Polypeptide derivatives, pharmaceutical compositions thereof and uses thereof

Abstract

A polypeptide derivative or a pharmaceutically acceptable salt thereof, through the introduction of fatty acid side chains at specific sites of the ISP polypeptide, and / or the formation of a cyclic structure within the polypeptide by generating amide bonds between E and K, significantly improves the stability and activity of the resulting polypeptide derivative. This allows for better preparation of drugs for treating diseases related to nerve damage.

Description

Polypeptide derivatives, pharmaceutical compositions and uses thereof

[0001] This application claims priority to the Chinese patent application filed on November 1, 2023, with application number 202311442146.7 and invention name “Polypeptide derivatives, pharmaceutical compositions thereof and uses thereof”, the contents of which should be understood as incorporated into this application by reference. Technical Field

[0002] This article relates to the technical field of polypeptide derivatives and their applications, and in particular to a polypeptide derivative for treating diseases related to nerve damage. Background Art

[0003] Nerve injury leads to the formation of a gelatinous scar, which primarily repairs the blood-brain barrier (BBB), isolating the injured area from healthy tissue to prevent further damage and initiate the healing process. However, within the glial scar, the expression of inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs) is upregulated, strongly inhibiting axonal growth and hindering the repair of damaged nerves (Nat Rev Neurosci. 2004;5:146-156). Studies have shown that CSPGs inhibit nerve regeneration by acting on protein tyrosine phosphatase σ (PTPσ) (Science. 2009;326(5952):592-596). PTPσ and related phosphatases contain a highly conserved wedge-shaped domain located within the cell, consisting of 24 amino acids, which can regulate a series of downstream signaling pathways. Researchers designed an intracellular sigma peptide (ISP) consisting of a 24-amino acid wedge-shaped domain linked to the transmembrane peptide tat. ISP can bind to recombinant human PTPσ and can weaken the neuroinhibitory effects of CSPG. Under the action of ISP, axonal growth can break through the CSPG area and is dose-dependent (Nature. 2015; 518: 404-40). In vivo experiments have shown that ISP can promote functional recovery in rats with spinal cord injury. After ISP administration, bladder function, Basso-Beattie-Bresnahan (BBB) ​​score, and grid walking motor test were significantly improved. However, ISP is a 35-mer peptide composed entirely of natural amino acids, with poor metabolic stability, which seriously affects its drugability.

[0004] Summary of the Invention

[0005] Based on the above background, the present application provides a polypeptide derivative or a pharmaceutically acceptable salt thereof, wherein the polypeptide derivative is derived from the following polypeptide sequence:

[0006] NH2-GRKKRRQRRRX1-DMAEHX2EX3LKAX4DSLKLSX5EYESI-NH2,

[0007] in:

[0008] X1 is selected from C or is absent;

[0009] X2 is selected from M or T;

[0010] X3 is selected from R, K, A, F, L, D, E or Cit;

[0011] X4 is selected from N or K;

[0012] X5 is selected from Q or K;

[0013] And among them,

[0014] When X1 is C, the polypeptide derivative introduces a fatty acid side chain at a position of the polypeptide selected from the group consisting of: position 21, position 23 and position 27, and / or

[0015] The polypeptide derivative forms an intramolecular cyclic structure by connecting the side chains of E and K via an amide bond at positions selected from the group consisting of: positions 15 and 21, positions 18 and 21, positions 27 and 31, positions 27 and 33, and positions 30 and 33, wherein when positions 30 and 33 are connected, X5 at position 30 is K;

[0016] When X1 is absent, the polypeptide derivative introduces a fatty acid side chain at a position of the polypeptide selected from the group consisting of: position 20, position 22, and position 26, and / or

[0017] The polypeptide derivative generates an intramolecular cyclic structure by connecting the side chains of E and K through an amide bond at a position of the polypeptide selected from the group consisting of: position 14 and position 20, position 17 and position 20, position 26 and position 30, position 26 and position 32, and position 29 and position 32, wherein when position 29 and position 32 are connected, X5 at position 29 is K.

[0018] On the other hand, the present application also provides a pharmaceutical composition comprising the polypeptide derivative described herein or a pharmaceutically acceptable salt thereof.

[0019] On the other hand, the present application also provides use of the polypeptide derivative described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, in the preparation of a drug for treating diseases associated with nerve damage.

[0020] In another aspect, the present invention further provides a method for treating a disease associated with nerve damage, comprising administering the polypeptide derivative described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein to a subject in need thereof.

[0021] In another aspect, the present invention also provides a polypeptide derivative described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in treating diseases associated with nerve damage.

[0022] Based on the ISP polypeptide sequence, this application significantly improves the stability of the polypeptide derivative by introducing fatty acid side chains at specific sites, while its affinity for the receptor remains comparable or even slightly improved. The second method is to form a cyclic structure within the polypeptide by forming an amide bond between E and K inside the polypeptide to obtain a cyclic peptide derivative. The stability and activity of the obtained cyclic peptide derivative are significantly improved. At the same time, the two methods are combined to introduce fatty acid side chains at specific sites and form a cyclic structure within the polypeptide, and the stability and activity of the obtained polypeptide derivative are also significantly improved.

[0023] Other features and advantages of the present application will be described in the following description, and in part will become apparent from the description, or will be understood by practicing the present application. Other advantages of the present application can be realized and obtained through the solutions described in the description and the drawings.

[0024] Summary of the Figures

[0025] The accompanying drawings are used to provide an understanding of the technical solution of the present application and constitute a part of the specification. Together with the embodiments of the present application, they are used to explain the technical solution of the present application and do not constitute a limitation on the technical solution of the present application.

[0026] FIG1 shows the effects of various polypeptides according to one embodiment of the present application on axonal growth of human neuroblastoma (SH-SY5Y) cells in a proteoglycan environment.

[0027] Figure 2 shows the changes in body weight over time in rats after SCI surgery and injection of saline or peptide. Groups 1, 2, and 4 in the PW337 group represent groups injected with 1 mg / kg, 2 mg / kg, and 4 mg / kg of PW337, respectively.

[0028] FIG3 shows the results of open field activity in rats of each group after SCI surgery and injection of saline or polypeptide.

[0029] FIG4 shows the results of BBB motility scores of rats in each group after SCI surgery and injection of saline or polypeptide.

[0030] Details

[0031] Unless otherwise indicated, the technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this application belongs. When a certain amount, concentration or other value or parameter is expressed in the form of a range, a preferred range, or a preferred upper numerical limit and a preferred lower numerical limit, it should be understood that it is equivalent to specifically revealing any range by combining any pair of upper range limits or preferred numerical values ​​with any lower range limit or preferred numerical value, without considering whether the range is specifically revealed. Unless otherwise indicated, the numerical ranges listed herein are intended to include the endpoints of the range and all integers and fractions (decimals) within the range.

[0032] As used herein, the terms "about" and "approximately" when used in conjunction with a numerical variable generally refer to the value of that variable and all values ​​of that variable are within experimental error (e.g., within a 95% confidence interval for the mean) or within ±10% of the specified value, or a wider range.

[0033] As used herein, the expression "comprising" or its synonymous similar expressions "including," "containing," and "having" are open-ended and do not exclude additional unrecited elements, steps, or ingredients. The expression "consisting of excludes any elements, steps, or ingredients not specified. The expression "consisting essentially of" means that the scope is limited to the specified elements, steps, or ingredients, plus any optional elements, steps, or ingredients that do not materially affect the basic and novel characteristics of the claimed subject matter. It should be understood that the expression "comprising" encompasses the expressions "consisting essentially of" and "consisting of."

[0034] As used herein, the expression "at least one" or "one or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0035] As used herein, the term "peptide" comprises a sequence of three or more amino acids, wherein the amino acids are naturally occurring or non-naturally occurring amino acids. Non-naturally occurring amino acids refer to amino acids that do not naturally occur in vivo, but which can be introduced into the peptide structures described herein. Three-letter or single-letter abbreviations for amino acids are used herein to represent different amino acids, which are well known in the art.

[0036] The abbreviations used for the genetically encoded amino acids are conventional and are as follows: alanine (Ala or A), arginine (Arg or R), asparagine (Asn or N), aspartic acid (Asp or D), cysteine ​​(Cys or C), glutamic acid (Glu or E), glutamine (Gln or Q), histidine (His or H), isoleucine (Ile or I), leucine (Leu or L), lysine (Lys or K), methionine (Met or M), phenylalanine (Phe or F), proline (Pro or P), serine (Ser or S), threonine (Thr or T), tryptophan (Trp or W), tyrosine (Tyr or Y) and valine (Val or V), citrulline (or N5-aminocarbonylornithine) (Cit).

[0037] When three-letter abbreviations are used, unless specifically preceded by "L" or "D" or otherwise clear from the context in which the abbreviation is used, the amino acid can be in either the L- or D-configuration about the α-carbon (Cα). For example, "Ala" represents alanine without specifying the configuration about the α-carbon, while "D-Ala" and "L-Ala" represent D-alanine and L-alanine, respectively.

[0038] When single-letter abbreviations are used, capital letters represent amino acids in the L-configuration about the α-carbon, and lowercase letters represent amino acids in the D-configuration about the α-carbon. For example, "A" represents L-alanine and "a" represents D-alanine.

[0039] When a polypeptide sequence is presented as a string of single-letter or three-letter abbreviations (or mixtures thereof), the sequence is presented in amino (N) to carboxyl (C) orientation according to conventional convention.

[0040] As used herein, the term "derivative" may refer to any compound having the same or similar core structure as a compound but having at least one structural difference (including substitution, deletion and / or addition of one or more atoms or functional groups). The term "derivative" with respect to a peptide refers to a peptide or analog thereof that has been chemically modified (such as covalently modified, etc.). Typical modifications include amides, sugars, alkyl groups, acyl groups, esters, etc. The term "pharmaceutically acceptable salt" refers to a salt of a polypeptide or protein that retains the biological activity of the parent.

[0041] As used herein, the numerical superscripts in a polypeptide sequence are used to number the amino acids from left to right in order to better indicate the position of the amino acids in the polypeptide. For example, "K 21 " represents the 21st amino acid "K" from left to right. 27 -E 31 " represents the formation of an amide bond between the amino acid "K" at position 27 and the amino acid "E" at position 31, thereby forming a ring structure within the polypeptide molecule. "N23 Mutation to K 23 " represents the mutation of the amino acid "N" at position 23 to the amino acid "K" at position 23. "N 23 Mutation to K 23 "After" is "K 23 ", This statement is intended to enable those skilled in the art to more clearly understand the changes in the polypeptide sequence and find the position of the amino acid.

[0042] As used herein, "loop" in a polypeptide sequence indicates that the amino acids enclosed in parentheses together form a cyclic structure within the polypeptide. For example, "loop (KLSQE)" indicates that within the polypeptide, the amino acids KLSQE form a loop, connected by an amide bond between K and E.

[0043] As used herein, "K()" in a polypeptide sequence indicates the introduction of a fatty acid side chain to the K side chain of the polypeptide. The fatty acid side chain is enclosed in parentheses. Fatty acid chains are indicated herein in bold italics to distinguish them from single-letter amino acid sequences. For example, "K(-AEEA-AEEA-γE-ODDA)" indicates the introduction of the fatty acid side chain -AEEA-AEEA-γE-ODDA at the amino acid K in the polypeptide chain.

[0044] As used herein, the Chinese explanations of the abbreviations or English full names used herein are shown in Table 1 below:

[0045] Table 1

[0046] General Note: The hyphen "-" in the middle of the compound number can be omitted. In some experiments, the hyphen is omitted, for example, PW-337 is equivalent to PW337. Unless otherwise specified, the peptide is in the trifluoroacetate form by default.

[0047] ISP's neural repair mechanisms are mediated by numerous endogenous repair mechanisms, including regeneration, plasticity, remyelination, immune regulation, and synapse formation. These repair mechanisms contribute to the treatment of neural damage associated with spinal cord injury, peripheral nerve injury, traumatic brain injury, and stroke, as well as neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia (FTD), and Parkinson's disease, and possess a wide range of potential medicinal applications. However, ISP is a 35-mer peptide composed entirely of natural amino acids, resulting in poor metabolic stability, which severely impacts its drugability.

[0048] The ISP sequence is as follows:

[0049] NH2-G 1 R 2 K 3K 4 R 5 R 6 Q 7 R 8 R 9 R 10 C 11 -D 12 M 13 A 14 E 15 H 16 M 17 E 18 R 19 L 20 K 21 A 22 N 23 D 24 S 25 L 26 K 27 L 28 S 29 Q 30 E 31 Y 32 E 33 S 34 I 35 -NH2

[0050] The structure of ISP is derived from the mouse PTPσ wedge domain, while in the human PTPσ wedge domain, the M at position 17 is mutated to T. Therefore, in the polypeptide derivatives provided herein, this site can be either M or T.

[0051] The introduction of long-chain fatty acids into the side chains of polypeptides can improve the binding of plasma proteins, increase metabolic stability, and improve drugability. However, the introduction of fatty acid side chains at certain sites may have a serious impact on the affinity of the polypeptide to the receptor. Therefore, the appropriate modification site is very important. The present application found that the introduction of fatty acid side chains at specific sites significantly improved the stability of polypeptide derivatives, while the receptor affinity remained the same or even slightly improved. In addition, cyclization also improved the stability of polypeptide compounds. When ISP interacts with the receptor, D 12 -K 21 and L 26 -I 35 They form α-helical structures respectively, among which the EK salt bridge plays an important role in the stability of the α-helix. In combination with the structural characteristics of ISP, the side chains of E and K are connected by amide bonds at appropriate sites in the two α-helical regions. Specific locations include but are not limited to: K 27 -E 31 、E 18 -K 21 , K 27 -E 33 、E 15 -K21 and K 30 -E 33 (Q 30 Mutation to K 30 The two α-helical regions can be cyclized separately or simultaneously. The present invention further stabilizes the α-helix by forming an amide bond between E and K to obtain cyclic peptide derivatives. It was found that the stability and activity of some of the polypeptide derivatives of the present invention were significantly improved.

[0052] In view of this, the present application provides a polypeptide derivative or a pharmaceutically acceptable salt thereof, wherein the polypeptide derivative is derived from the following polypeptide sequence:

[0053] NH2-GRKKRRQRRRX1-DMAEHX2EX3LKAX4DSLKLSX5EYESI-NH2,

[0054] in:

[0055] X1 is selected from C or is absent;

[0056] X2 is selected from M or T;

[0057] X3 is selected from R, K, A, F, L, D, E or Cit;

[0058] X4 is selected from N or K;

[0059] X5 is selected from Q or K;

[0060] And among them,

[0061] When X1 is C, the polypeptide derivative introduces a fatty acid side chain at a position of the polypeptide selected from the group consisting of: position 21, position 23 and position 27, and / or

[0062] The polypeptide derivative forms an intramolecular cyclic structure by connecting the side chains of E and K via an amide bond at positions selected from the group consisting of: positions 15 and 21, positions 18 and 21, positions 27 and 31, positions 27 and 33, and positions 30 and 33, wherein when positions 30 and 33 are connected, X5 at position 30 is K;

[0063] When X1 is absent, the polypeptide derivative introduces a fatty acid side chain at a position of the polypeptide selected from the group consisting of: position 20, position 22, and position 26, and / or

[0064] The polypeptide derivative generates an intramolecular cyclic structure by connecting the side chains of E and K through an amide bond at a position of the polypeptide selected from the group consisting of: position 14 and position 20, position 17 and position 20, position 26 and position 30, position 26 and position 32, and position 29 and position 32, wherein when position 29 and position 32 are connected, X5 at position 29 is K.

[0065] In some embodiments, the polypeptide derivative introduces a fatty acid side chain at a position of the polypeptide selected from the group consisting of: 21 , K 27 and N 23 Mutation to K 23 The side chain amino group.

[0066] In some embodiments, the polypeptide derivative introduces a fatty acid side chain at a position of the polypeptide selected from the group consisting of: 20 , K 26 and N 22 Mutation to K 22 The side chain amino group.

[0067] In some embodiments, the polypeptide derivative is cyclized by linking the side chains of E and K through an amide bond at a position of the polypeptide selected from the group consisting of: 27 -E 31 、E 18 -K 21 , K 27 -E 33 、E 15 -K 21 and Q 30 Mutation to K 30 Post-E 33 .

[0068] In some embodiments, the polypeptide derivative is cyclized by linking the side chains of E and K through an amide bond at a position of the polypeptide selected from the group consisting of: 26 -E 30 、E 17 -K 20 , K 26 -E 32 、E 14 -K 20 and Q 29 Mutation to K 29 Post-E 32 .

[0069] In some embodiments, the fatty acid side chain is: -Y1-Y2-Y3-Y4;

[0070] Wherein, Y1 may not exist; or be -NH-(CH2-CH2-O) m1 -(CH2) m2 -CO-, wherein m1 is a positive integer of 2-10, m2 is 1 or 2; or L / D-Glu, wherein the α- or γ-carboxyl group thereof is connected to the side chain amino group of the main chain amino acid of the polypeptide, and the amino group is connected to the carboxyl group of Y2, Y3 or Y4;

[0071] Y2 may not exist; or be -NH-(CH2-CH2-O) m3 -(CH2) m4 -CO-, wherein m3 is a positive integer from 2 to 10, and m4 is 1 or 2;

[0072] Y3 may not exist; or be -NH-(CH2-CH2-O) m5 -(CH2) m6 -CO-, wherein m5 is a positive integer of 2-10, and m6 is 1 or 2; or L / D-Glu, wherein the α- or γ-carboxyl group is connected to the side chain amino group of the main chain amino acid of the polypeptide or the Y1 amino group or the Y2 amino group, and the amino group is connected to the Y4 carboxyl group;

[0073] Y4 is HOOC-(CH2) n -CO- or CH3-(CH2) n -CO, such as stearoyl (-C18), palmitoyl (-C16), myristoyl (-C14) or lauroyl (-C12), wherein n is a positive integer of 10-20.

[0074] In some embodiments, the fatty acid side chain is selected from: -AEEA-AEEA-γE-ODDA, -AEEA-AEEA-γE-C18, -AEEA-AEEA-γE-C16, -AEEA-AEEA-γE-C14, -AEEA-AEEA-γE-C12, -AEEA-γE-ODDA, -AEEA-γE-C18, -AEEA-γE-C16, -AEEA-γE-C14 or -AEEA-γE-C12; preferably, the fatty acid side chain is -AEEA-AEEA-γE-ODDA, -AEEA-AEEA-γE-C16, -AEEA-γE-C16 or -AEEA-γE-C12.

[0075] In some embodiments, the amino acids in the cell-penetrating peptide tat sequence GRKKRRQRRRC (SEQ ID NO: 52) in the polypeptide are all L-amino acids, or all D-amino acids, or a mixture of D / L-amino acids; and wherein the C-terminal end of the cell-penetrating peptide tat is 11 exists or does not exist.

[0076] In some embodiments, the amino groups at both ends of the polypeptide may be optionally substituted with carboxyl groups or amide groups.

[0077] In some embodiments, the polypeptides or polypeptide derivatives provided herein are as shown in Table 2 below (SEQ ID NOs: 1-51):

[0078] Table 2

[0079] In another aspect, provided herein are pharmaceutical compositions comprising the polypeptide derivatives described herein or pharmaceutically acceptable salts thereof.

[0080] In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable components selected from the group consisting of diluents, buffers, excipients, salts, emulsifiers, osmotic pressure regulators, preservatives, stabilizers, and fillers.

[0081] In some embodiments, non-limiting examples of pharmaceutically acceptable excipients suitable for use in the present disclosure include granulating agents, binders, lubricants, disintegrants, sweeteners, glidants, anti-adherents, antistatic agents, surfactants, antioxidants, gums, coating agents, colorants, flavorings, plasticizers, suspending agents, antimicrobials, plant cellulosic materials, and spheronizing agents, and any combination thereof.

[0082] In some embodiments, the pharmaceutical composition is administered orally, intravenously, intradermally, transdermally, intrathecally, intraarterially, intraperitoneally, intranasally, intravaginally, intrarectally, intravesically, intratumorally, topically, intramuscularly, subcutaneously, mucosally, by inhalation, injection, infusion, or any combination thereof.

[0083] In some embodiments, the pharmaceutical composition of the present invention can be administered orally, such as directly orally, by incorporating it into drinking water or food, or by gavage.

[0084] In some embodiments, the dosage form of the pharmaceutical composition is selected from one or more of capsules, tablets, pills, liquids, powders, granules, fine granules, film coatings, pills, lozenges, sublingual preparations, peptizers, buccal preparations, pastes, syrups, suspensions, elixirs, emulsions, coatings, ointments, plasters, poultices, transdermal preparations, lotions, inhalants, aerosols, injections, or suppositories.

[0085] In another aspect, the present invention also provides use of the polypeptide derivative described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, in the preparation of a medicament for treating a disease associated with nerve damage.

[0086] In some embodiments, the disease associated with nerve injury is selected from one or more of spinal cord injury, peripheral nerve injury, traumatic brain injury, stroke, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, dementia, and Parkinson's disease.

[0087] In another aspect, the present invention also provides a method for treating a disease associated with nerve damage, comprising administering the polypeptide derivative described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein to a subject in need thereof.

[0088] In some embodiments, the disease associated with nerve injury is selected from one or more of spinal cord injury, peripheral nerve injury, traumatic brain injury, stroke, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, dementia, and Parkinson's disease.

[0089] In another aspect, the present invention also provides a polypeptide derivative described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in treating a disease associated with nerve damage.

[0090] In some embodiments, the disease associated with nerve injury is selected from one or more of spinal cord injury, peripheral nerve injury, traumatic brain injury, stroke, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, dementia, and Parkinson's disease.

[0091] This application describes multiple embodiments, but this description is exemplary rather than restrictive, and it is obvious to those skilled in the art that there may be more embodiments and implementations within the scope of the embodiments described in this application. Although many possible feature combinations are shown in the drawings and discussed in the detailed description, many other combinations of the disclosed features are also possible. Unless specifically limited, any feature of any embodiment may be used in combination with any other feature in any other embodiment, or may replace any other feature in any other embodiment.

[0092] This application includes and contemplates combinations of features known to those of ordinary skill in the art. The embodiments and features disclosed in this application may also be combined with any conventional features to form a unique inventive solution defined by the claims. Any feature of any embodiment may also be combined with features from other inventive solutions to form another unique inventive solution defined by the claims. Therefore, it should be understood that any feature shown and / or discussed in this application may be implemented individually or in any appropriate combination. Therefore, the embodiments are not subject to other limitations except as provided in the appended claims and their equivalents. In addition, various modifications and changes may be made within the scope of protection of the appended claims.

[0093] In addition, when describing representative embodiments, the specification may have presented the method and / or process as a specific sequence of steps. However, to the extent that the method or process does not rely on the specific order of the steps described herein, the method or process should not be limited to the steps in the specific order described. As will be understood by those skilled in the art, other orders of steps are also possible. Therefore, the specific order of the steps set forth in the specification should not be interpreted as a limitation to the claims. In addition, the claims for the method and / or process should not be limited to performing their steps in the order written, and those skilled in the art can readily understand that these orders can be changed and still remain within the spirit and scope of the embodiments of the present application.

[0094] The experimental methods in the following examples, for which specific conditions are not specified, are generally determined in accordance with national standards. The experimental materials in the following examples, for which the sources are not specified, are all commercially available raw materials. The equipment used in each step in the following examples is all conventional equipment. If there are no corresponding national standards, the methods are carried out in accordance with general international standards, conventional conditions, or conditions recommended by the manufacturer. Unless otherwise defined or indicated, all professional and scientific terms used in this application have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of this application.

[0095] The relevant materials used in the examples are as follows:

[0096] Reagents

[0097] The control drugs PW-5 and PW-6 used in this experiment were synthesized by our company using conventional synthesis methods based on the sequences reported in the literature.

[0098] Preparation Example: Synthesis of PW series compounds

[0099] 1. Synthesis of PW-89

[0100] 0.50 g (0.10 mmol) of Rink amide resin was placed in a reactor and swelled for 10 minutes with 10 mL of DCM. The mixture was filtered and washed twice with DMF. A 25% by volume 4-methylpiperidine / DMF solution was added and reacted for 30 minutes to remove the Fmoc group. The resin was filtered and washed four times with DMF and twice with DCM. Ninhydrin detection indicated a blue resin solution. Fmoc-Ile-OH (0.40 mmol, 4 eq.) and HBTU (0.36 mmol, 3.6 eq.) were weighed and dissolved in DMF. DIEA (0.80 mmol, 8 eq.) was added and mixed thoroughly. The resin was added to the resin and reacted with magnetic stirring at room temperature for 1 hour. The mixture was filtered and washed three times with DMF, MeOH, and DCM. Ninhydrin detection indicated that the resin was colorless and transparent, and the solution was light yellow, indicating complete reaction. The Fmoc group was removed by adding 25% by volume 4-methylpiperidine / DMF. This cycle was repeated to complete the coupling of the backbone sequence. Among them, K 27 Fmoc-Lys(Dde)-OH was used, and Boc-Gly-OH was used at the N-terminus. Subsequently, 2% hydrazine hydrate / DMF was added to the peptide resin for 10 min three times to remove the Dde from the Lys side chain. FMOC-AEEA-OH, FMOC-AEEA-OH, FMOC-Glu-α-OtBu, and OtBu-ODDA were then sequentially condensed. The peptide resin was drained and 15 mL of pre-chilled lysis buffer (TFA:TIS:H2O = 95:2.5:2.5) was added. The reaction was stirred at room temperature for 5 h. The reaction solution was removed and the resin was washed twice with a small amount of TFA and removed. The reaction solutions were combined and pre-chilled methyl tert-butyl ether was added to form a white precipitate. The mixture was centrifuged, and the supernatant was discarded. The precipitate was then added to methyl tert-butyl ether, vortexed, centrifuged, and the supernatant discarded. The precipitate was dried in a vacuum desiccator for 12 h to obtain the crude product. The crude peptide was dissolved in water, sonicated, filtered, and the filtrate was purified using preparative liquid chromatography. Preparative column: C18-10-100, 30 x 250 mm. Flow rate: 25 mL / min. Phase A: 0.1% TFA / water, Phase B: 0.1% TFA / 90% acetonitrile / water. Gradient elution was performed to obtain the pure target compound. Fractions of the target compound with a purity > 95% were combined, the acetonitrile was removed under reduced pressure, and freeze-dried to obtain the target compound. Mass spectrometry confirmed the correct molecular weight ([M+6] 6+ =835.1).

[0101] 2. Synthesis of PW-98

[0102] The peptide sequence was synthesized by referring to the method of PW-89. 27 Using Fmoc-Lys(Alloc)-OH, E 31Fmoc-Glu(OAll)-OH was used. Subsequently, under nitrogen protection, 0.3 equivalents of tetrakis(triphenylphosphine)palladium and 12 equivalents of phenylsilane in DCM were added to the peptide resin and reacted at room temperature for 2 hours to remove the allyl ester of the Glu side chain and the allyloxycarbonyl of the Lys side chain. The mixture was filtered, washed with DCM 5 times, washed with DMF 3 times, and 2 equivalents of PYBOP, 2 equivalents of HOBt and 4 equivalents of DIEA were added, dissolved in DMF, and reacted at room temperature for 5 hours. The mixture was filtered, washed with DMF 3 times, washed with DCM 3 times, and tested with ninhydrin. If the reaction was incomplete, the condensation was repeated once. The target compound was then cleaved and purified according to the method of PW-89 to obtain a pure product. The molecular weight was correct ([M+6] 6+ =713.0).

[0103] 3. Synthesis of PW-71

[0104] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+7] 7+ =720.1).

[0105] 4. Synthesis of PW-72

[0106] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+7] 7+ =720.1).

[0107] 5. Synthesis of PW-73

[0108] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+7] 7+ =722.0).

[0109] 6. Synthesis of PW-74

[0110] The target compound was obtained by referring to the synthesis method of PW-98. The molecular weight was correct ([M+5] 5+ =861.2).

[0111] 7. Synthesis of PW-75

[0112] The target compound was obtained by referring to the synthesis method of PW-98. The molecular weight was correct ([M+5] 5+ =861.2).

[0113] 8. Synthesis of PW-90

[0114] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+7] 7+=701.3).

[0115] 9. Synthesis of PW-92

[0116] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+7] 7+ =716.0).

[0117] 10. Synthesis of PW-93

[0118] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+7] 7+ =701.2).

[0119] 11. Synthesis of PW-95

[0120] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+7] 7+ =718.0).

[0121] 12. Synthesis of PW-96

[0122] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+7] 7+ =703.1).

[0123] 13. Synthesis of PW-99

[0124] The target compound was obtained by referring to the synthesis method of PW-98. The molecular weight was correct ([M+7] 7+ =596.4).

[0125] 14. Synthesis of PW-101

[0126] The target compound was obtained by referring to the synthesis method of PW-98. The molecular weight was correct ([M+6] 6+ =712.7).

[0127] 15. Synthesis of PW-102

[0128] The target compound was obtained by referring to the synthesis method of PW-98. The molecular weight was correct ([M+7] 7+ =596.4).

[0129] 16. Synthesis of PW-106

[0130] The target compound was obtained by referring to the synthesis method of PW-98. The molecular weight was correct ([M+6] 6+=712.7).

[0131] 17. Synthesis of PW-107

[0132] The target compound was obtained by referring to the synthesis method of PW-98. The molecular weight was correct ([M+6] 6+ =695.8).

[0133] 18. Synthesis of PW-109

[0134] The target compound was obtained by referring to the synthesis method of PW-98. The molecular weight was correct ([M+6] 6+ =712.7).

[0135] 19. Synthesis of PW-110

[0136] The target compound was obtained by referring to the synthesis method of PW-98. The molecular weight was correct ([M+4] 4+ =1042.9).

[0137] 20. Synthesis of PW-160

[0138] The target compound was obtained by referring to the synthesis method of PW-98. The molecular weight was correct ([M+4] 4+ =1042.9).

[0139] 21. Synthesis of PW-161

[0140] The target compound was obtained by referring to the synthesis method of PW-98. The molecular weight was correct ([M+6] 6+ =712.7).

[0141] 22. Synthesis of PW-164

[0142] Referring to the synthesis method of PW-98, the synthesis of C-terminal 9 peptides was completed first, wherein K 26 Using Fmoc-Lys(Alloc)-OH, E 32 Then, the first cyclization was completed by referring to the synthesis method of PW-98. Then, the synthesis of the remaining sequence was completed, wherein the N-terminal was Boc-Gly-OH, K 20 Using Fmoc-Lys(Alloc)-OH, E 17 Fmoc-Glu(OAll)-OH was used. Then, referring to the synthesis method of PW-98, the second cyclization was completed, and cleavage and purification were carried out to obtain the pure target compound. The molecular weight was correct ([M+6] 6+ =692.7).

[0143] 23. Synthesis of PW-165

[0144] The target compound was obtained by referring to the synthesis method of PW-164. The molecular weight was correct ([M+6] 6+ =709.8).

[0145] 24. Synthesis of PW-170

[0146] The target compound was obtained by referring to the synthesis method of PW-98. The molecular weight was correct ([M+6] 6+ =712.8).

[0147] 25. Synthesis of PW-173

[0148] The main chain was synthesized by referring to the synthesis method of PW-98, wherein the N-terminal was Boc-Gly-OH, K 21 Using Fmoc-Lys(Dde)-OH, K 27 Using Fmoc-Lys(Alloc)-OH, E 31 Fmoc-Glu(OAll)-OH was used. Following this, the Dde was removed by referring to the synthesis method of PW-89 to complete the side chain synthesis. Then, the cyclization was completed by referring to the synthesis method of PW-98. Finally, the target compound was cleaved and purified to obtain the pure product. The molecular weight was confirmed by mass spectrometry ([M+6] 6+ =832.1).

[0149] 26. Synthesis of PW-174

[0150] The target compound was obtained by referring to the synthesis method of PW-173. The molecular weight was correct ([M+6] 6+ =814.8).

[0151] 27. Synthesis of PW-175

[0152] The target compound was obtained by referring to the synthesis method of PW-173. The molecular weight was correct ([M+6] 6+ =832.1).

[0153] 28. Synthesis of PW-176

[0154] The target compound was obtained by referring to the synthesis method of PW-173. The molecular weight was correct ([M+6] 6+ =814.8).

[0155] 29. Synthesis of PW-177

[0156] The target compound was obtained by referring to the synthesis method of PW-173. The molecular weight was correct ([M+6] 6+ =832.1).

[0157] 30. Synthesis of PW-178

[0158] The target compound was obtained by referring to the synthesis method of PW-173. The molecular weight was correct ([M+6] 6+ =814.8).

[0159] 31. Synthesis of PW-179

[0160] The target compound was obtained by referring to the synthesis method of PW-173. The molecular weight was correct ([M+6] 6+ =832.1).

[0161] 32. Synthesis of PW-180

[0162] The target compound was obtained by referring to the synthesis method of PW-173. The molecular weight was correct ([M+6] 6+ =814.8).

[0163] 33. Synthesis of PW-181

[0164] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+6] 6+ =835.1).

[0165] 34. Synthesis of PW-182

[0166] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+7] 7+ =701.2).

[0167] 35. Synthesis of PW-337

[0168] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+4] 4+ =1234.1).

[0169] 36. Synthesis of PW-183

[0170] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+6] 6+ =835.1).

[0171] 37. Synthesis of PW-184

[0172] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+7] 7+ =701.2).

[0173] 38. Synthesis of PW-185

[0174] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+6] 6+ =837.5).

[0175] 39. Synthesis of PW-186

[0176] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+6] 6+ =820.1).

[0177] 40. Synthesis of PW-239

[0178] The target compound was obtained by referring to the synthesis method of PW-98. The molecular weight was correct ([M+6] 6+ =698.6).

[0179] 41. Synthesis of PW-240

[0180] The target compound was obtained by referring to the synthesis method of PW-98. The molecular weight was correct ([M+6] 6+ =681.4).

[0181] 42. Synthesis of PW-241

[0182] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+6] 6+ =820.8).

[0183] 43. Synthesis of PW-242

[0184] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+6] 6+ =803.7).

[0185] 44. Synthesis of PW-247

[0186] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+6] 6+ =830.3).

[0187] 45. Synthesis of PW-252

[0188] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+5] 5+ =990.4).

[0189] 46. ​​Synthesis of PW-253

[0190] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+5] 5+ =969.4).

[0191] 47. Synthesis of PW-257

[0192] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+7] 7+ =680.5).

[0193] 48. Synthesis of PW-259

[0194] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+5] 5+ =940.7).

[0195] 49. Synthesis of PW-261

[0196] The target compound was obtained by referring to the synthesis method of PW-89. The molecular weight was correct ([M+6] 6+ =774.7).

[0197] Experimental example: biological activity determination

[0198] 1. Axonal Growth of SH-SY5Y Cells

[0199] After retinoic acid (RA)-induced differentiation, the SH-SY5Y (human neuroblastoma) cell line exhibits neuronal morphology and gene expression, and expresses the PTPσ membrane receptor. Therefore, RA-induced differentiation of SH-SY5Y cells can be used to simulate neuronal axonal growth in vitro and to test the effects of PW peptides on axonal growth.

[0200] Prepare SH-SY5Y culture medium: 1) DMEM / F12 + 10% FBS + 1x penicillin-streptomycin + 1mM sodium pyruvate; 2) DMEM / F12 + 1% FBS + 1x penicillin-streptomycin + 1mM sodium pyruvate. To prepare a 50mM stock solution of retinoic acid: Weigh 15.02mg of retinoic acid and dissolve it in 1mL of dimethyl sulfoxide (DMSO). Aliquot and freeze at -80°C. Proteoglycan (ACAN / CSPG1) is a type of chondroitin sulfate proteoglycan (CSPG). To prepare a 1mg / mL stock solution of proteoglycan: Dissolve 1mg of ACAN solid in 1mL of distilled water. Aliquot and freeze at -80°C. To prepare a 1mM PW polypeptide cell-based solution: Weigh the appropriate amount of polypeptide powder, dissolve it in PBS, filter it through a 0.2μm filter, and freeze at -20°C.

[0201] 1 mg / mL proteoglycan was diluted to 250 μg / mL with distilled water and coated on a 24-well cell culture plate: 3 ACAN droplets were coated on each well, 2 μL per drop. SH-SY5Y cells were seeded on a 24-well proteoglycan-coated plate (20,000 cells / well) using a culture medium containing 10% FBS and incubated (37°C, 5% CO2) for 20 hours. The culture medium was replaced with 1% FBS and PW polypeptide (2.5 μM) or an equal volume of PBS solution was added. After incubation for 72 hours, the cells were fixed with 4% paraformaldehyde (room temperature, 30 minutes) and photographed using a 10× optical microscope to record cell morphology. 20-30 cells were randomly selected in each field of view, and axon length was measured using Image J-SNT.

[0202] Data Analysis: The mean of all measured axon lengths within each proteoglycan-coated area was used as one data point. Differences between groups were compared using one-way analysis of variance followed by a Tukey's test. P < 0.05 was considered significant. The results are shown in Figure 1.

[0203] The results in Figure 1 show that compared with the normal cell control (Ctrl), proteoglycan (ACAN) significantly inhibited the axonal growth of SH-SY5Y cells (PBS group). Compared with the scrambled peptide (Scr, negative control), PW6 (positive control), PW92, PW93, PW98, PW99, PW101, PW106, PW170, PW175, PW182, PW239, PW240, PW242, PW247, PW252, PW253, PW257, PW259, and PW261 all showed a significant effect in promoting axonal growth. Compared with PW6, the promoting effect of PW93, PW98, and PW182 on axonal growth was significantly enhanced. PW92, PW99, PW101, PW106, PW170, PW175, PW242, PW247, PW252, PW253, PW257, PW259, and PW261 showed no significant difference in promoting axonal growth compared with PW6. PW95, PW96, PW239, and PW240 showed no significant enhancement in promoting axonal growth compared with PW6. Data are presented as mean ± standard deviation; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001; one-way ANOVA followed by Tukey's test.

[0204] 2. Effects of PW337 (1, 2, 4 mg / kg) on ​​body weight and activity status in rats with spinal cord injury

[0205] Female Sprague-Dawley rats (250-270 g) were weighed and randomly divided into groups. After the dorsal T10 vertebral lamina was removed, the rats in each spinal cord injury (SCI) group underwent spinal cord impaction. Rats in the sham surgery (sham) group underwent spinal cord impaction without spinal cord impaction. Rats with a BBB motor score > 1 on day 1 after SCI surgery were excluded. The remaining rats were randomly divided into groups and subcutaneously injected daily with equal volumes of saline (solvent control), PW5 (1 mg / kg), and PW337 (1, 2, and 4 mg / kg). Rats in the sham surgery group received no injections. Weekly body weight measurements, BBB scores, and open-field activity tests were performed after SCI surgery.

[0206] The body weight results in Figure 2 show that compared with the spinal cord injury (SCI) group, the PW337 (2 mg / kg) group recovered significantly faster from 6 to 57 days after surgery; the PW5 (1 mg / kg) and PW337 (1 mg / kg) groups recovered significantly faster from 27 to 57 days after surgery; and the PW337 (4 mg / kg) group recovered significantly faster from 6 to 42 days after surgery. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, t-test.

[0207] Figure 3 shows the open field activity results. Six and seven weeks after surgery, the PW337 (2 mg / kg) group showed a greater increase (%) in distance traveled compared to the spinal cord injury (SCI) group. Six to eight weeks after surgery, the PW337 (2 mg / kg) group also showed a greater increase (%) in time spent traveling compared to the SCI group. *p<0.05, ***p<0.001, ****p<0.0001, t-test.

[0208] The experimental results in Figures 2 and 3 show that PW337 significantly improved the overall condition of rats after spinal cord injury surgery, as evidenced by accelerated recovery of body weight and locomotor activity. A 2 mg / kg dose of PW337 significantly enhanced locomotor activity in rats, suggesting that this dose may improve motor function in rats.

[0209] 3. Effect of PW337 (2 mg / kg) on ​​motor function recovery in rats with chronic spinal cord injury

[0210] Female SD rats (250-270 g) were weighed and randomly divided into groups. After the dorsal T10 segment vertebral lamina was removed, the rats in each spinal cord injury (SCI) group were subjected to spinal cord impaction. The rats in the sham operation (sham) group only had the T10 segment vertebral lamina removed without impaction. Rats with a BBB motor score > 1 point one day after SCI surgery were excluded, and the remaining rats were randomly divided into groups and subcutaneously injected daily with equal volumes of normal saline (solvent control), PW5 (2 mg / kg), and PW337 (2 mg / kg). The sham operation group rats were not injected. BBB scores were performed weekly after SCI surgery. The BBB score results in Figure 4 show that one day after surgery, the BBB scores of rats in the SCI group and each drug-treated group were 0, meeting the inclusion criteria. From 1 to 14 days after surgery (acute and subacute phases of SCI), there were no significant differences in the BBB scores of rats in the SCI, PW5, and PW337 groups. On day 56 after surgery (chronic phase of spinal cord injury), the BBB score in the PW337 group was significantly higher than that in the SCI group, indicating that PW337 can improve motor function in rats with chronic spinal cord injury. Comparing the BBB scores on day 56 with those on day 14, the increase in the BBB score in the PW337 group was significantly greater than that in the PW5 group, indicating that PW337 can accelerate motor function recovery in rats with chronic spinal cord injury compared to PW5. *p<0.05, ****p<0.0001, t-test.

[0211] 4. Determination of peptide half-life in rats

[0212] The polypeptide in this example was prepared according to the preparation example of the present invention.

[0213] Plasma sample collection: Two male Sprague-Dawley rats (280-300 g) were intravenously injected with PW5, PW6, PW182, or PW337 at a dose of 4 mg / kg of pure peptide in a 2 mL / kg volume. Blood samples (400 μL / sample) were collected via a jugular vein catheter at 0.5, 2, 5, 10, 15, 30, 60, and 120 min after tail vein injection. Blood samples were collected into tubes containing EDTA-K2 and 100x protease inhibitors (1:50, v:v; Roche, 11873580001) in an anticoagulant solution. Whole blood samples were placed on ice and centrifuged (3200 g, 4°C, 10 min) within 1 hour of collection. Plasma was transferred to a pre-chilled centrifuge tube, and protease inhibitors were added (1:50, v:v), mixed, and stored at −80°C.

[0214] Plasma sample preparation: Pipette plasma sample into a 96-well plate (50 μL / well), add pure methanol (300 μL / well), and vortex (1500 rpm, 10 min) to mix thoroughly. Centrifuge (4800 g, 4°C, 10 min), remove the supernatant to a new 96-well plate (100 μL / well), add 20% methanol in water containing 0.2% formic acid (100 μL / well), and vortex (1500 rpm, 3 min) to mix thoroughly. Inject 10.0 μL of the sample for LC-MS / MS analysis to determine the drug concentration in the sample.

[0215] Instrument model: (Waters TQ-XS)

[0216] Chromatographic column: SHIMADZU Shim-Pack Scepter Claris C4-300 (2.1×50mm, 1.9μm)

[0217] Test results:

[0218] Table 3. Half-life, plasma concentration and AUC data of the conjugate

Claims

1. A polypeptide derivative or a pharmaceutically acceptable salt thereof, wherein: The polypeptide derivative is derived from the following polypeptide sequence: NH2-GRKKRRQRRRX1-DMAEHX2EX3LKAX4DSLKLSX5EYESI-NH2, in: X1 is selected from C or is absent; X2 is selected from M or T; X3 is selected from R, K, A, F, L, D, E or Cit; X4 is selected from N or K; X5 is selected from Q or K; And among them, When X1 is C, the polypeptide derivative introduces a fatty acid side chain at a position of the polypeptide selected from the group consisting of: position 21, position 23 and position 27, and / or The polypeptide derivative generates an intramolecular cyclic structure by connecting the side chains of E and K through an amide bond at positions of the polypeptide selected from the group consisting of: positions 15 and 21, positions 18 and 21, positions 27 and 31, positions 27 and 33, and positions 30 and 33, wherein when positions 30 and 33 are connected, X5 at position 30 is K; When X1 is absent, the polypeptide derivative introduces a fatty acid side chain at a position of the polypeptide selected from the group consisting of: position 20, position 22 and position 26, and / or The polypeptide derivative generates an intramolecular cyclic structure by connecting the side chains of E and K through an amide bond at a position of the polypeptide selected from the group consisting of: the 14th and 20th positions, the 17th and 20th positions, the 26th and 30th positions, the 26th and 32nd positions, and the 29th and 32nd positions, wherein when the 29th and 32nd positions are connected, the X5 at the 29th position is K.

2. The polypeptide derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The fatty acid side chain is: -Y1-Y2-Y3-Y4; Wherein, Y1 is absent; or is -NH-(CH2-CH2-O) m1 -(CH2) m2 -CO-, wherein m1 is a positive integer of 2-10, and m2 is 1 or 2; or L / D-Glu, whose α- or γ-carboxyl group is connected to the side chain amino group of the main chain amino acid of the polypeptide, and the amino group is connected to the carboxyl group of Y2, Y3 or Y4; Y2 does not exist; or is -NH-(CH2-CH2-O) m3 -(CH2) m4 -CO-, wherein m3 is a positive integer of 2-10, and m4 is 1 or 2; Y3 does not exist; or is -NH-(CH2-CH2-O) m5 -(CH2) m6 -CO-, wherein m5 is a positive integer of 2-10, and m6 is 1 or 2; or L / D-Glu, whose α- or γ-carboxyl group is connected to the side chain amino group of the main chain amino acid of the polypeptide or the Y1 amino group or the Y2 amino group, and the amino group is connected to the Y4 carboxyl group; Y4 is HOOC-(CH2) n -CO-, CH3-(CH2) n -CO-, palmitoyl (-C16) or lauroyl (-C12), wherein n is a positive integer of 10-20.

3. The polypeptide derivative or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: The amino acids in the cell-penetrating peptide tat sequence GRKKRRQRRRC in the polypeptide are all L-amino acids, or all D-amino acids, or a mixture of D / L-amino acids; and the C at the C-terminus of the cell-penetrating peptide tat is present or absent.

4. The polypeptide derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: The polypeptide derivative is selected from any one of the following:

5. A pharmaceutical composition comprising the polypeptide derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to claim 5, wherein The pharmaceutical composition further comprises one or more pharmaceutically acceptable components selected from the group consisting of diluents, buffers, excipients, salts, emulsifiers, osmotic pressure regulators, preservatives, stabilizers and fillers.

7. The pharmaceutical composition according to claim 5, wherein The pharmaceutical composition is administered orally, intravenously, intradermally, transdermally, intrathecally, intraarterially, intraperitoneally, intranasally, intravaginally, intrarectally, intravesically, intratumorally, topically, intramuscularly, subcutaneously, mucosally, by inhalation, injection, infusion, or any combination thereof.

8. Use of the polypeptide derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 or the pharmaceutical composition according to any one of claims 5 to 7 in the preparation of a medicament for treating diseases associated with nerve damage.

9. The use according to claim 8, wherein: The disease associated with nerve damage is selected from one or more of spinal cord injury, peripheral nerve injury, traumatic brain injury, stroke, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, dementia and Parkinson's disease.

10. A method for treating a disease associated with nerve damage, the method comprising administering the polypeptide derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 or the pharmaceutical composition according to any one of claims 5 to 7 to a subject in need thereof.

11. The method according to claim 10, wherein: The disease associated with nerve damage is selected from one or more of spinal cord injury, peripheral nerve injury, traumatic brain injury, stroke, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, dementia and Parkinson's disease.

12. The polypeptide derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to any one of claims 5 to 7, for use in treating diseases associated with nerve damage.

13. The polypeptide derivative for use or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 12, wherein: The disease associated with nerve damage is selected from one or more of spinal cord injury, peripheral nerve injury, traumatic brain injury, stroke, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, dementia and Parkinson's disease.

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