the art to obtain polypeptides with amino acid sequences as shown in SEQ1 and SEQ2, respectively, which are named GBM (G3BP1 binding motif)1 and GBM2, respectively.

[0035] SEQ1(GBM1):GRKKRRQRRRFNLGEL.

[0036] SEQ2(GBM2):GRKKRRQRRRYEYGRM.

[0037] TAT transmembrane peptides are recognized as single-function transmembrane tools whose role is limited to delivering functional peptides into cells, without participating in or contributing any specific biological activity.

[0038] In embodiments of the present invention, a drug combination comprising a peptide containing the sequence FNLGEL or YEYGRM and an antitumor drug is provided. The antitumor drug includes any one or a combination of sorafenib, 5-fluorouracil, paclitaxel, anthracyclines, platinum-based drugs, oxaliplatin, bortezomib, docetaxel, or cabazitaxel. When used in combination, the peptide and the antitumor drug can be administered simultaneously or sequentially, preferably the peptide first, followed by the antitumor drug, for example, administering the peptide 0.5-2 hours before the antitumor drug, to precisely control variables and ensure optimal efficacy and safety of both drugs in vivo.

[0039] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0040] Example 1

[0041] GBM1 and GBM2 are used in combination with different antitumor drugs to enhance the sensitivity of various tumors to the drugs, including the following steps (1)-(11).

[0042] Step (1) Cell culture: Huh7, MDA-MB-231, H1299, HGC27 or U2OS were cultured in 9 cm culture dishes using Durbeco modified Eagle medium (DMEM medium) containing 10% (v / v) fetal bovine serum and cultured in a constant temperature incubator at 37°C and 5% carbon dioxide (CO2).

[0043] Step (2) Cell washing: When the cell confluence reaches 80%, the culture medium is aspirated and phosphate-buffered saline (PBS) is added to gently wash the cells.

[0044] Step (3) Pancreatic enzyme digestion: After discarding PBS, add 2 mL of pancreatic enzyme and digest at 37 °C for 3 min.

[0045] Step (4) Cell collection: Transfer the cell suspension to Eppendorf tubes (EP tubes), centrifuge at 1200×g for 5 min, and discard the supernatant.

[0046] Step (5) Cell seeding: Resuspend the cells in 1 mL of DMEM medium and dilute to a density of 4000 cells / mL. Seed the cells in 96-well plates and culture for 24 h to allow the cells to adhere completely. The cell confluence in each well should reach 50%-70%.

[0047] Step (6) Peptide administration treatment: A control group (anti-tumor drug alone), a negative control group (anti-tumor drug combined with TAT membrane-penetrating peptide), and an experimental group (anti-tumor drug combined with peptide) were set up. TAT membrane-penetrating peptide was added to the negative control group to make the final concentration of the membrane-penetrating peptide in the wells 50 μM; GBM1 or GBM2 (synthesized by Shanghai Sangon Biotech Co., Ltd.) solution was added to the experimental group to make the final concentration of the peptide in the wells 50 μM; and an equal amount of PBS was added to the control group.

[0048] Step (7) After incubating the cells from step (6) in an incubator for 1 hour, add the anti-tumor drug.

[0049] Step (8) Administration of antitumor drugs:

[0050] a. Sorafenib administration in Huh7: Take 10 μL of serially diluted sorafenib into the corresponding positions of a 96-well plate containing Huh7 (both peptide treatment wells and control wells need to be administered), so that the final concentrations are 200, 100, 50, 25, 12.5, 6.25, 3.125, 1.5625, and 0.78125 μM, respectively, with 6 replicates per group.

[0051] b. Administration of paclitaxel or epirubicin in MDA-MB-231: Take 10 μL of serially diluted paclitaxel or epirubicin into the corresponding positions of a 96-well plate coated with MDA-MB-231 (both peptide treatment wells and control wells need to be administered), so that the final concentrations are 2000, 1000, 400, 200, 100, 50, 25, 12.5, 6.25, and 3.125 nM, respectively, with 6 replicates per group.

[0052] c. Cisplatin administration in H1299: Take 10 μL of serially diluted cisplatin and add it to the corresponding positions of the 96-well plate containing H1299 (both peptide treatment wells and control wells need to be administered), so that the final concentrations are 200, 100, 50, 25, 12.5, 6.25, 3.125, 1.5625, and 0.78125 μM, respectively, with 6 replicates per group.

[0053] d. Paclitaxel administration in HGC27: Take 10 μL of serially diluted paclitaxel into the corresponding positions of a 96-well plate coated with H1299 (both peptide treatment wells and control wells need to be administered), so that the final concentrations are 2000, 1000, 400, 200, 100, 50, 25, 12.5, 6.25, and 3.125 nM, respectively, with 6 replicates per group.

[0054] f. Paclitaxel administration in U2OS: Take 10 μL of serially diluted paclitaxel into the corresponding positions of a 96-well plate coated with U2OS (both peptide treatment wells and control wells need to be administered), so that the final concentrations are 2000, 1000, 400, 200, 100, 50, 25, 12.5, 6.25, and 3.125 nM, respectively, with 6 replicates per group.

[0055] Step (9) Drug incubation: The cells of the control group and the experimental group were placed in a 37°C, 5% CO2 incubator and cultured for 72 h.

[0056] Step (10) CCK8 detection: Discard the original culture medium, add 100 μL of a mixture of CCK8 reagent (Beyotime C0038) and DMEM culture medium (volume ratio of 1:10) to each well, and incubate in a 37℃ incubator in the dark for 1 h.

[0057] Step (11) Data Analysis: The absorbance of cells at 450 nm was detected using an ELISA reader, and the IC50 of the combination of antitumor drugs and peptides on cells was calculated using data analysis software. 50 and the effect of antitumor drugs on the IC50 of cells 50 .

[0058] Figure 2 The half-maximal inhibitory concentration (IC50) of GBM1 and GBM2 in combination with sorafenib in hepatocellular carcinoma cells (Huh7) is given. 50 (Image of test results)

[0059] a. Inhibitory effect of GBM1 or GBM2 in combination with sorafenib on Huh7: The inhibitory effect of GBM1 or GBM2 in combination with sorafenib on Huh7 is as follows: Figure 2 As shown. Sorafenib alone for Huh7 IC 50 The IC50 of sorafenib combined with TAT membrane-penetrating peptide was 22.23 μM. 50 The concentration was 20.32 μM, indicating that the TAT membrane-penetrating peptide did not affect the IC50 of sorafenib against Huh7. 50 And after combining 50μM GBM1, sorafenib showed improved IC50 response to Huh7. 50 The concentration decreased to 9.205 μM (a 58.6% reduction); after combining with 50 μM GBM2, sorafenib reduced its IC50 against Huh7. 50 It decreased to 7.758 μM (a reduction of 65.1%).

[0060] The above results indicate that both GBM1 and GBM2, containing the Φ1XΦ2XXΦ3 motif, can target G3BP1, significantly enhancing the sensitivity of Huh7 to the anti-tumor drug sorafenib. Specifically, GBM1 increases the killing efficacy of sorafenib against Huh7 by 2.4 times (IC50). 50 From 22.23 to 9.205 μM); GBM2 increased the lethality of sorafenib against Huh7 by 2.9 times (IC). 50 (From 22.23 → 7.758 μM).

[0061] Figure 3 IC50 of GBM1 and GBM2 in combination with paclitaxel in breast cancer cells (MDA-MB-231) 50 Detection results image.

[0062] b. Inhibitory effect of GBM1 or GBM2 in combination with paclitaxel or epirubicin on MDA-MB-231: The inhibitory effect of GBM1 or GBM2 in combination with paclitaxel on MDA-MB-231 is as follows: Figure 3 As shown. IC50 of paclitaxel alone against MDA-MB-231.50 The IC50 of paclitaxel combined with TAT membrane-penetrating peptide was 29.25 nM. 50 The value was 28.2 nM, indicating that the TAT membrane-penetrating peptide did not affect the IC50 of paclitaxel against MDA-MB-231. 50 However, when combined with 50 μM GBM1, the IC50 of paclitaxel was significantly reduced. 50 The concentration decreased to 10.29 nM (a reduction of 64.8%); after combination with 50 μM GBM2, the IC50 of paclitaxel was... 50 It decreased to 9.759 nM (a reduction of 66.6%).

[0063] Figure 4 IC50 of GBM1 and GBM2 in combination with epirubicin in MDA-MB-231 50 Detection results image.

[0064] The inhibitory effect of GBM1 or GBM2 in combination with epirubicin on MDA-MB-231 is as follows: Figure 4 As shown. The IC of MDA-MB-231 is used alone with the Rhodopsin. 50 The IC50 of epirubicin combined with TAT membrane-penetrating peptide was 182.3 nM. 50 The value was 201.5 nM, indicating that the TAT membrane-penetrating peptide did not affect the IC50 of epirubicin against MDA-MB-231. 50 And after combining 50 μM GBM1, the IC50 of epirubicin... 50 The concentration decreased to 100.8 nM (a 45% reduction); after combining with 50 μM GBM2, the IC50 of epirubicin decreased. 50 It decreased to 82.62 nM (a reduction of 54.7%).

[0065] The above results indicate that both GBM1 and GBM2 can target G3BP1, significantly enhancing the sensitivity of MDA-MB-231 to anti-tumor drugs. Specifically, GBM1 increased the killing efficacy of paclitaxel against MDA-MB-231 by 2.8 times (IC50). 50 From 29.25 to 10.29 nM); GBM2 increased the killing efficacy of paclitaxel against MDA-MB-231 by 3 times (IC50). 50 From 29.25 → 9.759 nM). GBM1 increased the lethality of epirubicin against MDA-MB-231 by 1.8 times (IC). 50 From 182.3 to 100.8 nM); GBM2 increased the lethality of epirubicin against MDA-MB-231 by 2.2 times (IC). 50 From 182.3 → 82.62 nM).

[0066] Figure 5IC50 of GBM1 and GBM2 in combination with cisplatin in lung cancer cells (H1299) 50 Detection results image.

[0067] c. Inhibitory effect of GBM1 or GBM2 in combination with cisplatin on H1299: The inhibitory effect of GBM1 or GBM2 in combination with cisplatin on H1299 is as follows: Figure 5 As shown. Cisplatin alone is used for H1299 IC. 50 The IC50 of cisplatin combined with TAT membrane-penetrating peptide was 15.6 μM. 50 The concentration was 12.88 μM, indicating that the TAT membrane-penetrating peptide did not affect the IC50 of cisplatin against H1299. 50 And when combined with 50 μM GBM1, cisplatin's IC50 response to H1299 was significantly improved. 50 Reduced to 5.265 μM (a 66.3% decrease); after combining with 50 μM GBM2, cisplatin's IC50 against H1299 was significantly reduced. 50 It decreased to 4.042 μM (a 74% reduction).

[0068] The above results indicate that both GBM1 and GBM2 can target G3BP1, significantly enhancing the sensitivity of H1299 to the anti-tumor drug cisplatin. Specifically, GBM1 increased the killing efficacy of cisplatin against H1299 by 3 times (IC50). 50 From 15.6 to 5.265 μM); GBM2 increased the cytotoxicity of cisplatin against H1299 by 3.9 times (IC50). 50 From 15.6 to 4.042 μM.

[0069] Figure 6 IC50 of GBM1 and GBM2 in combination with paclitaxel in gastric cancer cells (HGC27) 50 Detection results image.

[0070] d. Inhibitory effect of GBM1 or GBM2 in combination with paclitaxel on HGC27: The inhibitory effect of GBM1 or GBM2 in combination with paclitaxel on HGC27 is as follows: Figure 6 As shown. IC50 of paclitaxel alone against HGC27. 50 The IC50 of paclitaxel combined with TAT membrane-penetrating peptide was 59.62 nM. 50 The value was 65.41 nM, indicating that the TAT membrane-penetrating peptide did not affect the IC50 of paclitaxel on HGC27. 50 However, when combined with 50 μM GBM1, paclitaxel's IC50 for HGC27 was significantly reduced. 50 The concentration decreased to 30.5 nM (a 48.8% reduction); after combination with 50 μM GBM2, the IC50 of paclitaxel against HGC27 was... 50 It decreased to 37.27 nM (a decrease of 37.5%).

[0071] The above results indicate that both GBM1 and GBM2 can target G3BP1, significantly enhancing the sensitivity of HGC27 to the anti-tumor drug paclitaxel. Specifically, GBM1 increases the killing efficacy of paclitaxel against HGC27 by 2 times (IC50). 50 From 59.62 to 30.5 nM); GBM2 increased the killing efficacy of paclitaxel against HGC27 by 1.6 times (IC50). 50 From 59.62 to 37.27 nM).

[0072] Figure 7 IC50 of GBM1 and GBM2 in combination with paclitaxel in osteosarcoma cells (U2OS) 50 Detection results image.

[0073] e. Inhibitory effect of GBM1 or GBM2 in combination with paclitaxel on U2OS: The inhibitory effect of GBM1 or GBM2 in combination with paclitaxel on U2OS is as follows: Figure 7 As shown. The IC of U2OS using paclitaxel alone. 50 The IC50 of paclitaxel combined with TAT membrane-penetrating peptide was 78.19 nM. 50 The concentration was 66.61 μM, indicating that the TAT membrane-penetrating peptide did not affect the IC50 of paclitaxel for U2OS. 50 However, when combined with 50 μM GBM1, paclitaxel's IC50 for U2OS... 50 The concentration decreased to 35.85 nM (a 54.2% reduction); after combining with 50 μM GBM2, the IC50 of paclitaxel against U2OS was reduced. 50 It decreased to 15.24 nM (a reduction of 80.5%).

[0074] The above results indicate that both GBM1 and GBM2 can target G3BP1 and significantly enhance the sensitivity of U2OS to the anti-tumor drug paclitaxel. Specifically, GBM1 increases the killing efficacy of paclitaxel against U2OS by 2 times (IC50). 50 From 78.19 to 38.85 nM); GBM2 increased the killing efficacy of paclitaxel against U2OS by 5.1 times (IC50). 50 From 78.19 → 15.24 nM).

[0075] This invention demonstrates that GBM1 or GBM2 containing the Φ1XΦ2XXΦ3 motif, when combined with different antitumor drugs (sorafenib, paclitaxel, epirubicin, and cisplatin), can effectively enhance the drug sensitivity of various tumor cells (Huh7, MDA-MB-231, H1299, HGC27, and U2OS), showing potential to overcome drug resistance in multiple tumors. Therefore, peptides containing the Φ1XΦ2XXΦ3 motif can serve as novel chemosensitizers, overcoming drug resistance in cancers such as liver cancer, breast cancer, lung cancer, gastric cancer, and osteosarcoma by targeting G3BP1 binding. Similarly, GBM1 or GBM2 containing the Φ1XΦ2XXΦ3 motif can also serve as promising peptide drugs to treat other G3BP1-related diseases, such as neurodegenerative diseases and viral infections.

[0076] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above descriptions are merely specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A polypeptide, characterized in that, The polypeptide is GBM1 or GBM2, with the amino acid sequence of GBM1 shown in SEQ1 and the amino acid sequence of GBM2 shown in SEQ2.

2. The use of the polypeptide as described in claim 1 in the preparation of a drug that reduces the resistance of tumor cells to antitumor drugs, wherein the tumor is selected from any one of lung adenocarcinoma, triple-negative breast cancer, gastric adenocarcinoma, hepatocellular carcinoma, and osteosarcoma; and the antitumor drug is selected from any one of sorafenib, paclitaxel, epirubicin, and cisplatin.

3. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises an antitumor drug and the polypeptide as described in claim 1, wherein the antitumor drug is any one of sorafenib, paclitaxel, epirubicin, and cisplatin.

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