A short peptide targeting cGAS, a fusion polypeptide and its application

Abstract

The present invention relates to a short peptide, fusion polypeptide and application targeting cGAS. Based on the molecular mechanism by which key linker molecules of the innate immune signaling pathway play a role in acute myocardial infarction, the present invention designs a fusion polypeptide capable of protecting cell homeostasis and cardiac function, comprising the 150-163 region of the cGAS binding protein USP27X, and a cell-penetrating peptide fused to the N-terminus of the short peptide. The fusion polypeptide can inhibit the binding of cGAS to USP27X, reduce the expression of interferon and chemokines, and reduce excessive immune response. Animal models have shown that the fusion polypeptide can effectively reduce the infarct area of ​​acute myocardial infarction and effectively improve new functions. Compared with the full-length protein, the fusion polypeptide has a small molecular weight, is easy to synthesize, has weak immunogenicity, and has relatively weak side effects; it has better absorption with a cell-penetrating peptide and is easy to track and observe with a polypeptide tag, providing a reference for the clinical treatment of acute cardiovascular disease and having great potential as a clinical drug.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to a short peptide capable of maintaining cell homeostasis and protecting cardiac function, a fusion polypeptide comprising the short peptide, and its application in inhibiting excessive immune response drugs or exerting a cardioprotective effect in acute cardiovascular diseases. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance understanding of the overall background of the invention and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to those skilled in the art.

[0003] Acute myocardial infarction (AMI) is a serious cardiovascular disease. Prolonged hypoxia and ischemia cause severe tissue damage, accompanied by elevated peripheral blood cardiac biomarkers, leading to myocardial tissue death and heart failure, resulting in extremely high morbidity and mortality. Current treatment strategies for AMI primarily rely on drug-mediated thrombus dissolution and / or intravascular stent implantation to restore coronary blood flow (reperfusion). Although reperfusion strategies have some benefits in reducing infarct size, the accumulation of reactive oxygen species in damaged mitochondria exacerbates ischemia-reperfusion injury and is a major factor in the increased risk of heart failure in AMI patients. Therefore, there is an urgent need to improve AMI treatment strategies to prevent adverse cardiac remodeling and heart failure.

[0004] Ischemic myocardial injury triggers an inflammatory response, and the cascade inflammatory response clears necrotic tissue. However, excessive inflammatory activation exacerbates myocardial damage, leading to infarct expansion, myocardial rupture, and adverse remodeling. Currently, anti-inflammatory treatment still faces several problems: Multiple clinical studies of anti-inflammatory treatments have failed, with numerous inflammatory targets and limited selectivity. Furthermore, several inhibitors are ineffective, including those for Lp-PLA2 and p38-MAPK. There are no clinically available NLRP3-specific inhibitors. The inhibitors have limited efficiency in entering cells; The toxic side effects of inhibitor metabolites are highly harmful to the human body. Cyclooxygenase-2 inhibitors increase the risk of myocardial infarction, tumor necrosis factor-α antagonists increase platelet activation, and interleukin-6 antagonists lead to elevated low-density lipoprotein cholesterol. Therefore, developing alternative drugs with greater specificity and faster metabolism is crucial for improving the prognosis of acute myocardial infarction.

[0005] Reperfusion exacerbates acute myocardial injury, leading to the accumulation of ROS and mitochondrial damage. Voltage-dependent anion channel (VDAC) oligomers on the mitochondrial outer membrane form micropores, allowing intracellular mitochondrial DNA to leak, triggering the release of danger-associated molecular patterns (DAMPs). DAMPs activate DNA signaling pathways by binding to pattern recognition receptors (PRRs). DAMPs are a heterogeneous group of molecules with specific chemical and physical properties that, when bound to PRRs, activate immune responses, inducing the production of type I interferons, chemokines, and inflammatory cytokines. However, existing research is limited to inhibitor interventions, which have poor specificity and slow metabolism.

[0006] Targeted therapy based on important linker molecules in the innate immune DNA signaling pathway and the design of short peptide synthetic drugs based on the target are new strategies to reduce infarct size and prevent heart failure after AMI. Summary of the Invention

[0007] Based on the above technical background, the present invention aims to provide a fusion polypeptide with cardioprotective effects. The active small peptide in the fusion polypeptide targets cGAS and can specifically bind to cGAS, thereby inhibiting the binding of cGAS to USP27X, thereby inhibiting the activation of the downstream interferon signaling pathway and achieving the effect of suppressing excessive immunity. The present invention also provides a fusion peptide Tat USP27X, which is a cell-penetrating peptide modified with the above-mentioned active small peptide. It has been verified that Tat USP27X can significantly inhibit the excessive activation of the endothelial cell DNA signaling pathway, reduce the immune response in mice, and significantly improve the cardiac function of mice compared with the control drug.

[0008] Therefore, the present invention provides the following technical solutions:

[0009] In a first aspect, the present invention provides a short peptide targeting cGAS, wherein the amino acid sequence of the short peptide is as follows:

[0010] (1) the amino acid sequence shown in SEQ ID NO: 1;

[0011] (2) A derivative polypeptide formed by adding, substituting or deleting one or more amino acids from the amino acid sequence shown in SEQ ID NO: 1, and the derivative polypeptide still has the same or substantially the same function as the short peptide shown in SEQ ID NO: 1.

[0012] The amino acid sequence shown in SEQ ID NO: 1 is derived from the amino acid region 150-163 of the cGAS-binding protein USP27X. By constructing truncated fragments and conducting immunoprecipitation experiments, the inventors identified the key region of USP27X that binds to cGAS. This region was further refined into seven short sequences, confirming that the amino acid region 150-163 of USP27X mediates its binding to cGAS. The present invention has demonstrated that short peptides from this region specifically bind to cGAS. Exogenous supplementation of these peptides can effectively inhibit the activation of downstream interferon signaling pathways and significantly reduce the expression levels of the cytokines IRF7 and CXCL10, thereby suppressing excessive immune responses and achieving cardioprotection. These peptides are suitable for use in the treatment of acute cardiovascular diseases.

[0013] In the above aspect (2), the addition, deletion or substitution may occur at the N-terminus and / or C-terminus or in the sequence of the amino acid sequence shown in SEQ ID NO: 1; further, the sequence of the derived polypeptide has a similarity of 90% or more to the amino acid sequence shown in SEQ ID NO: 1; further, the similarity is at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%; the similarity of the amino acid sequences can be compared using a method commonly used in the art, such as the Blast method.

[0014] The same or substantially the same physiological functions include the ability to bind to cGAS, the ability to block activation of downstream interferon signaling pathways, or the ability to inhibit excessive immune response.

[0015] In addition, the derivative polypeptides described in (1) above also broadly include derivative polypeptides formed by chemical or genetic modification of the polypeptide with the sequence shown in SEQ ID NO: 1, and feasible modification methods include streptavidin, biotin, radioactive isotopes, fluorescent agents, enzymes, cytotoxic substances, anti-tumor agents, etc.; in addition, the derivative polypeptides also include immobilized products of the polypeptide with the sequence shown in SEQ ID NO: 1, including but not limited to products obtained by fixing or modifying the above-mentioned antibodies using physical adsorption, carriers, resin cross-linking materials, etc.

[0016] In a second aspect, the present invention provides a fusion polypeptide, wherein the fusion protein comprises the short peptide targeting cGAS according to the first aspect, and further comprises an effector binding fragment.

[0017] Preferably, the effector binding fragment is an effector fragment for prolonging the half-life of the short peptide in vivo, increasing the transmembrane effect of the short peptide or increasing the targeting effect of the polypeptide; further, the effector binding fragment is a transmembrane peptide, specifically a type such as Tat, Penetratin, Polyarginine, P22N, DPV3 or DPV6; in one embodiment verified by the present invention, the transmembrane peptide is Tat.

[0018] Preferably, the short peptide targeting cGAS and the effector binding fragment are connected via an amide bond, and further, the effector binding fragment is connected to the N-terminus or C-terminus of the short peptide via an amide bond; in a specific embodiment, in the fusion polypeptide, the N-terminus of the short peptide targeting cGAS is connected to the transmembrane peptide Tat, and the sequence of the fusion polypeptide is shown in SEQ ID NO: 2; in another specific embodiment, the fusion peptide of the sequence shown in SEQ ID NO: 2 is also biotin-labeled.

[0019] In the practical application of the present invention, the sources of the short peptide or fusion polypeptide targeting cGAS include constructing an engineered bacterium for expression, and also include preparing it by chemical synthesis methods such as solid phase synthesis or liquid phase synthesis. Based on the above preparation method of expressing it by constructing an engineered bacterium, the present invention also provides the following technical solutions in the third to fifth aspects:

[0020] In a third aspect, the present invention provides a nucleic acid encoding the short peptide targeting cGAS described in the first aspect or the fusion polypeptide described in the second aspect.

[0021] The nucleic acid material includes a nucleic acid encoding a short peptide or fusion polypeptide targeting cGAS that can be translated due to codon degeneracy, including DNA or RNA forms. DNA forms include cDNA, genomic DNA, or synthetic DNA, and can be single-stranded or double-stranded, and can be either the coding strand or the non-coding strand. Methods for isolating the nucleic acid material should be known to those skilled in the art, and for example, the nucleic acid material can be prepared by automated DNA synthesis and / or recombinant DNA technology, or isolated from a suitable natural source.

[0022] In a fourth aspect, the present invention provides an expression vector comprising the nucleic acid substance described in the third aspect.

[0023] The methods for constructing the expression vector are conventional for those skilled in the art, and can be constructed, for example, by in vitro recombinant DNA techniques, DNA synthesis techniques, in vivo recombination techniques, or the like. More specifically, the expression vector can be constructed by inserting the isolated polynucleotide into the multiple cloning site of an expression vector. The expression vector of the present invention can employ various commercially available expression vectors well known in the art, such as bacterial plasmids, bacteriophages, yeast plasmids, plant cell viruses, mammalian cell viruses such as adenoviruses, retroviruses, or other vectors.

[0024] In a fifth aspect, the present invention provides a host cell, comprising the short peptide targeting cGAS according to the first aspect, the fusion polypeptide according to the second aspect, the nucleic acid substance according to the third aspect, and / or the expression vector according to the fourth aspect.

[0025] The aforementioned host cells are any cells capable of being transformed with an expression vector and expressing the cGAS-targeting short peptide or fusion polypeptide, including prokaryotic cells (e.g., bacterial cells), lower eukaryotic cells (e.g., yeast cells), and higher eukaryotic cells (e.g., mammalian cells). Specific examples include Escherichia coli, Salmonella typhimurium, yeast, filamentous fungi, plant cells, Drosophila S2 or Sf9 insect cells, CHO, COS, HEK293 cells, or Bowes melanoma cells. Those skilled in the art can routinely select such host cell types. Methods for constructing such expression systems are known to those skilled in the art and include, but are not limited to, one or more of microinjection, gene gun techniques, electroporation, virus-mediated transformation, electron bombardment, and calcium phosphate precipitation.

[0026] In a sixth aspect, the present invention provides a pharmaceutical composition, comprising the short peptide targeting cGAS according to the first aspect or the fusion polypeptide according to the second aspect.

[0027] Preferably, the pharmaceutical composition further comprises the aforementioned necessary carriers for pharmaceutical purposes, including but not limited to buffers (such as acetate, Tris, phosphate, citrate and other organic acids), antioxidants (such as ascorbic acid and methionine), preservatives (such as octadecyldimethylbenzyl ammonium chloride, phenol, butyl alcohol or benzyl alcohol, methyl parahydroxybenzoate or propyl parahydroxybenzoate, catechol, resorcinol, cyclohexanol, 3-pentanol and m-cresol), bactericides (such as hexamethonium chloride, benzalkonium chloride, benzethonium chloride), etc.

[0028] Preferably, the dosage of the short peptide or fusion polypeptide targeting cGAS in the pharmaceutical composition should be an active dose, which can be determined by conventional means based on the subject being treated and the specific route of administration. For example, based on the total mass of the pharmaceutical composition, the content of the short peptide or fusion polypeptide targeting cGAS can range from approximately 0.01 to 99%, 0.1 to 70%, 1 to 30%, 0.01 to 0.05%, 0.05 to 0.1%, 0.1 to 0.3%, 0.3 to 0.5%, 0.5 to 1%, 1 to 3%, 3 to 5%, 5 to 10%, 10 to 20%, 20 to 30%, 30 to 50%, 50 to 70%, or 70 to 99%.

[0029] In a seventh aspect, the present invention provides the use of the short peptide targeting cGAS described in the first aspect, the fusion polypeptide described in the second aspect, or the pharmaceutical composition described in the third aspect in any one of the following aspects:

[0030] (1) Used to reduce pathological damage caused by excessive immune response diseases, or to prevent, improve, and treat acute cardiovascular diseases;

[0031] (2) Used to prepare drugs for suppressing excessive immune responses or drugs for acute cardiovascular diseases;

[0032] (3) Used to prepare model agents that inhibit the binding of cGAS to USP27X, or model agents that degrade cGAS, or inhibitors of cellular interferon and chemokine expression.

[0033] Preferably, the acute cardiovascular disease includes acute myocardial infarction, reperfusion injury and heart failure induced by acute myocardial infarction; it has been verified by the present invention that the above-mentioned short peptide or fusion polypeptide can exert a cardioprotective effect and can significantly reduce the infarct area of ​​acute myocardial infarction.

[0034] The above aspect (2) is intended to protect drugs comprising the above short peptides and fusion polypeptides, wherein the dosage form of the drugs is a solution preparation, a semi-solid preparation or a solid preparation; preferably a solution preparation, such as a microcapsule, nanocapsule, microsphere, nanosphere or liposome solution preparation.

[0035] In addition, the above aspect (3) also provides the use of the above short peptide and fusion polypeptide as a modeling reagent in a disease model, the application purpose of which is such as screening of active drugs, etc., and does not involve the diagnosis and treatment of diseases; further, the inhibitor of chemokine expression is an inhibitor of IRF7 and CXCL10.

[0036] The beneficial effects of one or more of the above technical solutions are:

[0037] Based on the newly discovered role and molecular mechanism of innate immune responses in myocardial injury induced by acute myocardial infarction, this study designed a fusion polypeptide that can reduce excessive immune responses in myocardial injury and protect the heart from damage. Later experiments confirmed that this fusion polypeptide can competitively bind to cGAS, reduce cGAS / USP27X binding, and promote cGAS ubiquitination. It also effectively reduces cGAS protein levels and the release of downstream immune factors in hypoxic injury, and can improve cardiac function in mice, showing great potential as a clinical drug.

[0038] This short peptide can target cGAS, inhibiting its binding to USP27X and suppressing excessive immune responses. Animal models have shown that the short peptide can effectively treat myocardial damage caused by acute myocardial infarction. Compared with the full-length protein, this short peptide has a smaller molecular weight, is easier to process and synthesize, has weaker immunogenicity, relatively milder side effects, and exhibits superior anti-inflammatory activity. Furthermore, the cell-penetrating peptide allows for better absorption and the peptide tag facilitates tracking and observation, providing a reference for the clinical treatment of inflammatory diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] The accompanying drawings, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0040] Figure 1 This is a photo of the results of Tat USP27X analysis by liquid chromatography tandem mass spectrometry;

[0041] Figure 2 This is a photo of the results of secondary mass spectrometry analysis of Tat USP27X;

[0042] Figure 3 This is a photograph of the SDS-PAGE electrophoresis results showing that Tat USP27X inhibits the binding of cGAS to USP27X;

[0043] Figure 4 The SDS-PAGE electrophoresis results show that Tat USP27X promotes the ubiquitination of cGAS and reduces its stability.

[0044] Among them: 4A is the SDS-PAGE electrophoresis result of Tat USP27X promoting cGAS ubiquitination in mouse endothelial cells; 4B is the SDS-PAGE electrophoresis result of Tat USP27X reducing cGAS protein level;

[0045] Figure 5 The effect of Tat USP27X on the activation of the innate immune DNA signaling pathway;

[0046] in, Figure 5A is the immunofluorescence detection result of IRF3 nuclear entry;

[0047] Figure 5 B is the Western blot result showing that Tat USP27X inhibits the activation of TBK1 and IRF3;

[0048] Figure 6 The effect of Tat USP27X on the expression of cytokines in the innate immune DNA signaling pathway;

[0049] in, Figure 6 A shows the result of Tat USP27X inhibiting IFN-β mRNA expression;

[0050] Figure 6 B shows the results of Tat USP27X inhibiting IFN-β expression;

[0051] Figure 6 C shows the result of peptide Tat USP27X inhibiting IRF7 expression;

[0052] Figure 6 D shows the result of peptide Tat USP27X inhibiting CXCL10 expression;

[0053] Figure 7 Ultrasound images and bar graphs show that Tat USP27X improves myocardial function in mice;

[0054] in, Figure 7 A is the myocardial ultrasound images of mice in the control and experimental groups;

[0055] Figure 7 B is the left ventricular end-diastolic volume, left ventricular end-systolic volume and ventricular ejection fraction EF calculated using these two data; left ventricular end-diastolic diameter, left ventricular end-systolic diameter and fractional shortening FS calculated using these two data of mice in the control group and experimental group;

[0056] Figure 8 This figure shows the result that Tat USP27X significantly reduced the infarct area of ​​acute myocardial infarction in mice;

[0057] in, Figure 8 A is a partial photo of myocardial infarction in TAT-con mice in the control group. Figure 8 B is a partial photograph of myocardial infarction in Tat USP27X mice in the experimental group. DETAILED DESCRIPTION

[0058] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs.

[0059] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is intended to include the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, they indicate the presence of features, steps, operations, devices, components and / or combinations thereof.

[0060] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0061] Example 1

[0062] 1. Synthesis, Purity, and Chemical Structure Elucidation of Tat USP27X

[0063] Tat USP27X was synthesized directly by GL Company through chemical synthesis. The sequence is as follows:

[0064] Biotin-YGRKKRRQRRRVWIHARHLAGYRQQ.

[0065] Liquid chromatography-tandem mass spectrometry analysis revealed that the peptide had a purity of 97.85% ( Figure 1 , Table 1), mass spectrometry analysis revealed that the molecular weight of this polypeptide was 3503.15 Da ( Figure 2 ):

[0066] Table 1

[0067]

[0068] 2. Functional characterization of Tat USP27X in cultured human aortic endothelial cells

[0069] 1. Experimental subjects:

[0070] Human aortic endothelial cells were cultured in vitro for subsequent experiments;

[0071] 2. Experimental groups:

[0072] A hypoxia-reoxygenation model was established using aortic endothelial cell culture medium (ECM basal medium plus ECGS (purchased from SclenCell)). The hypoxia treatment time was 24 hours and the reoxygenation treatment time was 8 hours. Protein was collected and subsequently analyzed. The experiment was divided into two groups: control group and experimental group.

[0073] The sequence of the experimental group is as follows: Biotin-YGRKKRRQRRRVWIHARHLAGYRQQ, named Tat-USP27X.

[0074] Control group: The polypeptide sequence of the control group used in subsequent signaling pathway and animal experiments is the same as that of the experimental group, but the sequence is arranged in a random order.

[0075] 3. Research methods and experimental procedures

[0076] 1) Regarding the inhibition of intracellular cGAS and USP27X binding by peptides: First, human Flag-cGAS and Myc-USP27X expression plasmids were transfected into 293T cells using liposome transfection to allow intracellular protein expression. The peptides were then added 48 hours later, and the cells were lysed 1 hour later. The cell lysate was then centrifuged at 12,000 g for 15 minutes, and the supernatant was collected. 400 μL of the supernatant was added with 2 μL of anti-Flag antibody and mixed at 4°C for two hours. Protein A beads (purchased from Sigma) were then added for immunoprecipitation. The next day, the immunoprecipitated complexes were separated by molecular weight using 10% SDS-PAGE to test whether the peptides could affect the binding of USP27X and cGAS proteins.

[0077] 2) Regarding the effect of peptides on intracellular cGAS protein: Endothelial cells cultured in vitro were subjected to a hypoxia-reoxygenation model. The hypoxia treatment time was 24 hours, followed by an 8-hour reoxygenation treatment time. The drug peptide was then added for 1 hour, and the protein was harvested for subsequent experimental analysis.

[0078] 3) Regarding the effect of peptides on the activation of intracellular DNA signaling pathways: Cells cultured in vitro were stimulated with the DNA pathway activator ISD at different time points, followed by the addition of drug peptides for 1 hour. Proteins were collected for subsequent experimental analysis, or the cells were fixed for immunohistochemical analysis.

[0079] 4. Experimental results:

[0080] 1) Effect of Tat USP27X on the binding of cGAS and USP27X: Figure 3 As shown, the immunoblotting experiment showed that in the control group, the control peptide could not prevent the binding of cGAS to USP27X, while the peptide Tat USP27X designed by the present invention prevented the binding of cGAS to USP27X, confirming the effect of the peptide;

[0081] 2) Effects of Tat USP27X on cGAS protein: Figure 4As shown, the immunoblotting experiment showed that in the control group, the control peptide could not reduce the cGAS protein level, while the peptide Tat USP27X designed by the present invention reduced the cGAS protein level, confirming that the peptide can reduce the stability of cGAS by inhibiting the binding of USP27X to cGAS;

[0082] 3) Effects of Tat USP27X on activation of innate immune DNA signaling pathways: Figure 5 As shown in A, immunofluorescence results revealed that Tat USP27X inhibited IRF3 nuclear translocation. Figure 5 B Western blot results showed that Tat USP27X inhibited the activation of HEACTBK1 and IRF3 signals.

[0083] 4) Effects of Tat USP27X on the expression of cytokines in the innate immune DNA signaling pathway: Figure 6 As shown, the results of Realtime PCR and luciferase reporter gene analysis showed that compared with the control group, the polypeptide TatUSP27X designed by the present invention inhibited the expression of genes such as IFN-β, IRF7 and CXCL10, and inhibited the activity of the IFN-β promoter.

[0084] 3. Identification of the protective effect of Tat USP27X on mouse heart in an acute myocardial infarction model.

[0085] Mouse MI model: 8-week-old mice were used for modeling after one week of acclimatization in SPF-grade housing. Cardiac function was assessed by ultrasound on the third day. Myocardial infarction size was assessed by TTC staining on the fourth day.

[0086] Experimental results:

[0087] Effects of Tat USP27X on cardiac function in mice: Figure 7 As shown, compared with the control group, the polypeptide Tat USP27X designed by the present invention has a better protective effect on the cardiac function of mice. Figure 8 These results suggest that the peptide Tat USP27X significantly reduces the myocardial infarction area in mice after acute myocardial infarction.

[0088] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A fusion polypeptide, characterized in that: The fusion polypeptide includes a short peptide targeting cGAS, the amino acid sequence of which is shown in SEQ ID NO: 1, and also includes an effector binding fragment; The effector binding fragment is the cell-penetrating peptide TAT; the N-terminus of the short peptide targeting cGAS is connected to the cell-penetrating peptide TAT, and the sequence of the fusion polypeptide is shown in SEQ ID NO:

2.

2. A nucleic acid encoding the fusion polypeptide according to claim 1; characterized in that: The nucleic acid material includes a nucleic acid encoding a short peptide or fusion polypeptide targeting cGAS that can be translated due to codon degeneracy, including DNA or RNA forms; wherein the DNA form includes cDNA, genomic DNA or artificially synthesized DNA, which is single-stranded or double-stranded, and is a coding strand or a non-coding strand.

3. An expression vector comprising the nucleic acid substance according to claim 2, characterized in that: The expression vector is specifically a bacterial plasmid, a bacteriophage, a yeast plasmid, a plant cell virus or a mammalian cell virus, and the mammalian cell virus is an adenovirus or a retrovirus.

4. A host cell, characterized in that The host cell comprises the fusion polypeptide according to claim 1, the nucleic acid substance according to claim 2 and / or the expression vector according to claim 3.

5. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the fusion polypeptide according to claim 1.

6. The pharmaceutical composition according to claim 5, wherein The pharmaceutical composition also includes the aforementioned necessary carriers for pharmacy, and the types of the carriers include buffers, antioxidants, preservatives, and bactericides.

7. Use of the fusion polypeptide according to claim 1 or the pharmaceutical composition according to claim 5 or 6 in the preparation of drugs for treating acute myocardial infarction, reperfusion injury and heart failure induced by acute myocardial infarction.

8. The use of the fusion polypeptide or pharmaceutical composition according to claim 7, wherein: The dosage form of the drug is a solution preparation, a semi-solid preparation or a solid preparation.

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