HDAC11 binding polypeptide and application thereof

Abstract

The invention relates to an HDAC11 binding polypeptide and application thereof. The amino acid sequence of the HDAC11 binding polypeptide comprises an amino acid sequence as shown in any one of SEQ ID NO. 1 to SEQ ID NO. 20, and an amino acid sequence as shown in any one of SEQ ID NO. Or the amino acid sequence is obtained by substitution, insertion and / or deletion of at least one or more amino acids compared with the amino acid sequence as shown in any one of SEQ ID NO.1-SEQ ID NO.20. A targeted binding peptide is developed aiming at an HDAC11 extracellular region, and the obtained HDAC11 binding polypeptide has high affinity with HDAC11, can recognize and bind HDAC11, can be used as a drug for treating individual tumors or cancers, provides a new strategy for treating HDAC11 related diseases, and opens up a new way for treating cancers and other related diseases.

Description

Technical Field

[0001] The present invention relates to the field of biotechnology, and in particular to HDAC11 binding polypeptides and applications thereof. Background Art

[0002] HDAC11 is the smallest member of the HDAC family, consisting of 347 amino acids, and contains a catalytic core structure similar to other HDAC members, but also has unique features. Its N-terminal and C-terminal extensions are short and do not contain predicted protein binding sites. The catalytic channel of HDAC11 is unique in the HDAC family, being funnel-shaped and further extended, making it particularly significant in terms of fatty acid deacylase activity, making it one of the strongest fatty acid deacylases in the HDAC family.

[0003] HDAC11 is mainly localized in the nucleus and cytoplasm, and regulates gene expression and cell function by removing acetyl groups from histones and other proteins. HDAC11 can also interact with histones, transcription factors, and non-coding RNA to further regulate gene expression. For example, in colorectal cancer (CRC), HDAC11 reduces the invasion and migration ability of CRC cells by inhibiting the acetylation level of H3K9. In multiple myeloma (MM), HDAC11 inhibits the acetylation of IRF4, regulates the expression of its target genes, hinders the differentiation of B cells into plasma cells, and causes MM cell death. In esophageal squamous cell carcinoma (ESCC), HDAC11 plays a key role in the progression of ESCC as a target of C9orf139 / miR-661. These studies reveal the importance of HDAC11 in tumorigenesis and development, as well as its association with multiple signaling pathways and biological processes.

[0004] The role of HDAC11 in cancer varies depending on the cancer type. Although HDAC11 is highly expressed in cancers such as non-small cell lung cancer (NSCLC) and endocrine tumors (ET) and promotes cancer progression, in some cancers (such as colorectal cancer), HDAC11 expression is low and plays an inhibitory role. This suggests that the function of HDAC11 in cancer may depend on the specific cancer type. Currently, research on the regulatory network of HDAC11 in cancer is relatively limited, mainly focusing on the upstream regulation of HDAC11 by non-coding RNA and the downstream regulation of HDAC11 on its substrates.

[0005] Although the mechanism of action of HDAC11 in tumors is not yet fully understood, increasing evidence suggests that it is closely related to the occurrence and development of certain cancers. HDAC11 may promote tumor progression by regulating biological characteristics such as cell invasion, migration, stemness, apoptosis, and immune escape. For example, some studies have found that HDAC11 inhibits the invasion and metastasis of cancer cells by inhibiting the expression of Twist / HAS2. In addition, HDAC11 also affects the proliferation, invasion, migration, and stemness of cancer cells by regulating signaling pathways such as AMPK and JAK / STAT. HDAC11 not only regulates the biological behavior of tumor cells, but also participates in the resistance mechanism of tumors to chemotherapeutic drugs, targeted drugs, and radiotherapy, which makes HDAC11 a potential therapeutic target for the development of new cancer therapies.

[0006] Although there are currently no clinically approved specific HDAC11 inhibitors, many natural and synthetic HDAC11 inhibitors have shown promising therapeutic effects in preclinical studies. For example, the specific HDAC11 inhibitors MIR002 and GEM144 induce cell cycle arrest and apoptosis in human lung cancer and hematological cancer cell lines by inhibiting the transcriptional activity of HDAC11. It is particularly noteworthy that targeting HDAC11 only induces tumor cell apoptosis in colorectal cancer, breast cancer, and ovarian cancer without affecting the metabolic activity and survival of normal cells, indicating that HDAC11 has potential as a target for tumor therapy.

[0007] The current HDAC11 binding peptides have low affinity for HDAC11, making them difficult to use as therapeutic drugs for diseases such as cancer. Summary of the invention

[0008] Based on this, it is necessary to provide an HDAC11 binding polypeptide and its application. The HDAC11 binding polypeptide has a high affinity with HDAC11 and can specifically bind to HDAC11.

[0009] An HDAC11 binding polypeptide, the amino acid sequence of the HDAC11 binding polypeptide comprising:

[0010] The amino acid sequence shown in any one of SEQ ID NO.1 to SEQ ID NO.20; or

[0011] An amino acid sequence obtained by substitution, insertion and / or deletion of at least one or several amino acids compared to the amino acid sequence shown in any one of SEQ ID NO.1 to SEQ ID NO.20.

[0012] The present application develops a targeted binding peptide for the extracellular region of HDAC11. The obtained HDAC11 binding polypeptide has a high affinity with HDAC11, can recognize and bind to HDAC11, and can be used as a drug for treating individual tumors or cancers, providing a new strategy for treating HDAC11-related diseases and opening up new avenues for the treatment of cancer and other related diseases. It has been verified by experiments that the binding force of the HDAC11 binding polypeptide with an amino acid sequence such as SEQ ID NO.1 to SEQ ID NO.20 with HDAC11 is 4.97E-07 (M) to 5.07E-05 (M), that is, the HDAC11 binding polypeptide has a high affinity with HDAC11.

[0013] A polynucleotide comprises a coding sequence of the HDAC11 binding polypeptide.

[0014] A recombinant vector carries the above-mentioned polynucleotide.

[0015] A recombinant cell, comprising the recombinant vector.

[0016] A polypeptide-carrier protein conjugate, comprising a coupled carrier protein and the above-mentioned HDAC11 binding polypeptide.

[0017] In some embodiments, the carrier protein is selected from at least one of bovine serum albumin, ovalbumin, keyhole limpet hemocyanin and casein;

[0018] And / or, the HDAC11 binding polypeptide is coupled to the carrier protein via a linker sequence; optionally, the amino acid sequence of the linker sequence is shown in SEQ ID NO.21;

[0019] And / or, each of the carrier proteins is coupled to 2 to 50 of the HDAC11 binding polypeptides; further, each of the carrier proteins is coupled to 5 to 50 of the HDAC11 binding polypeptides.

[0020] A polypeptide composition comprises: a polypeptide with an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.20, and at least two polypeptides obtained by replacing, inserting and / or deleting at least one or several amino acids compared with the polypeptide with an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.20.

[0021] A drug comprises at least one of the HDAC11 binding polypeptide, the polynucleotide, the recombinant vector, the recombinant cell, the polypeptide-carrier protein conjugate, and the polypeptide composition.

[0022] In some embodiments, an adjuvant and / or a pharmaceutically acceptable carrier is further included; optionally, the adjuvant includes at least one of aluminum phosphate, aluminum hydroxide and alum; the pharmaceutically acceptable carrier is selected from at least one of a sustained-release agent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption promoter, an adsorption carrier, a surfactant and a lubricant;

[0023] And / or, further comprising a polypeptide stabilizer; optionally, the polypeptide stabilizer comprises PLGA nanoparticle material, or the polypeptide stabilizer comprises 150mM to 180mM NaCl, 100mM to 140mM polylysine hydrochloride;

[0024] And / or, the drug comprises the HDAC11 binding polypeptide, and the effective dose of the HDAC11 binding polypeptide is 0.1 μM to 0.1 M or 0.001 mg to 1000 mg.

[0025] Use of at least one of the HDAC11 binding polypeptide, the polynucleotide, the recombinant vector, the recombinant cell, the polypeptide-carrier protein conjugate, and the polypeptide composition in the preparation of anti-tumor drugs, anti-cancer drugs, drugs for treating malignant vascular hyperplasia diseases, and / or health products. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1-Figure 6 This is a diagram showing the data distribution of the peptide chip and the correlation results between samples in Example 1;

[0027] Figure 7-Figure 8 This is a fitting result diagram of the deep learning model in Example 1;

[0028] Figure 9-Figure 28 The mass spectrometry result diagram of 20 polypeptides with amino acid sequences as shown in SEQ ID NO.1 to SEQ ID NO.20 in Example 3;

[0029] Figure 29-Figure 48 This is a graph showing the results of an SPR experiment of 20 polypeptides with amino acid sequences as shown in SEQ ID NO.1 to SEQ ID NO.20 in Example 4 and the HDAC11 target. DETAILED DESCRIPTION

[0030] Below in conjunction with embodiment and example, the application is further described in detail.It should be understood that these embodiments and examples are only used to illustrate the application and are not used to limit the scope of the application, and the purpose of providing these embodiments and examples is to make the understanding of the disclosure of the application more thorough and comprehensive.It should also be understood that the application can be implemented in many different forms, is not limited to the embodiment and example described in the application, and those skilled in the art can make various changes or modifications without violating the connotation of the application, and the equivalent form obtained also falls within the protection scope of the application.In addition, in the description below, a large number of specific details are given in order to provide a more comprehensive understanding of the application, and it should be understood that the application can be implemented without one or more of these details.

[0031] Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used in this application and in the specification of this application are only for the purpose of describing the implementation methods and embodiments and are not intended to limit this application.

[0032] Unless otherwise specified or there is a contradiction, the terms and phrases used in this application have the following meanings:

[0033] The terms "and / or", "or / and", and "and / or" used in this application include any one of two or more related listed items, and also include any and all combinations of related listed items, and the arbitrary and all combinations include any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that in this application, the technical solution undoubtedly includes technical solutions that are all connected by "logical and", and undoubtedly includes technical solutions that are all connected by "logical or". For example, "A and / or B" includes three parallel solutions of A, B and A+B. For example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, the technical solution that is all connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, the combination of any two or any three of A, B, C, and D, and also includes the combination of four of A, B, C, and D (that is, the technical solution that is all connected by "logical AND").

[0034] In the present application, "plurality", "multiple", "multiple times", "multiples", etc., unless otherwise specified, refer to a number greater than 2 or equal to 2. For example, "one or more" means one or greater than or equal to two.

[0035] The terms "combination thereof", "any combination thereof", "any combination thereof" and the like used in this application include all suitable combinations of any two or more of the listed items.

[0036] In this application, the "suitable" mentioned in "suitable combination", "suitable method", "any suitable method", etc. is based on the ability to implement the technical solution of this application, solve the technical problems of this application, and achieve the expected technical effects of this application.

[0037] In the present application, "preferred", "better", "more preferred" and "suitable" are only used to describe implementation methods or examples with better effects. It should be understood that they do not constitute limitations on the scope of protection of the present application.

[0038] In the present application, "further", "further", "particularly" and the like are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of the present application.

[0039] In this application, "optionally", "optional", and "optional" mean optional or dispensable, that is, any one of the two parallel schemes of "yes" or "no". If multiple "options" appear in a technical solution, unless otherwise specified and there is no contradiction or mutual restriction, each "optional" is independent.

[0040] In the present application, the terms "first", "second", "third", "fourth", etc. in "the first aspect", "the second aspect", "the third aspect", "the fourth aspect", etc. are used only for descriptive purposes and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first", "second", "third", "fourth", etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity.

[0041] In the present application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0042] In the present application, when it comes to numerical intervals (i.e., numerical ranges), unless otherwise specified, the optional numerical distribution is considered continuous within the above numerical interval, and includes the two numerical endpoints (i.e., the minimum value and the maximum value) of the numerical range, and each numerical value between the two numerical endpoints. Unless otherwise specified, when the numerical interval only refers to the integers within the numerical interval, it includes the two endpoint integers of the numerical range, and each integer between the two endpoints. In the present application, it is equivalent to directly listing each integer, such as t is an integer selected from 1 to 10, indicating that t is any integer selected from the group of integers consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, the ranges disclosed in the present application should be understood to include any and all sub-ranges included therein.

[0043] The temperature parameters in this application, unless otherwise specified, are allowed to be either constant temperature treatment or to vary within a certain temperature range. It should be understood that the constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuations within the range of ±5°C, ±4°C, ±3°C, ±2°C, and ±1°C are allowed.

[0044] In the present application, % (w / w) and wt% both represent weight percentage, % (v / v) refers to volume percentage, and % (w / v) refers to mass volume percentage.

[0045] In the present application, "polypeptide", unless otherwise specified, refers to a linear polymer composed of three or more amino acids connected by peptide bonds.

[0046] In the present application, "polynucleotide", unless otherwise specified, refers to a linear polymer of more than 10 nucleotides linked by 3',5'-phosphodiester bonds.

[0047] In the present application, "gene", unless otherwise specified, refers to a genetic unit occupying a specific locus on a chromosome.

[0048] In the present application, "fragment", unless otherwise specified, refers to a polypeptide that lacks one or more (several) amino acids from the amino and / or carboxyl termini of the polypeptide.

[0049] In this application, unless otherwise specified, "variant" means a polypeptide having the activity of a parent or wild-type polypeptide, comprising an amino acid change at one or more (several) positions, i.e., substitution, insertion and / or deletion of one or more (several) amino acid residues. "Substitution" means replacing an amino acid occupying a certain position with a different amino acid; "deletion" means removing an amino acid occupying a certain position; and "insertion" means adding one or more amino acids adjacent to an amino acid occupying a certain position.

[0050] In the present application, unless otherwise specified, "polypeptide-carrier protein conjugate" refers to a conjugate formed by coupling a polypeptide to a carrier protein, wherein one carrier protein can be coupled to one or more polypeptides, and when multiple polypeptides are coupled, the multiple polypeptides have the same amino acid sequence. According to the differences in the physicochemical properties of the specific coupled polypeptide sequences, the different types of specific carrier proteins, and the different coupling methods, the number of polypeptides coupled to each carrier protein varies. In the present application, 2 to 50 are preferred, and 3 to 45, 5 to 40, 5 to 35, 5 to 30, 8 to 30, 10 to 30, 12 to 30, and 15 to 30 are more preferred; or, more preferably, any one of 6 to 36, 8 to 32, 10 to 28, 10 to 26, 10 to 24, 10 to 22, 10 to 20, 10 to 18, 10 to 16, and 10 to 15 are preferred.

[0051] In this application, AE-0b means A×10 -b , for example, 3E-07 means 3×10 -7 ; The unit M represents molar, that is, "molar"; the unit μM represents micromole; the unit mM represents millimole.

[0052] All documents mentioned in this application are cited as references in this application, just as each document is cited as reference separately. Unless they conflict with the application purpose and / or technical solution of this application, the cited documents involved in this application are cited with all contents and all purposes. When the cited documents are involved in this application, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited. When the cited documents are involved in this application, the examples and preferred methods of the cited relevant technical features can also be incorporated into this application as references, but are limited to the implementation of this application. It should be understood that when the cited content conflicts with the description in this application, the present application shall prevail or be modified adaptively according to the description of this application.

[0053] In a first aspect of an embodiment of the present application, there is provided an HDAC11 binding polypeptide, wherein the amino acid sequence of the HDAC11 binding polypeptide comprises:

[0054] The amino acid sequence shown in any one of SEQ ID NO.1 to SEQ ID NO.20; or

[0055] An amino acid sequence obtained by substitution, insertion and / or deletion of at least one or several amino acids compared to the amino acid sequence shown in any one of SEQ ID NO.1 to SEQ ID NO.20.

[0056] The present application develops a targeted binding peptide for the extracellular region of HDAC11. The obtained HDAC11 binding polypeptide has a high affinity with HDAC11, can recognize and bind to HDAC11, and can be used as a drug for treating individual tumors or cancers, providing a new strategy for treating HDAC11-related diseases and opening up new avenues for the treatment of cancer and other related diseases. It has been verified by experiments that the binding force of the HDAC11 binding polypeptide with an amino acid sequence such as SEQ ID NO.1 to SEQ ID NO.20 with HDAC11 is 4.97E-07 (M) to 5.07E-05 (M), that is, the HDAC11 binding polypeptide has a high affinity with HDAC11.

[0057] In some embodiments, "several" means no more than 5, preferably no more than 3, and most preferably no more than 2. For example, the polypeptide variant may have 5, 4, 3, 2 or 1 amino acid residue substitutions, insertions and / or deletions compared to the polypeptide having an amino acid sequence as shown in any one of SEQ ID NO.1 to SEQ ID NO.20.

[0058] Alternatively, the amino acid change is a conservative substitution. Conservative substitution is to replace in the following amino acid range: basic amino acid group (arginine, lysine and histidine), acidic amino acid group glutamic acid and aspartic acid, polar amino acid group (glutamine and asparagine), hydrophobic amino acid group (leucine, isoleucine and valine), aromatic amino acid group (phenylalanine, tryptophan and tyrosine) and small amino acid group (glycine, alanine, serine, threonine and methionine).

[0059] In addition to the 20 standard amino acids, non-standard amino acids (e.g., 4-hydroxyproline, 6-N-methyllysine, 2-aminoisobutyric acid, isovaline, and α-methylserine) can also be used to replace amino acid residues in polypeptides. A limited number of non-conservative amino acids, amino acids not encoded by the genetic code, and non-natural amino acids can replace amino acid residues. Non-natural amino acids can be synthesized by chemical methods or can be commercially available, including, but not limited to, hexahydropyridine carboxylic acid, thiazolidine carboxylic acid, dehydroproline, 3- and 4-methylproline, and 3,3-dimethylproline.

[0060] In addition, essential amino acids in the parent polypeptide can be identified according to methods known in the art, such as site-directed mutagenesis or alanine scanning mutagenesis (Cunningham and Wells, 1989, Science 244: 1081-1085). In the latter technique, single alanine mutations are introduced into each residue in the molecule, and the biological activity of the resulting mutant molecules is tested to identify amino acid residues that are critical to the activity of the molecule. See Hilton et al., 1996, J. Biol. Chem. 271: 4699-4708.

[0061] The polypeptides of the present application can be prepared using known techniques. For example, the polypeptides can be prepared using recombinant DNA technology or by chemical synthesis. The polypeptides of the present application can also be expressed by viral vectors or bacterial vectors. Examples of suitable expression vectors include, but are not limited to: viral vectors, such as lentivirus, vaccinia virus, fowlpox virus, adenovirus and adeno-associated virus vectors, retroviral vectors; BCG (Bacille Calmette Guerin) vectors; bacterial vectors, such as Salmonella typhi vectors. Alternatively, the viral vector is a vector without replication ability and pathogenicity. In a specific embodiment, the viral vector is a lentiviral vector.

[0062] The polypeptide of the present application is optionally an isolated polypeptide. The term "isolated polypeptide" as used in the present application refers to a polypeptide isolated from its source. For example, the polypeptide is at least 60% pure, preferably at least 80% pure, more preferably at least 90% pure and most preferably at least 95% pure, as determined by SDS-PAGE and HPLC. Alternatively, an "isolated polypeptide" is a substantially pure polypeptide. A "substantially pure polypeptide" refers to a polypeptide preparation in the present application, which contains by weight up to 10%, preferably up to 8%, more preferably up to 6%, more preferably up to 5%, more preferably up to 4%, more preferably up to 3%, even more preferably up to 2%, most preferably up to 1%, and even most preferably up to 0.5% other polypeptide substances naturally or recombinantly combined with it.

[0063] In some embodiments, in order to better achieve directional coupling of the polypeptide, the polypeptide can be a cysteine-modified peptide. Optionally, the cysteine ​​modification is to add cysteine ​​at any of the following positions of the polypeptide: N-terminus, C-terminus, both ends of NC or in the middle of the peptide chain; more optionally, adding cysteine ​​in the middle of the peptide chain includes inserting one or more cysteines in the middle of the peptide chain, or one or more cysteines are connected to the middle of the peptide chain in the form of a branched chain.

[0064] The second aspect of the embodiment of the present application provides a polynucleotide, comprising the coding sequence of the HDAC11 binding polypeptide. It should be noted that the polynucleotide can be designed and prepared according to the polypeptide sequence according to methods known to those skilled in the art.

[0065] According to a third aspect of the embodiments of the present application, a recombinant vector is provided, which carries the above-mentioned polynucleotide.

[0066] The recombinant vector can be used to clone or express the HDAC11 binding polypeptide, so that it can be applied to industrial large-scale preparation of HDAC11 binding polypeptide.

[0067] In some embodiments, the recombinant vector is an expression vector or a cloning vector carrying the polynucleotide, and further comprises one or more regulatory sequences operably linked to the polynucleotide and directing the expression of the HDAC11 binding polypeptide in a host cell.

[0068] In some embodiments, the recombinant vector is, for example, a cloning vector or expression vector of a virus, bacteria, eukaryote or BCG (bacillus Calmette-Guerin). Viruses include, but are not limited to, lentivirus, vaccinia virus, fowlpox virus, adenovirus and adeno-associated virus vectors, and retroviruses. Preferably, it is a lentivirus. More preferably, it is an attenuated or detoxified virus. Bacteria include, but are not limited to, Salmonella typhi, Bacillus subtilis, Escherichia coli, etc. Eukaryotes include, but are not limited to, yeast, such as, for example, Saccharomyces cerevisiae.

[0069] A fourth aspect of the embodiments of the present application provides a recombinant cell, which contains the above-mentioned recombinant vector.

[0070] The recombinant embryos can be transformed or transfected into host cells to obtain recombinant cells capable of expressing the HDAC11 binding polypeptide. The HDAC11 binding polypeptide can be obtained by culturing the recombinant cells, which is convenient for industrial and large-scale preparation of HDAC11 binding polypeptides.

[0071] In some embodiments, the host cell is, for example, a virus, a bacterium, a eukaryote or BCG (bacillus Calmette-Guerin). Viruses include, but are not limited to, lentivirus, vaccinia virus, fowl pox virus, adenovirus and adeno-associated virus vectors, and retroviruses. Bacteria include, but are not limited to, Salmonella typhi, Bacillus subtilis, Escherichia coli, and the like. Eukaryotes include, but are not limited to, yeast, such as, for example, Saccharomyces cerevisiae.

[0072] According to a fifth aspect of the embodiments of the present application, a polypeptide-carrier protein conjugate is provided, wherein the polypeptide-carrier protein conjugate comprises a coupled carrier protein and the above-mentioned HDAC11 binding polypeptide.

[0073] By coupling the HDAC11 binding polypeptide to a carrier protein, the transmembrane transport of the HDAC11 binding polypeptide can be achieved.

[0074] In some embodiments, the carrier protein is selected from at least one of bovine serum albumin, ovalbumin, keyhole limpet hemocyanin and casein. It should be noted that the carrier protein is not limited to the above-mentioned proteins, and may also be other carrier proteins, which can be selected according to needs.

[0075] In some embodiments, the HDAC11 binding polypeptide is coupled to the carrier protein via a connecting sequence. According to the amino acid sequence composition of different polypeptides, in order to facilitate coupling with the carrier protein, it is necessary to couple the carrier protein via a connecting sequence (also called a linker). Optionally, the amino acid sequence of the connecting sequence is shown in SEQ ID NO.21. Specifically, the sequence shown in SEQ ID NO.21 is CGSG.

[0076] Depending on the physicochemical properties of the polypeptide amino acids, the different carrier proteins used, and the different coupling methods, the number of polypeptides that can be coupled to each carrier protein is also different. In some embodiments, each carrier protein is coupled to 2 to 50 HDAC11 binding polypeptides. Alternatively, each carrier protein is coupled to 5 to 50 polypeptides. Further optionally, each carrier protein is coupled to 5 to 30 polypeptides. In some embodiments, the number of HDAC11 binding polypeptides coupled to each carrier protein is 3 to 45, 5 to 40, 5 to 35, 5 to 30, 8 to 30, 10 to 30, 12 to 30, or 15 to 30. In other embodiments, the number of HDAC11 binding polypeptides coupled to each carrier protein is 6 to 36, 8 to 32, 10 to 28, 10 to 26, 10 to 24, 10 to 22, 10 to 20, 10 to 18, 10 to 16, or 10 to 15.

[0077] The sixth aspect of the embodiments of the present application provides a polypeptide composition, comprising: a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.20, and at least two polypeptides obtained by replacing, inserting and / or deleting at least one or several amino acids compared to the polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.20.

[0078] In some embodiments, the polypeptide composition comprises at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 or a variant thereof, and a polypeptide having an amino acid sequence as shown in SEQ ID NO.2 to SEQ ID NO.20 or a variant thereof.

[0079] In some embodiments, the polypeptide composition comprises at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.2 or a variant thereof, and a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 or SEQ ID NO.3 to SEQ ID NO.20 or a variant thereof.

[0080] In some embodiments, the polypeptide composition comprises a polypeptide having an amino acid sequence as shown in SEQ ID NO.3 or a variant thereof, and at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.1, SEQ ID NO.2 or SEQ ID NO.4 to SEQ ID NO.20 or a variant thereof.

[0081] In some embodiments, the polypeptide composition comprises at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.4 or a variant thereof, and a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.3 or SEQ ID NO.5 to SEQ ID NO.20 or a variant thereof.

[0082] In some embodiments, the polypeptide composition comprises at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.5 or a variant thereof, and a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.4 or SEQ ID NO.6 to SEQ ID NO.20 or a variant thereof.

[0083] In some embodiments, the polypeptide composition comprises at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.6 or a variant thereof, and a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.5 or SEQ ID NO.7 to SEQ ID NO.20 or a variant thereof.

[0084] In some embodiments, the polypeptide composition comprises at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.7 or a variant thereof, and a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.6 or SEQ ID NO.8 to SEQ ID NO.20 or a variant thereof.

[0085] In some embodiments, the polypeptide composition comprises at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.8 or a variant thereof, and a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.7 or SEQ ID NO.9 to SEQ ID NO.20 or a variant thereof.

[0086] In some embodiments, the polypeptide composition comprises at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.9 or a variant thereof, and a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.8 or SEQ ID NO.10 to SEQ ID NO.20 or a variant thereof.

[0087] In some embodiments, the polypeptide composition comprises at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.10 or a variant thereof, and a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.9 or SEQ ID NO.11 to SEQ ID NO.20 or a variant thereof.

[0088] In some embodiments, the polypeptide composition comprises at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.11 or a variant thereof, and a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.10 or SEQ ID NO.12 to SEQ ID NO.20 or a variant thereof.

[0089] In some embodiments, the polypeptide composition comprises at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.12 or a variant thereof, and a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.11 or SEQ ID NO.13 to SEQ ID NO.20 or a variant thereof.

[0090] In some embodiments, the polypeptide composition comprises at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.13 or a variant thereof, and a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.12 or SEQ ID NO.14 to SEQ ID NO.20 or a variant thereof.

[0091] In some embodiments, the polypeptide composition comprises at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.14 or a variant thereof, and a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.13 or SEQ ID NO.15 to SEQ ID NO.20 or a variant thereof.

[0092] In some embodiments, the polypeptide composition comprises at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.15 or a variant thereof, and a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.14 or SEQ ID NO.16 to SEQ ID NO.20 or a variant thereof.

[0093] In some embodiments, the polypeptide composition comprises at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.16 or a variant thereof, and a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.15 or SEQ ID NO.17 to SEQ ID NO.20 or a variant thereof.

[0094] In some embodiments, the polypeptide composition comprises at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.17 or a variant thereof, and a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.16 or SEQ ID NO.18 to SEQ ID NO.20 or a variant thereof.

[0095] In some embodiments, the polypeptide composition comprises at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.18 or a variant thereof, and a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.17 or SEQ ID NO.19 to SEQ ID NO.20 or a variant thereof.

[0096] In some embodiments, the polypeptide composition comprises at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.19 or a variant thereof, and a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.18 or SEQ ID NO.20 or a variant thereof.

[0097] In some embodiments, the polypeptide composition comprises a polypeptide having an amino acid sequence as shown in SEQ ID NO.20 or a variant thereof, and at least one of a polypeptide having an amino acid sequence as shown in SEQ ID NO.1 to SEQ ID NO.20 or a variant thereof.

[0098] In a seventh aspect of the embodiments of the present application, a drug is provided, comprising at least one of the HDAC11 binding polypeptide of the above embodiment, the polynucleotide of the above embodiment, the recombinant vector of the above embodiment, the recombinant cell of the above embodiment, the polypeptide-carrier protein conjugate of the above embodiment, and the polypeptide composition of the above embodiment.

[0099] In some embodiments, the above-mentioned drug further comprises an adjuvant and / or a pharmaceutically acceptable carrier. Optionally, the adjuvant comprises at least one of aluminum phosphate, aluminum hydroxide and alum. The pharmaceutically acceptable carrier is selected from at least one of a sustained-release agent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption promoter, an adsorption carrier, a surfactant and a lubricant;

[0100] In some embodiments, the above-mentioned drug further comprises a polypeptide stabilizer. The polypeptide stabilizer is used to maintain the storage stability of the polypeptide. It should be noted that the above-mentioned drug may contain a polypeptide stabilizer and an adjuvant and / or a pharmaceutically acceptable carrier at the same time, or may contain any one or any two of the polypeptide stabilizer, adjuvant, and pharmaceutically acceptable carrier.

[0101] In some embodiments, the polypeptide stabilizer includes a nanoparticle material, such as PLGA (poly(lactic-co-glycolic acid)) nanoparticle material. By using the nanoparticle material, the controlled release of the drug can be achieved by controlling the degradation rate of the polymer.

[0102] In another embodiment, the polypeptide stabilizer includes 150mM to 180mM NaCl and 100mM to 140mM polylysine hydrochloride. The polypeptide stabilizer can increase polypeptide stability and prevent polypeptide aggregation. Further, the polypeptide stabilizer also includes a solvent, such as water.

[0103] In one specific example, the polypeptide stabilizer includes 154mM NaCl, 126.4mM polylysine hydrochloride and water. In some examples, the concentration of NaCl in the polypeptide stabilizer can be 150mM, 151mM, 152mM, 153mM, 154mM, 155mM, 156mM, 157mM, 158mM, 159mM, 160mM, 161mM, 162mM, 163mM, 164mM, 165mM, 166mM, 167mM, 168mM, 169mM, 170mM, 171mM, 172mM, 173mM, 174mM, 175mM, 176mM, 177mM, 178mM, 179mM or more. the concentration of polylysine hydrochloride can be 110mM, 111mM, 112mM, 113mM, 114mM, 115mM, 116mM, 117mM, 118mM, 119mM, 120mM, 121mM, 122mM, 123mM, 124mM, 125mM, 126mM, 127mM, 128mM, 129mM, 130mM, 131mM, 132mM, 133mM, 134mM, 135mM, 136mM, 137mM, 138mM, 139mM or 140mM.

[0104] In some embodiments, the drug includes the HDAC11 binding polypeptide, and the effective dose of the HDAC11 binding polypeptide is 0.1 μM to 0.1 M. The HDAC11 binding polypeptide can work in a wider range of concentrations. In some examples, the effective dose of the HDAC11 binding polypeptide is 0.1 μM to 100 μM. In some examples, the effective dose of the HDAC11 binding polypeptide is 0.1 mM to 100 mM. In some examples, the effective dose of the HDAC11 binding polypeptide is 10 μM to 10 mM. In some examples, the effective dose of the HDAC11 binding polypeptide is 10 μM to 1000 μM. In some specific examples, the effective dose of the HDAC11 binding polypeptide is 0.1 μM, 0.2 μM, 0.5 μM, 0.75 μM, 1 μM, 5 μM, 10 μM, 20 μM, 50 μM, 80 μM, 100 μM, 200 μM, 500 μM, 750 μM, 1 mM, 5 mM, 10 mM, 20 mM, 50 mM, 75 mM, 100 mM, etc., or a range consisting of any values ​​therebetween.

[0105] In some embodiments, the drug includes the HDAC11 binding polypeptide, and the effective dose of the HDAC11 binding polypeptide is 0.001 mg to 1000 mg. Alternatively, the effective dose of the HDAC11 binding polypeptide is 0.01 mg to 100 mg. Further optionally, the effective dose of the HDAC11 binding polypeptide is 0.1 mg to 10 mg, for example, 3 mg.

[0106] In some embodiments, in addition to the HDAC11 binding polypeptide of the above embodiment, other active ingredients may be included in the drug, such as anticancer components. Suitable anticancer components include, but are not limited to, at least one of abarelix, aclarubicin, aminopurine, aldesleukin, alemtuzumab, aloxitam, hexamethylmelamine, amifostine, aminoglutethimide, anakinra, anastrozole, azacitidine, bleomycin, bortezomib, busulfan, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dasatinib, decitabine, docetaxel, exemestane, gemtuzumab, rituximab, vincristine, vindesine, vorinoside, and zoledronic acid.

[0107] In some embodiments, the drug of the present application may also be in the form of a polynucleotide, nucleic acid construct, vector, host cell, polypeptide-carrier protein conjugate comprising the above-mentioned embodiments. Those skilled in the art may formulate the drug into a suitable dosage form, such as liposomes, granules, powders, etc. as needed. The composition may be administered systemically or locally to the target tumor by, for example, oral, intradermal, subcutaneous, intravenous injection, etc.

[0108] The drug can be used to treat diseases related to overexpression of HDAC11, such as cancer. The cancer includes but is not limited to cancer, leukemia, lymphoma, hemangioma, bone cancer, cervical cancer, uterine cancer, ovarian cancer, fatty cancer, breast cancer, brain tumor, squamous cell carcinoma, skin cancer, thyroid cancer, lip cancer, melanoma, tongue cancer, thymus cancer, and brain or central nervous system cancer.

[0109] In an eighth aspect, the present application provides the use of at least one of the polypeptides of the above embodiments, the polynucleotides of the above embodiments, the recombinant vectors of the above embodiments, the recombinant cells of the above embodiments, the polypeptide compositions of the above embodiments, the polypeptide-carrier protein conjugates of the above embodiments, and the drugs of the above embodiments in the preparation of anti-tumor drugs, anti-cancer drugs, drugs for treating malignant vascular hyperplasia diseases and / or health products.

[0110] In some embodiments, the tumor or cancer is selected from HDAC11-related tumors or cancers. The polypeptide treats HDAC11-related tumors or cancers by inhibiting the growth or proliferation of HDAC11-related tumor or cancer cells.

[0111] In some embodiments, the tumor or cancer is selected from at least one of lung cancer, nasopharyngeal cancer, laryngeal cancer, gastric cancer, liver cancer, esophageal cancer, intestinal cancer, pancreatic cancer, gallbladder cancer, kidney cancer, bladder cancer, prostate cancer, leukemia, lymphoma, hemangioma, bone cancer, cervical cancer, uterine cancer, ovarian cancer, fatty cancer, breast cancer, brain tumor, squamous cell carcinoma, skin cancer, thyroid cancer, lip cancer, melanoma, tongue cancer, thymus cancer, and brain or central nervous system cancer.

[0112] In some embodiments, the applicable subjects of the anti-tumor drug, anti-cancer drug, anti-angiogenic malignant hyperplasia drug and / or health product include mammals. Optionally, the applicable subjects are humans, non-human primates, mice, rats, dogs, cats, horses or cattle. Among them, humans are, for example, humans suffering from the tumor or cancer.

[0113] Those skilled in the art can formulate the drug into a suitable dosage form as required, such as liposomes, particles, powders, etc. The composition can be systemically administered or locally administered to the target tumor by, for example, oral administration, intradermal, subcutaneous, intravenous injection, etc.

[0114] Those skilled in the art can appropriately adjust the dosage of the polypeptide, polynucleotide, nucleic acid construct, vector, host cell, polypeptide composition, polypeptide-carrier protein conjugate, or drug in the medicine of the present application according to the disease to be prevented or treated, the age, weight, administration method, etc. of the subject, because the selection and optimization of these dosages are within the capabilities of those skilled in the art.

[0115] The embodiments of the present application will be described in detail below in conjunction with examples. It should be understood that these examples are only used to illustrate the present application and are not intended to limit the scope of the present application. The experimental methods for which specific conditions are not specified in the following examples are preferably referred to the guidance provided in the present application, and can also be based on the experimental manual or normal conditions in this area, can also be based on the conditions recommended by the manufacturer, or refer to experimental methods known in the art.

[0116] In the following specific embodiments, the measured parameters of raw material components may have slight deviations within the range of weighing accuracy unless otherwise specified. For temperature and time parameters, acceptable deviations caused by instrument test accuracy or operation accuracy are allowed.

[0117] Example 1: Peptide chip detection and learning model construction

[0118] After protein fluorescence labeling, peptide chip detection is performed to obtain the binding force signal between the peptide and the protein. Based on this binding force data, a deep learning model is constructed to obtain the prediction pattern of the binding force between the peptide and the protein.

[0119] 1) Select candidate HDAC11 protein (Wuhan Huamei Bioengineering Co., Ltd., catalog number: CSB-YP010237HU) and fluorescently label it (kit: ThermoFisher, Alexa Fluor TM 555 Micro Protein Labeling Kit, Catalog No.: A30007).

[0120] 2) The fluorescently labeled HDAC11 protein was detected by high-throughput short peptide array chip (Zhuhai Carbon Cloud Intelligent Technology Co., Ltd., V16 chip) at four concentrations:

[0121] a. Prepare the fluorescently labeled sample into a 0.2 mg / mL stock solution, dilute it into 50 ng / mL and 20 ng / mL solutions for detection, and use PBSTP solution as the diluent. The chip is assembled into an assay cassette (i.e., a container for placing the chip) according to the experimental design.

[0122] b. Add the diluted sample to the assembled chip at 600 μL / well and incubate on a constant temperature oscillator for 1 hour.

[0123] c. Place the assay cassette in a plate washer for washing.

[0124] d. The chips in the assay cassette are disassembled, cleaned, dried, assembled into the imaging cassette, and placed into the ImageXpress micro 4 imager from Molecular Devices for scanning and imaging. Finally, a TIFF image file is obtained for each test sample, which is the original data.

[0125] e. Data standardization

[0126] Extract the fluorescence intensity value of the feature and output a GPR5 data file and a corner images file. The GPR5 file contains all the information of a sample and the fluorescence intensity information of all features.

[0127] Extract the characteristic fluorescence intensity information from the GPR5 data files of all samples to generate the original fluorescence intensity (FG, foreground) data matrix. Then perform logarithmic transformation on the data of each sample to obtain the LFG (log-transferred foreground) data matrix, and perform z-score normalization to obtain the NLFG (normalized and log-transferred foreground) data matrix. This step will also generate a sample chip information file, which includes information such as the sample array position and the chip number used. According to the LFG data matrix, Figure 1-Figure 6 As shown, the signal distribution increases with the concentration, and the correlation between samples is very good.

[0128] 3) The ~3,200,000 data on the V16 chip were randomly split in a ratio of 7:2:1, with 7 as training sets, 2 as validation sets, and 1 as test sets. A neural network was constructed using a multi-layer perceptron and residuals, and a deep learning model was built using one-hot encoded peptide sequences. Figure 7-Figure 8 As shown, the model fit is very good.

[0129] The peptide chip used in this application is the V16 chip of Zhuhai Carbon Cloud Intelligent Technology Co., Ltd., which has 4 repeated peptide arrays, each of which has about 3,200,000 peptides. These 3,200,000 peptides are peptide sequences formed by 5-16 unbiased random amino acid combinations, and can achieve a diversity coverage rate of 99.9% for pentamers (5 peptides). At the same time, in this version of the chip peptide array, some target sequences are also included, for example, 1,328,926 target sequences (including potential therapeutic sequences, epitope sequences, antibody sequences and influenza protein therapeutic sequences of some drug target proteins, etc.).

[0130] Example 2: Screening of candidate polypeptides

[0131] On the basis of constructing the search space of peptide sequences, the deep learning model constructed with chip data is used to predict the binding force of peptide sequences, and peptides with high computational binding are selected for verification:

[0132] 1) Construction of peptide search space

[0133] a, There are about 3,200,000 peptide sequences on the chip;

[0134] b, There are about 1,000 peptides recorded in the data that are marketed or have therapeutic effects;

[0135] c, there are about 25,000,000 peptides recorded in the data that are endogenous or naturally derived;

[0136] d, Peptides designed computationally based on the spatial structure of HDAC11, about 20,000;

[0137] 2) Prediction and selection of peptide binding capacity

[0138] A deep learning model built based on chip data is used to predict the binding force of sequences in the peptide search space, and the sequences are sorted according to the predicted binding force, and the top 30 with high signals are selected for synthesis.

[0139] Example 3: Peptide Synthesis

[0140] The candidate peptides were synthesized by Jier Biotechnology Co., Ltd. (as shown in Table 1) and analyzed by HPLC (ultraviolet detector, detection wavelength 220 nm) and mass spectrometry. The test results are as follows: Figure 9-Figure 28 shown.

[0141] Example 4: SPR evaluation of peptide affinity to HDAC11 target

[0142] 1) Running buffer preparation (1x PBS-P buffer containing 0.5% DMSO)

[0143] 2) Protein coupling

[0144] a. Take 60 μL of protein (200 μg / mL) and add it to 240 μL of sodium acetate buffer (10 mM sodium acetate, pH 4.5) and mix thoroughly. The final protein concentration is about 40 μg / mL.

[0145] b. Load the CM5 chip into the device;

[0146] c. According to the sample position information displayed on the screen, place the protein and sodium hydroxide (50mM sodium hydroxide) into the corresponding designated positions;

[0147] d, run pH scouting program for pre-enrichment;

[0148] e. Ligand coupling: Protein immobilization is performed by amino coupling method. Ligand coupling can be completed by applying the coupling (Immobiliztion) program in Biacore 8K control software;

[0149] 3) Preparation and detection of peptide gradient solution

[0150] A series of peptide DMSO solutions with different concentration gradients were prepared using the two-fold dilution method;

[0151] a. Add the corresponding volume of DMSO to the polypeptide powder and mix well to obtain a polypeptide stock solution with a concentration of 100 mM;

[0152] b. Take a clean 96-well plate and add 5 μL DMSO to each well from column 1 to column 5.

[0153] c. Take 5 μL of peptide master solution and add it to the first column of the 96-well plate. Add different types of peptide master solution to each row and use a pipette to gently pipette 7-10 times to mix them evenly. At this time, the peptide concentration is diluted to 50 mM.

[0154] d. Use the two-fold dilution method to dilute. Take 5 μL of the solution in the first column and add it to the second column. Mix well. Take 5 μL of the solution in the second column and add it to the third column. Mix well. Repeat this process until the fifth column. That is, each peptide dilutes 5 peptide gradient solutions. Seal the 96-well plate with a sealing mold and store it at 4°C.

[0155] e. Take another clean 96-well plate, add 199 μL of 1×PBSP solution to each well, take 1 μL of the diluted peptide gradient solution and add it to the 96-well plate, mix thoroughly, at this time, the highest concentration of peptide dilution is 250 uM (the highest concentration is adjusted according to the purpose of the experiment), and the concentration of DMSO is 0.5%;

[0156] f. Apply the Multi-cycle Kinetics / Affinity program in Biacore 8K control software to complete the detection and fitting of affinity and kinetic data and obtain the KD value. The detection results are shown in Figure 29-Figure 48 As shown in Table 1. The binding force in Table 1 refers to the binding ability of the polypeptide to Nectin-4, that is, the affinity between the two.

[0157] Table 1

[0158]

[0159] From Table 1 and Figure 29-Figure 48 It can be seen that the binding force between the HDAC11 binding polypeptides of amino acid sequences such as SEQ ID NO.1 to SEQ ID NO.20 and HDAC11 is 4.97E-07 (M) to 5.07E-05 (M), indicating that the HDAC11 binding polypeptides of the present application have a high affinity with HDAC11, can recognize and bind to HDAC11, and can be used as drugs for treating individual tumors or cancers, providing a new strategy for treating HDAC11-related diseases, and opening up new avenues for the treatment of cancer and other related diseases.

[0160] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0161] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. An HDAC11 binding polypeptide, characterized in that The amino acid sequence of the HDAC11 binding polypeptide comprises: The amino acid sequence shown in any one of SEQ ID NO.1 to SEQ ID NO.20; or An amino acid sequence obtained by substitution, insertion and / or deletion of at least one or several amino acids compared to the amino acid sequence shown in any one of SEQ ID NO.1 to SEQ ID NO.

20.

2. A polynucleotide, characterized in that The method comprises the coding sequence of the HDAC11 binding polypeptide according to claim 1.

3. A recombinant vector, characterized in that: The recombinant vector carries the polynucleotide according to claim 2.

4. A recombinant cell, characterized in that The recombinant cell contains the recombinant vector according to claim 3.

5. A polypeptide-carrier protein conjugate, characterized in that: The polypeptide-carrier protein conjugate comprises a coupled carrier protein and the HDAC11 binding polypeptide of claim 1.

6. The polypeptide-carrier protein conjugate according to claim 5, characterized in that: The carrier protein is selected from at least one of bovine serum albumin, ovalbumin, keyhole limpet hemocyanin and casein; And / or, the HDAC11 binding polypeptide is coupled to the carrier protein via a linker sequence; optionally, the amino acid sequence of the linker sequence is shown in SEQ ID NO.21; And / or, each of the carrier proteins is coupled to 2 to 50 of the HDAC11 binding polypeptides; further, each of the carrier proteins is coupled to 5 to 50 of the HDAC11 binding polypeptides.

7. A polypeptide composition, characterized in that: include: At least two of the polypeptides whose amino acid sequences are shown in SEQ ID NO.1 to SEQ ID NO.20, and polypeptides obtained by substitution, insertion and / or deletion of at least one or several amino acids compared to the polypeptides whose amino acid sequences are shown in SEQ ID NO.1 to SEQ ID NO.

20.

8. A drug, characterized in that The method comprises at least one of the HDAC11 binding polypeptide according to claim 1, the polynucleotide according to claim 2, the recombinant vector according to claim 3, the recombinant cell according to claim 4, the polypeptide-carrier protein conjugate according to any one of claims 5 to 6, and the polypeptide composition according to claim 7.

9. The drug according to claim 8, characterized in that Also includes an adjuvant and / or a pharmaceutically acceptable carrier; optionally, the adjuvant includes at least one of aluminum phosphate, aluminum hydroxide and alum; the pharmaceutically acceptable carrier is selected from at least one of a sustained-release agent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption promoter, an adsorption carrier, a surfactant and a lubricant; And / or, further comprising a polypeptide stabilizer; optionally, the polypeptide stabilizer comprises PLGA nanoparticle material, or the polypeptide stabilizer comprises 150mM to 180mM NaCl, 100mM to 140mM polylysine hydrochloride; And / or, the drug comprises the HDAC11 binding polypeptide, and the effective dose of the HDAC11 binding polypeptide is 0.1 μM to 0.1 M or 0.001 mg to 1000 mg.

10. Use of at least one of the HDAC11 binding polypeptide according to claim 1, the polynucleotide according to claim 2, the recombinant vector according to claim 3, the recombinant cell according to claim 4, the polypeptide-carrier protein conjugate according to any one of claims 5 to 6, and the polypeptide composition according to claim 7 in the preparation of anti-tumor drugs, anti-cancer drugs, drugs for treating malignant vascular hyperplasia diseases and / or health products.

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