GLP-1r / GIPR / GCGR triple agonist analogue and use thereof

Abstract

Provided is a polypeptide or a derivative thereof or a pharmaceutically acceptable salt thereof. The polypeptide or the derivative thereof has a structure as represented by formula (I): X1X2X3GTX6X7X8DX10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25LX27X28X29X30PX32SX34X35PPPX39 (I); the structure represented by formula (I) contains two amino acids with -SH on the side chain or two amino acids with -NH2 on the side chain, wherein -SH or -NH2 is used for linking a modification group. The polypeptide or the derivative thereof or the pharmaceutically acceptable salt thereof exhibits strong agonistic activity on three receptor targets of GLP-1R, GCGR and GIPR, can effectively control blood sugar and reduce body weight, and can be used for preventing or treating metabolic disorder related diseases and the like.

Description

GLP-1R / GIPR / GCGR triple agonist analogs and uses thereof Technical Field

[0001] The present invention belongs to the field of biopharmaceutical technology. Specifically, the present invention relates to a GLP-1R / GIPR / GCGR triple agonist analog and its use. More specifically, the present invention relates to a polypeptide or its derivative or their pharmaceutically acceptable salts, pharmaceutical compositions and their use. Background Art

[0002] Diabetes (e.g., type 2 diabetes mellitus, T2DM) is a type of energy metabolism disorder that has become a growing health problem in many countries and has led to a wide range of related and dangerous diseases, such as cardiovascular and cerebrovascular diseases, dyslipidemia, kidney disease, liver disease, osteoporosis, and neurodegenerative diseases. The primary characteristic of type 2 diabetes is hyperglycemia caused by insulin resistance, with obesity being one of the main causes of insulin resistance. Obesity is a condition in which excessive fat accumulates in the body due to excessive energy intake or metabolic abnormalities. This excessive fat accumulation can impair pancreatic cell function and worsen the condition of diabetes. Furthermore, obesity and insulin resistance are two major pathogenic factors of non-alcoholic fatty liver disease (NAFLD / NASH). Therefore, there is an urgent need to find safe and effective treatments for these metabolic disorders. Furthermore, for the growing number of obese people, there is an urgent need for a more effective, broader, and safer treatment for weight control.

[0003] Incretins are substances secreted by the intestine under normal physiological conditions. They include glucose-dependent insulin-like polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon (GCG). Their secretion is regulated by glucose levels and they maintain pancreatic β-cell function, stimulate insulin secretion from these cells, regulate glucose levels, inhibit gastric acid secretion, delay gastric emptying, increase satiety, and modulate fat metabolism. These effects are crucial for the treatment and management of diabetes, obesity, and related metabolic diseases.

[0004] Glucagon-like peptide-1 (GLP-1) is a 31-amino acid polypeptide expressed by the proglucagon gene in intestinal mucosal L cells. GLP-1 primarily stimulates insulin secretion and inhibits glucagon secretion by binding to the GLP-1 receptor (GLP-1R), protecting pancreatic beta cells and regulating blood glucose homeostasis. Furthermore, GLP-1 can suppress appetite and gastric emptying through central nervous system signaling pathways, increasing satiety and thereby reducing weight.

[0005] Glucagon-dependent insulin-releasing polypeptide (GIP) is a 42-amino acid single-chain polypeptide produced by K cells in the small intestinal mucosa. GIP primarily acts on GIP receptors (GIPR) in pancreatic islet cells and adipocytes. GIP can regulate glucose metabolism by promoting insulin secretion, enhancing pancreatic β-cell mass, inhibiting gastric acid secretion, and slowing gastric motility. Furthermore, GIP can stimulate the uptake and utilization of fatty acids by adipose tissue cells. Studies have also shown that GIP has physiological effects on bone protection, such as promoting osteoblast differentiation, inhibiting osteoblast apoptosis, inhibiting bone resorption, and increasing bone mineral density.

[0006] Glucagon (GCG) is a 29-amino acid polypeptide secreted by pancreatic alpha cells. It primarily targets the glucagon receptor (GCGR), which is primarily found in the liver and kidneys. GCG stimulates hepatic glycogenolysis, increases blood glucose levels, activates lipase, promotes fat breakdown, and enhances fatty acid oxidation, thereby increasing ketone body production. Research results have shown that GCG is effective in reducing food intake, increasing adipose tissue energy expenditure, and reducing body fat.

[0007] Therefore, there is an urgent need to develop an incretin analog that is active on the glucagon-like peptide-1 receptor (GLP-1R), glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon receptor (GCGR) simultaneously, so as to effectively treat metabolic disorders such as diabetes.

[0008] Summary of the Invention

[0009] The present invention aims to solve, at least to some extent, at least one of the technical problems existing in the prior art. To this end, the present invention provides a GLP-1R / GIPR / GCGR triple agonist analog, which simultaneously exhibits agonist activity at the glucagon-like peptide-1 receptor (GLP-1R), the glucose-dependent insulinogenic polypeptide receptor (GIPR), and the glucagon receptor (GCGR).

[0010] The present invention is accomplished based on the following findings of the inventors:

[0011] Natural GLP-1 is easily degraded by dipeptidyl peptidase-IV (DPP-IV) and neutral endopeptidase (NEP) which are commonly found in plasma, and has a half-life of less than 2 minutes. In order to improve the half-life of GLP-1 and the effect of diabetes treatment, a variety of GLP-1 analogs are currently available for the treatment of T2DM, including Exenatide, Liraglutide and Semaglutide. Currently, GLP-1 drugs used for obesity generally reduce weight by around 5-10%, and the overall average weight loss rate does not exceed 10% of the patient's body weight. At the same time, many GLP-1 analogs currently on the market have limited dosage due to gastrointestinal side effects such as nausea and vomiting.

[0012] In addition, some GLP-1R / GCGR dual agonists developed based on gastrin (Oxyntomodulin) are also believed to have better effects in reducing food intake, reducing weight, and improving blood sugar and triglyceride levels than GLP-1R single agonists. However, the development of peptide drugs on the market is often hindered by short half-life and low bioavailability. Patients tend to receive higher doses of therapeutic drugs more frequently, which may lead to reduced compliance, increased costs and increased risk of side effects. Therefore, the present invention has developed a therapeutic agent with balanced GLP-1R / GIPR / GCGR triple receptor agonist activity, good stability, and a sufficiently long duration of action to support low-frequency, high-efficiency administration, for example, once a week, once every two weeks, or even once a month.

[0013] Based on this, in the first aspect of the present invention, the present invention provides a polypeptide or its derivative or its pharmaceutically acceptable salt. According to an embodiment of the present invention, the polypeptide or its derivative has a structure shown in formula (I):

[0014] X1X2X3GTX6X7X8DX 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 LX 27 X 28 X 29 X 30 PX 32 SX 34 X35 PPPX 39 (I);

[0015] wherein X1 is Y, H, 3-iodo-Y, 4-Pal or 4-amino-F;

[0016] X2 is Aib, s or Ac4c;

[0017] X3 is Q, H or Dab(Ac);

[0018] X6 is F, F(2-F) or αMeF;

[0019] X8 is S, HoS or αMeS;

[0020] X 10 is Z2, Y, Z1, L or 4-Pal;

[0021] X 11 is S or αMeS;

[0022] X 12 is K, R or I;

[0023] X 13 is Z2, Z1, Y, L, A, αMeL, Q, Aib or Iva;

[0024] X 14 is Z2, Z1, L, K(Ac), HoL, Npg or Tle;

[0025] X 15 is D, E or Aad;

[0026] X 16 is K, E, K(Ac) or αMeK;

[0027] X 17 is R, Z2, Z1, K(Ac), Q or I;

[0028] X 18 is Z2, Z1, A, R or Y;

[0029] X 19 is A, Q, Aib, H or K(Ac);

[0030] X 20 is Q, Z2, Aib, H, R, a or Z1;

[0031] X 21 is Z1, D, A, L, Z2, or Aib;

[0032] X 22 F or HoF;

[0033] X 23 is V or I;

[0034] X 24 is Z2, Q, Z1 or E;

[0035] X 25 is Z2, Z1, W or Y;

[0036] X 27 is L, K or I;

[0037] X 28 is A, D, E, Z1 or Z2;

[0038] X 29 is G or H;

[0039] X 30 is G or H;

[0040] X 32 is Z2, Z1, S or P;

[0041] X 34 is G or Aib;

[0042] X 35 A, Q or K;

[0043] X 39 is S or K;

[0044] In the structure represented by formula (I), two sites in any of the following groups are independently selected from amino acids Z1 having a side chain containing -SH, or in the structure represented by formula (I), two sites in any of the following groups are independently selected from amino acids Z2 having a side chain containing -NH2:

[0045] 1)i and i+3;

[0046] 2)i and i+4;

[0047] 3) i and i+7; or

[0048] 4)i and i+11;

[0049] Wherein, i is 10, 14, 17 or 21;

[0050] The two amino acids Z1 containing -SH on the side chains are each independently selected from C, C, αMeC, HoC, Hoc, Pen or N-Me-C;

[0051] The two amino acids Z2 containing -NH2 side chains are each independently selected from K, k, αMeK, HoK, Dap, Dab, Orn or N-Me-K.

[0052] The above-mentioned polypeptides or their derivatives or pharmaceutically acceptable salts of the present invention can be used as incretin analogs, which can show strong agonist activity on the three receptor targets of GLP-1R, GCGR and GIPR, can effectively control blood sugar and reduce body weight, and can be used to prevent or treat metabolic disorder-related diseases, bone-related diseases, cardiovascular diseases and neurodegenerative diseases.

[0053] In the second aspect of the present invention, the present invention provides a polypeptide derivative or a pharmaceutically acceptable salt thereof, characterized in that the polypeptide derivative has any structure shown in Table A (see claims for details).

[0054] In its third aspect, the present invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises the polypeptide or its derivative or pharmaceutically acceptable salt described in the first aspect, or the polypeptide derivative or pharmaceutically acceptable salt described in the second aspect. As previously mentioned, the polypeptide or its derivative or pharmaceutically acceptable salt of the present invention exhibits strong agonist activity against all three receptor targets: GLP-1R, GCGR, and GIPR, effectively controlling blood sugar and reducing body weight. Thus, drugs containing the polypeptide or its derivative or pharmaceutically acceptable salt can effectively prevent or treat diseases related to metabolic disorders, bone-related diseases, cardiovascular diseases, and neurodegenerative diseases.

[0055] In the fourth aspect of the present invention, the present invention proposes a use of the polypeptide or its derivative or pharmaceutically acceptable salts described in the first aspect, the polypeptide derivative or pharmaceutically acceptable salts described in the second aspect, or the pharmaceutical composition described in the third aspect in the preparation of a drug, wherein the drug is used to treat or prevent at least one of metabolic disorder-related diseases, bone-related diseases, cardiovascular diseases and neurodegenerative diseases.

[0056] According to the embodiments of the present application, the present invention proposes a use of the polypeptide or its derivatives or pharmaceutically acceptable salts described in the first aspect or the pharmaceutical composition described in the second aspect in treating or preventing at least one of metabolic disorder-related diseases, bone-related diseases, cardiovascular diseases and neurodegenerative diseases.

[0057] According to the embodiments of the present application, the present invention proposes a polypeptide or its derivatives or their pharmaceutically acceptable salts as described in the first aspect or the pharmaceutical composition as described in the second aspect, for treating or preventing at least one of metabolic disorder-related diseases, bone-related diseases, cardiovascular diseases and neurodegenerative diseases.

[0058] In a fifth aspect, the present invention provides a method for preventing and / or treating metabolic disorders, bone diseases, cardiovascular diseases, and / or neurodegenerative diseases. According to an embodiment of the present invention, the method comprises administering a pharmaceutically acceptable amount of the polypeptide or derivative thereof or a pharmaceutically acceptable salt thereof described in the first aspect, or the pharmaceutical composition described in the second aspect, to a subject. The method of the present invention is effective in preventing and / or treating metabolic disorders, bone diseases, cardiovascular diseases, and / or neurodegenerative diseases.

[0059] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] FIG1 is a synthetic route of Staple-A1 in Example 1 of the present invention.

[0061] FIG2 is a schematic diagram of the steps of connecting the linear peptide TG30 and Staple-A1 in Example 1 of the present invention.

[0062] FIG3 is a schematic diagram of the steps of connecting the linear peptide TG85 and Stable B1 in Example 2 of the present invention.

[0063] FIG4 is a curve showing the body weight changes of DIO obese mice after injection of different doses of the compound TG52 of the present invention in Test Example 3 of the present invention.

[0064] FIG5 is a curve showing the change in daily total food intake of each group of mice after injection of different doses of the compound TG52 of the present invention into DIO obese mice in Test Example 3 of the present invention.

[0065] FIG6 is a curve showing changes in blood glucose levels in DIO obese mice after injection of different doses of the compound TG52 of the present invention in Test Example 3 of the present invention.

[0066] FIG7 is the stability test results of compound TG52 and Retatrutide (positive control) in test example 4 of the present invention in artificial gastric fluid.

[0067] FIG8 is a result of serum albumin binding test of the target peptide in Test Example 5 of the present invention.

[0068] FIG9 shows the results of changes in blood insulin levels in DIO obese mice after long-term treatment with the target peptide in Test Example 6 of the present invention.

[0069] FIG10 shows the results of fat content in liver tissue of NASH mouse model after long-term treatment with target peptide in Test Example 6 of the present invention.

[0070] FIG11 is the quantitative analysis results of various indicators in liver tissue of the NASH mouse model after long-term treatment with the target peptide in Test Example 6 of the present invention. DETAILED DESCRIPTION

[0071] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0072] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood to indicate or imply relative importance or implicitly specify the number of the technical features indicated. Therefore, features defined as "first" or "second" may explicitly or implicitly include one or more of such features. Furthermore, in the description of the present invention, unless otherwise specified, "plurality" means two or more.

[0073] Detailed description of the invention

[0074] Definitions and General Terms

[0075] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention, but not excluding other contents.

[0076] As used herein, the terms "optionally," "optional," or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0077] As used herein, the terms "optionally substituted," "optionally substituted," and "substituted or unsubstituted" are used interchangeably. Generally, the term "optionally," whether or not preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specified group, the substituents may be the same or different at each position. Such substituents may include, but are not limited to, F, Cl, Br, CN, OH, NH2, NO2, and the like.

[0078] As used herein, the term "one or more" (e.g., in the definition of substituents of the compounds of the general formulae of the invention (modifying groups)) means "one, two, three, four or five, in particular one, two, three or four, more in particular one, two or three, even more in particular one or two".

[0079] In addition, it should be noted that, unless otherwise explicitly stated, the description methods used in the present invention such as "each...independently is" and "...each independently is" and "...independently is" can be interchanged and should be understood in a broad sense. They can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0080] As used herein, the term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.

[0081] In this document, the minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Refers to a carbon atom containing "a" to "b". For example, "C 1～n ” refers to a linear or branched saturated / unsaturated carbon chain containing 1, 2, 3, 4, 5, ... or n carbon atoms; it is further understood that “C 1～n " shall be interpreted as including any sub-ranges therein, such as C 1～20 Including C 1～20 、C 1～18 、C 10～8 、C 12～18 、C 14～18 、C 1～10 、C 1～6 、C 1～3 、C 1～2 、C 2～10 、C 2～9 、C 2～8 、C 2～7 、C 2～6 、C 2～5 、C 2～4 、C 2～3 、C 3～10 、C 3～9 、C 3～8 、C 3～7 、C 3～6 、C 3～5 、C 3～4 、C 4～10 、C 4～9 、C 4～8 、C 4～7 、C 4～6 、C 4～5 .

[0082] In this context, the term "alkyl" is represented by the general formula Alkylene can be a straight chain alkyl or a branched chain alkyl. 1～20 "Alkyl" refers to an alkyl group having 1 to 20 carbon atoms; the term "C 1～6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms.

[0083] In this context, the term "alkylene" is Alkylene can be a straight chain alkylene or a branched chain alkylene. 1～20 "Alkylene" refers to an alkylene group having 1 to 20 carbon atoms; the term "C 1～6 "Alkylene" refers to an alkylene group having 1 to 6 carbon atoms.

[0084] In this article, the term “C 1～6 "Alkoxy" refers to a C 1～6 Alkyl, wherein the term "alkyl" is as defined above. For example: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, isopentyloxy and n-hexyloxy, or isomers of the above groups. In particular, the "C 1～6 The "alkoxy" group may contain 1, 2, 3, 4 or 5 carbon atoms ("C 1～5 Alkoxy”), preferably, may contain 1, 2, 3 or 4 carbon atoms (“C 1～4 alkoxy").

[0085] As used herein, the term "oxyalkylene" refers to a group formed by removing a hydrogen atom from an "oxyalkyl" group.

[0086] As used herein, the term "aryl" refers to a carbon ring system containing monocyclic, bicyclic, and tricyclic rings, wherein at least one ring system is aromatic, and wherein each ring system comprises a ring composed of 6-10 atoms. An aryl group is typically, but not necessarily, attached to the parent molecule via the aromatic ring of the aryl group. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring." Aryl groups can include phenyl, indenyl, naphthyl, and anthracenyl. The aryl group is optionally substituted with one or more substituents described herein.

[0087] As used herein, the term "arylene" refers to a group formed by removing a hydrogen atom from an "aryl" group.

[0088] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, and tricyclic carbon ring system containing at least one heteroatom, wherein at least one of the ring systems is aromatic. Here, heteroatoms include nitrogen atoms, oxygen atoms, sulfur atoms, and the like. It generally refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon.

[0089] As used herein, the term "heteroarylene" refers to a group formed by removing a hydrogen atom from a "heteroaryl" group.

[0090] The group description of the present invention It is used to describe the position of group substitution.

[0091] In this context, the structural formula of the term "-NH-CO-" or "-NH-C(=O)-" is

[0092] In this document, amino acids are referred to using the conventional single-letter and three-letter codes for natural amino acids, as well as the commonly accepted three-letter codes for other α-amino acids, for example, α-aminoisobutyric acid can be represented by both codes Aib and B. Unless otherwise specified, all amino acid residues in the present invention are preferably in the L-configuration.

[0093] Among them, the structural formula of the term "Aib" is

[0094] In this context, the structural formula of the term "Ac4c" is

[0095] In this context, the structural formula of the term "αMeC" is

[0096] In this context, the structural formula of the term "αMeL" is

[0097] In this context, the structural formula of the term "αMeS" is

[0098] In this context, the structural formula of the term "αMeF" is

[0099] In this context, the structural formula of the term "αMeK" is

[0100] In this context, the structural formula of the term "Iva" is

[0101] In this context, the structural formula of the term "F(2-F)" is

[0102] In this article, the structural formula of the term "4-Pal" is

[0103] In this context, the structural formula of the term "K(Ac)" is

[0104] In this context, the structural formula of the term "HoL" is

[0105] In this context, the structural formula of the term "Tle" is

[0106] In this context, the structural formula of the term "Npg" is

[0107] In this context, the structural formula of the term "HoC" is

[0108] In this context, the structural formula of the term "Hoc" is

[0109] In this context, the structural formula of the term "HoF" is

[0110] In this context, the structural formula of the term "HoS" is

[0111] In this context, the structural formula of the term "HoK" is

[0112] In this context, the structural formula of the term "3-iodo-Y" is

[0113] In this context, the structural formula of the term "4-amino-F" is

[0114] In this context, the structural formula of the term "Dab(Ac)" is

[0115] In this context, the structural formula of the term "Aad" is

[0116] In this document, the structural formula of the term "Pen" is

[0117] In this context, the term "N-Me-C" has the structural formula

[0118] In this article, the structural formula of the term "N-Me-K" is

[0119] In this context, the structural formula of the term "Orn" is

[0120] In this context, the structural formula of the term "Dab" is

[0121] In this context, the structural formula of the term "Dap" is

[0122] As used herein, "pharmaceutical composition" may refer to a composition used for the treatment of a disease or for in vitro cell culture experiments. When used for the treatment of a disease, the term "pharmaceutical composition" generally refers to a unit dosage form and can be prepared by any method well known in the pharmaceutical art. All methods include the step of combining the active ingredient with an excipient that constitutes one or more auxiliary ingredients. Typically, the composition is prepared by uniformly and thoroughly combining the active polypeptide or its derivative or revitalizing agent with a liquid excipient, a finely divided solid excipient, or both.

[0123] As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the polypeptide or derivative thereof and / or the mammal to be treated therewith. Preferably, the "pharmaceutically acceptable" herein means approved by federal regulatory agencies or national governments or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in animals, particularly humans.

[0124] As used herein, the term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the polypeptides of the present invention or their derivatives. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed with non-toxic acids include, but are not limited to, inorganic acid salts (such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates) formed by reaction with amino groups, and organic acid salts (such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates), or other methods described in the literature, such as ion exchange methods, to obtain these salts.

[0125] In the chemical structure of the ligand or compound disclosed herein, the bond Indicates that the configuration is not specified. If chiral isomers exist in the chemical structure, the bond Can be or include both Although all of the above structural formulae are drawn as certain isomers for simplicity, the present disclosure may include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates, and enantiomers.

[0126] As used herein, the term "pharmaceutically acceptable excipient" may include any solvent, solid excipient, diluent, or other liquid excipient, etc., suitable for a particular target dosage form. Except to the extent that any conventional excipient is incompatible with the polypeptide or derivative thereof, pharmaceutical composition, or medicament containing the same, such as by producing any adverse biological effect or interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, their use is also contemplated by the present invention.

[0127] In addition to any conventional excipients, to the extent that they are incompatible with the polypeptides of the present invention or their derivatives, pharmaceutical compositions or drugs containing them, such as any adverse biological effects produced or interactions with any other components of the pharmaceutically acceptable composition in a harmful manner, their use is also within the scope of the present invention.

[0128] The pharmaceutical compositions of the present disclosure include formulations suitable for parenteral administration. The formulations can be conveniently presented in unit dosage form and can be prepared by any method known in the pharmaceutical art. The amount of active ingredient that can be combined with excipients to prepare a single dose form is generally the amount of polypeptide or its derivative that produces a therapeutic effect.

[0129] As used herein, the term "agonist" refers to a substance (ligand) that activates the receptor type in question.

[0130] As used herein, the term "treatment" refers to any agent used to obtain a desired pharmacological and / or physiological effect. The effect may be preventive in terms of completely or partially preventing a disease or its symptoms, and / or therapeutic in terms of partially or completely curing a disease and / or the adverse effects caused by the disease. "Treatment" as used herein covers diseases in mammals, particularly humans, and includes: (a) preventing the occurrence of a disease or condition in individuals who are susceptible to the disease but have not yet been diagnosed with the disease; (b) inhibiting the disease, such as arresting the progression of the disease; or (c) alleviating the disease, such as alleviating the symptoms associated with the disease. "Treatment" as used herein covers any medication that administers a polypeptide or a derivative thereof to an individual to treat, cure, alleviate, improve, reduce or inhibit the individual's disease, including but not limited to administering a drug containing a polypeptide or a derivative thereof as described herein to an individual in need.

[0131] In this article, the term "non-alcoholic fatty liver disease (NAFLD)" generally refers to a clinical pathological syndrome characterized by excessive fat deposition in hepatocytes, excluding alcohol and other clear liver-damaging factors. It is an acquired metabolic stress-induced liver injury closely related to insulin resistance and genetic susceptibility, including but not limited to simple fatty liver (SFL), non-alcoholic steatohepatitis (NASH) and its related cirrhosis.

[0132] Detailed description of the polypeptide or its derivatives or their pharmaceutically acceptable salts, pharmaceutical compositions and their uses of the present invention

[0133] The present invention provides a polypeptide or its derivatives or their pharmaceutically acceptable salts, a pharmaceutical composition and their uses, which are described in detail below.

[0134] Polypeptide or its derivative or pharmaceutically acceptable salt thereof

[0135] In the first aspect of the present invention, the present invention provides a polypeptide or a derivative thereof or a pharmaceutically acceptable salt thereof. According to an embodiment of the present invention, the polypeptide or a derivative thereof has a structure shown in formula (I):

[0136] X1X2X3GTX6X7X8DX 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 LX 27 X 28 X 29 X 30 PX 32 SX 34 X 35 PPPX 39 (I);

[0137] wherein X1 is Y, H, 3-iodo-Y, 4-Pal or 4-amino-F;

[0138] X2 is Aib, s or Ac4c;

[0139] X3 is Q, H or Dab(Ac);

[0140] X6 is F, F(2-F) or αMeF;

[0141] X8 is S, HoS or αMeS;

[0142] X 10 is Z2, Y, Z1, L or 4-Pal;

[0143] X 11 is S or αMeS;

[0144] X12 is K, R or I;

[0145] X 13 For Z2, Z1, Y, L, A, αMeL, Q, Aib, Iva;

[0146] X 14 is Z2, Z1, L, K(Ac), HoL, Npg or Tle;

[0147] X 15 is D, E or Aad;

[0148] X 16 is K, E, K(Ac) or αMeK;

[0149] X 17 is R, Z2, Z1, K(Ac), Q or I;

[0150] X 18 is Z2, Z1, A, R or Y;

[0151] X 19 is A, Q, Aib, H or K(Ac);

[0152] X 20 is Q, Z2, Aib, H, R, a or Z1;

[0153] X 21 is Z1, D, A, L, Z2, or Aib;

[0154] X 22 F or HoF;

[0155] X 23 is V or I;

[0156] X 24 is Z2, Q, Z1 or E;

[0157] X 25 is Z2, Z1, W or Y;

[0158] X 27 is L, K or I;

[0159] X 28 is A, D, E, Z1 or Z2;

[0160] X 29 is G or H;

[0161] X 30 is G or H;

[0162] X 32 is Z2, Z1, S or P;

[0163] X 34 is G or Aib;

[0164] X 35 A, Q or K;

[0165] X 39 is S or K;

[0166] In the structure represented by formula (I), two sites in any of the following groups are independently selected from amino acids Z1 having a side chain containing -SH, or in the structure represented by formula (I), two sites in any of the following groups are independently selected from amino acids Z2 having a side chain containing -NH2:

[0167] 1)i and i+3;

[0168] 2)i and i+4;

[0169] 3) i and i+7; or

[0170] 4)i and i+11;

[0171] Wherein, i is 10, 14, 17 or 21;

[0172] The two amino acids Z1 containing -SH on the side chains are each independently selected from C, C, αMeC, HoC, Hoc, Pen or N-Me-C;

[0173] The two amino acids Z2 containing -NH2 side chains are each independently selected from K, k, αMeK, HoK, Dap, Dab, Orn or N-Me-K.

[0174] The above-mentioned polypeptides or their derivatives or pharmaceutically acceptable salts of the present invention exhibit strong agonist activity on the three receptor targets of GLP-1R, GCGR and GIPR, can effectively control blood sugar and reduce body weight, and can be used to prevent or treat metabolic disorder-related diseases, bone-related diseases, cardiovascular diseases and neurodegenerative diseases.

[0175] Unless otherwise specified, in this article, for amino acids with single-letter abbreviations, capital letters represent L-configuration amino acids (e.g., S (i.e., L-configuration Ser), A (i.e., L-configuration Ala), etc.), and lowercase letters represent D-configuration amino acids (e.g., s (i.e., D-configuration Ser), a (i.e., D-configuration Ala), etc.).

[0176] In this article, X in the structure shown in formula (I) i represents an amino acid, wherein i represents the position of the amino acid. For example, X9 is the ninth amino acid in the structure shown in formula (I).

[0177] It should be noted that the two positions in group 1) are i and i+3, respectively; the two positions in group 2) are i and i+4, respectively; the two positions in group 3) are i and i+7, respectively; and the two positions in group 4) are i and i+11, respectively. Furthermore, the two positions in groups 1) through 4) are both amino acids Z1, or the two positions in groups 1) through 4) are both amino acids Z2. The two amino acids Z1 in each group of positions may be the same or different, and the two amino acids Z2 in each group of positions may be the same or different.

[0178] In some preferred embodiments of the present invention, the two amino acids Z1 in the structure shown in formula (I) are identical.

[0179] In some preferred embodiments of the present invention, the two amino acids Z2 in the structure shown in formula (I) are identical.

[0180] According to an embodiment of the present invention, the positions of the two amino acids Z1 whose side chains contain -SH in the structure shown in formula (I) are i and i+3, i and i+4, i and i+7, or i and i+11, respectively, and i is 10, 14, 17 or 21.

[0181] According to an embodiment of the present invention, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (I) are respectively i and i+3, i is 10, 14, 17 or 21, and preferably i is 17.

[0182] According to an embodiment of the present invention, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (I) are respectively i and i+4, i is 10, 14, 17 or 21, and preferably i is 10.

[0183] According to an embodiment of the present invention, the positions of the two amino acids Z1 containing -SH in the side chains in the structure shown in formula (I) are i and i+7, respectively, i is 10, 14, 17 or 21, preferably i is 14, 17 or 21.

[0184] According to an embodiment of the present invention, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (I) are respectively i and i+11, i is 10, 14, 17 or 21, preferably i is 10 or 17.

[0185] According to an embodiment of the present invention, the positions of the two amino acids Z2 whose side chains contain -NH2 in the structure shown in formula (I) are i and i+3, i and i+4, i and i+7, or i and i+11, respectively, and i is 10, 14, 17 or 21.

[0186] According to an embodiment of the present invention, the positions of the two amino acids Z2 whose side chains contain -NH2 in the structure represented by formula (I) are respectively i+3, or i and i+7, and i is 17 or 21.

[0187] According to an embodiment of the present invention, the positions of the two amino acids Z2 whose side chains contain -NH2 in the structure represented by formula (I) are 17 and 20, or 21 and 28, respectively.

[0188] According to an embodiment of the present invention, X1 is Y or H.

[0189] According to an embodiment of the present invention, X2 is Aib or Ac4c.

[0190] According to an embodiment of the present invention, X3 is Q or H.

[0191] According to an embodiment of the present invention, X6 is F or F(2-F).

[0192] According to an embodiment of the present invention, X6 is F(2-F).

[0193] According to an embodiment of the present invention, X 10 Y, C, L or 4-Pal.

[0194] According to an embodiment of the present invention, X 10 Y, L or 4-Pal.

[0195] According to an embodiment of the present invention, X 10 It is Y or 4-Pal.

[0196] According to an embodiment of the present invention, X 11 is S or αMeS.

[0197] According to an embodiment of the present invention, X 12 It is K or I.

[0198] According to an embodiment of the present invention, X 13 is Y, L, A, αMeL, Q, Aib or Iva.

[0199] According to an embodiment of the present invention, X 13 is Y, L, αMeL, Q, Aib or Iva.

[0200] According to an embodiment of the present invention, X 13 is Y, L, αMeL, Q or Iva.

[0201] According to an embodiment of the present invention, X 13 is L or αMeL.

[0202] According to an embodiment of the present invention, X 13 It is Y, L or A.

[0203] According to an embodiment of the present invention, X 13 is αMeL, Y or Iva.

[0204] According to an embodiment of the present invention, X 13 It is αMeL, Q or L.

[0205] According to an embodiment of the present invention, X 13 It is Y or L.

[0206] According to an embodiment of the present invention, X 14 is Z1, L, K(Ac), HoL, Npg or Tle.

[0207] According to an embodiment of the present invention, X 14 is L, K(Ac), HoL, Npg or Tle.

[0208] According to an embodiment of the present invention, X 14 is C, L, K(Ac), HoL, Npg or Tle.

[0209] According to an embodiment of the present invention, X 15 It is D or E.

[0210] According to an embodiment of the present invention, X 16 It is K or E.

[0211] According to an embodiment of the present invention, X 16 is E, K, αMeK or K(Ac).

[0212] According to an embodiment of the present invention, X 16 is K or αMeK.

[0213] According to an embodiment of the present invention, X 17 is Z1, Q, K(Ac), R or I.

[0214] According to an embodiment of the present invention, X 17 is C, Q, K(Ac), R or I.

[0215] According to an embodiment of the present invention, X 17 is R, Z2, K(Ac), Q or I.

[0216] According to an embodiment of the present invention, X 17 is R, K, K(Ac), Q or I.

[0217] According to an embodiment of the present invention, X 17 is K(Ac) or K.

[0218] According to an embodiment of the present invention, X 17is C or K(Ac).

[0219] According to an embodiment of the present invention, X 17 It is R, K or Q.

[0220] According to an embodiment of the present invention, X 18 A, R or Y.

[0221] According to an embodiment of the present invention, X 18 A or Y.

[0222] According to an embodiment of the present invention, X 19 It is A, Q or Aib.

[0223] According to an embodiment of the present invention, X 19 For Q or A.

[0224] According to an embodiment of the present invention, X 19 It is Q or H.

[0225] According to an embodiment of the present invention, X 20 is Q, Z2, Aib, H, a or Z1.

[0226] According to an embodiment of the present invention, X 20 It is Q, K, Aib, H, a or C.

[0227] According to an embodiment of the present invention, X 20 It is Aib, Q, H, Z1 or a.

[0228] According to an embodiment of the present invention, X 20 is Aib, Q, H, C or a.

[0229] According to an embodiment of the present invention, X 20 is Q, Aib, H or R.

[0230] According to an embodiment of the present invention, X 20 It is Q, Z2 or Aib.

[0231] According to an embodiment of the present invention, X 20 It is Q, K or Aib.

[0232] According to an embodiment of the present invention, X 20 It is Aib or Q.

[0233] According to an embodiment of the present invention, X 20 It is Aib or K.

[0234] According to an embodiment of the present invention, X 21 It is Z1, D, A or Z2.

[0235] According to an embodiment of the present invention, X21 is Z1, D, A, L or Aib.

[0236] According to an embodiment of the present invention, X 21 is C, D, A, L or Aib.

[0237] According to an embodiment of the present invention, X 21 It is D, A or C.

[0238] According to an embodiment of the present invention, X 21 D, A or L.

[0239] According to an embodiment of the present invention, X 21 It is K or A.

[0240] According to an embodiment of the present invention, X 21 It is D or C.

[0241] According to an embodiment of the present invention, X 22 F or HoF.

[0242] According to an embodiment of the present invention, X 23 I or V.

[0243] According to an embodiment of the present invention, X 24 It is Q, Z1 or E.

[0244] According to an embodiment of the present invention, X 24 E, C or Q.

[0245] According to an embodiment of the present invention, X 24 E or C.

[0246] According to an embodiment of the present invention, X 24 It is Q or E.

[0247] According to an embodiment of the present invention, X 25 W or Y.

[0248] According to an embodiment of the present invention, X 28 A, E, Z1 or Z2.

[0249] According to an embodiment of the present invention, X 28 A, E, or Z1.

[0250] According to an embodiment of the present invention, X 28 A, D, E, or Z1.

[0251] According to an embodiment of the present invention, X 28 A, D, E, C or HoC.

[0252] According to an embodiment of the present invention, X 28A, D or E.

[0253] According to an embodiment of the present invention, X 28 A or E.

[0254] According to an embodiment of the present invention, X 28 E or C.

[0255] According to an embodiment of the present invention, X 28 It is K or A.

[0256] According to an embodiment of the present invention, X 32 It is S or P.

[0257] According to an embodiment of the present invention, X 35 It is A or Q.

[0258] According to an embodiment of the present invention, X 35 It is A or K.

[0259] According to an embodiment of the present invention, X 39 is S, wherein the C-terminus of the S is amidated.

[0260] According to an embodiment of the present invention, the polypeptide represented by formula (I) or its derivative has a structure represented by formula (Ia):

[0261] X1X2X3GTX6TSDX 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 FX 23 X 24 X 25 LLX 28 GGPSSGGPPPS (Ia).

[0262] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X1 is Y, or H;

[0263] X2 is Aib, s, or Ac4c;

[0264] X3 is Q, H or Dab(Ac);

[0265] X6 is F, F(2-F) or αMeF;

[0266] X 10 Y, or 4-Pal;

[0267] X 11 is S or αMeS;

[0268] X 12 is K or I;

[0269] X 13 is Y, L, αMeL, Q, or Iva;

[0270] X 14 is Z1, L, K(Ac), HoL, Npg or Tle;

[0271] X 15 D, or E;

[0272] X 16 is K, E, K(Ac), or αMeK;

[0273] X 17 is R, Z2, Z1, K(Ac), Q or I;

[0274] X 18 A or Y;

[0275] X 19 A, or Q;

[0276] X 20 is Q, Z2, Aib, H, a or Z1;

[0277] X 21 is Z1, D, A, Z1 or Z2;

[0278] X 23 is V or I;

[0279] X 24 Q, Z1 or E;

[0280] X 25 is W or Y;

[0281] X 28 A, E, Z1 or Z2.

[0282] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X1 is Y, or H;

[0283] X2 is Aib, s, or Ac4c;

[0284] X3 is Q, H or Dab(Ac);

[0285] X6 is F, F(2-F) or αMeF;

[0286] X 10 Y, or 4-Pal;

[0287] X 11 is S or αMeS;

[0288] X 12 is K or I;

[0289] X 13 is Y, L, αMeL, Q, or Iva;

[0290] X 14 is Z1, L, K(Ac), HoL, Npg or Tle;

[0291] X 15 D, or E;

[0292] X 16 is K, E, K(Ac), or αMeK;

[0293] X 17 is R, Z2, Z1, K(Ac), Q or I;

[0294] X 18 A or Y;

[0295] X 19 A, or Q;

[0296] X 20 is Q, Z2, Aib, H, a or Z1;

[0297] X 21 is Z1, D, A, or Z2;

[0298] X 23 is V or I;

[0299] X 24 Q, Z1 or E;

[0300] X 25 is W or Y;

[0301] X 28 It is E or Z1.

[0302] In some optional embodiments of the present invention, in the structure represented by formula (Ia), X1 is Y or H.

[0303] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 10 It is Y or 4-Pal.

[0304] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 12 It is K or I.

[0305] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 13 is Y, L, αMeL, Q or Iva.

[0306] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 14 is C, L, K(Ac), HoL, Npg or Tle.

[0307] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 15 It is D or E.

[0308] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 16 is E, K, αMeK or K(Ac).

[0309] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 17 is C, Q, K(Ac), R or I.

[0310] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 18 A or Y.

[0311] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 19 For Q or A.

[0312] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 20 is Aib, Q, H, C or a.

[0313] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 21 It is D, A or C.

[0314] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 24 E, C or Q.

[0315] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 25 W or Y.

[0316] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 28 E or C.

[0317] In some optional embodiments of the present invention, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (Ia) are 14 and 21, 17 and 24, 21 and 28, or 17 and 20, respectively.

[0318] In some optional embodiments of the present invention, the positions of the two amino acids Z2 whose side chains contain -NH2 in the structure represented by formula (Ia) are 21 and 28 or 17 and 20, respectively.

[0319] In some optional embodiments of the present invention, the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (Ia) are 14 and 21, respectively.

[0320] In some optional embodiments of the present invention, the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (Ia) are 17 and 24, respectively.

[0321] In some optional embodiments of the present invention, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (Ia) are 21 and 28, respectively.

[0322] In some optional embodiments of the present invention, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (Ia) are 17 and 20 respectively.

[0323] In some optional embodiments of the present invention, in the structure represented by formula (Ia), the two amino acids Z1 are each independently selected from C, C, αMeC, HoC, Hoc, Pen or N-Me-C.

[0324] In some optional embodiments of the present invention, in the structure represented by formula (Ia), the two amino acids Z1 are each independently selected from C, C, αMeC or HoC.

[0325] In some optional embodiments of the present invention, in the structure shown in formula (Ia), both amino acids Z1 are C.

[0326] In some optional embodiments of the present invention, in the structure shown in formula (Ia), both amino acids Z1 are c.

[0327] In some optional embodiments of the present invention, in the structure shown in formula (Ia), both amino acids Z1 are αMeC.

[0328] In some optional embodiments of the present invention, in the structure represented by formula (Ia), both amino acids Z1 are HoC.

[0329] In some optional embodiments of the present invention, the positions of the two amino acids Z2 containing -NH2 in the side chain of the structure shown in formula (Ia) are 21 and 28 respectively.

[0330] In some optional embodiments of the present invention, the positions of the two amino acids Z2 whose side chains contain -NH2 in the structure represented by formula (Ia) are 17 and 20 respectively.

[0331] In some optional embodiments of the present invention, in the structure represented by formula (Ia), the two amino acids Z2 are each independently selected from K, k, αMeK, HoK, Dap, Dab, Orn or N-Me-K.

[0332] In some optional embodiments of the present invention, in the structure represented by formula (Ia), the two amino acids Z2 are each independently selected from K or Orn.

[0333] In some optional embodiments of the present invention, in the structure shown in formula (Ia), both amino acids Z2 are K.

[0334] In some optional embodiments of the present invention, in the structure shown in formula (Ia), both amino acids Z2 are Orn.

[0335] According to an embodiment of the present invention, the polypeptide represented by formula (I) or its derivative has a structure represented by formula (Ib):

[0336] X1X2X3GTX6TSDYX 11 X 12 X 13 LDX 16 X 17 X 18 X 19 X 20 X 21 FX 23 X 24 X 25 LLX 28 GGPSSGGPPPS (Ib).

[0337] In some optional embodiments of the present invention, in the structure represented by formula (Ib), X1 is Y or H.

[0338] In some optional embodiments of the present invention, in the structure represented by formula (Ib), X2 is Aib or Ac4c.

[0339] In some optional embodiments of the present invention, in the structure represented by formula (Ib), X3 is Q or H.

[0340] In some optional embodiments of the present invention, in the structure represented by formula (Ib), X6 is F or F(2-F).

[0341] In some optional embodiments of the present invention, in the structure shown in formula (Ib), X 11 is S or αMeS.

[0342] In some optional embodiments of the present invention, in the structure shown in formula (Ib), X 12It is K or I.

[0343] In some optional embodiments of the present invention, in the structure shown in formula (Ib), X 13 is αMeL, Y or Iva.

[0344] In some optional embodiments of the present invention, in the structure shown in formula (Ib), X 16 is K or αMeK.

[0345] In some optional embodiments of the present invention, in the structure shown in formula (Ib), X 17 is C or K(Ac).

[0346] In some optional embodiments of the present invention, in the structure shown in formula (Ib), X 18 A or Y.

[0347] In some optional embodiments of the present invention, in the structure shown in formula (Ib), X 19 For Q or A.

[0348] In some optional embodiments of the present invention, in the structure shown in formula (Ib), X 20 It is Aib or Q.

[0349] In some optional embodiments of the present invention, in the structure shown in formula (Ib), X 21 It is D or C.

[0350] In some optional embodiments of the present invention, in the structure shown in formula (Ib), X 23 I or V.

[0351] In some optional embodiments of the present invention, in the structure shown in formula (Ib), X 24 E or C.

[0352] In some optional embodiments of the present invention, in the structure shown in formula (Ib), X 25 W or Y.

[0353] In some optional embodiments of the present invention, in the structure shown in formula (Ib), X 28 E or C.

[0354] In some optional embodiments of the present invention, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (Ib) are 17 and 24, or 21 and 28, respectively.

[0355] In some optional embodiments of the present invention, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (Ib) are 17 and 24, respectively.

[0356] In some optional embodiments of the present invention, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (Ib) are 21 and 28, respectively.

[0357] In some optional embodiments of the present invention, in the structure represented by formula (Ib), the two amino acids Z1 are each independently selected from C, C, αMeC, HoC, Hoc, Pen or N-Me-C.

[0358] In some optional embodiments of the present invention, in the structure shown in formula (Ib), the two amino acids Z1 are each independently selected from C, C, αMeC or HoC.

[0359] In some optional embodiments of the present invention, in the structure shown in formula (Ib), both amino acids Z1 are C.

[0360] In some optional embodiments of the present invention, in the structure shown in formula (Ib), both amino acids Z1 are c.

[0361] In some optional embodiments of the present invention, in the structure shown in formula (Ib), both amino acids Z1 are αMeC.

[0362] In some optional embodiments of the present invention, in the structure shown in formula (Ib), both amino acids Z1 are HoC.

[0363] According to an embodiment of the present invention, the polypeptide represented by formula (I) or its derivative has a structure represented by formula (II):

[0364] The polypeptide represented by formula (I) or its derivative has the structure represented by formula (II):

[0365] X1X2X3GTX6X7X8DX 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 FX 23 X 24 X 25 LX 27 X 28 X 29 X 30 PX 32 SX 34 X 35 PPPX 39 (II).

[0366] In some optional embodiments of the present invention, in the structure shown in formula (II), X 10 Y, C, L or 4-Pal.

[0367] In some optional embodiments of the present invention, in the structure shown in formula (II), X 13 is Y, L, A, αMeL, Q, Aib or Iva.

[0368] In some optional embodiments of the present invention, in the structure shown in formula (II), X 14 is C, L, K(Ac), HoL, Npg or Tle.

[0369] In some optional embodiments of the present invention, in the structure shown in formula (II), X 18 A, R or Y.

[0370] In some optional embodiments of the present invention, in the structure shown in formula (II), X 21 is C, D, A, L or Aib.

[0371] In some optional embodiments of the present invention, in the structure shown in formula (II), X 24 It is Q, C or E.

[0372] In some optional embodiments of the present invention, in the structure shown in formula (II), X 25 W or Y.

[0373] In some optional embodiments of the present invention, in the structure shown in formula (II), X 28 A, D, E, C or HoC.

[0374] In some optional embodiments of the present invention, in the structure shown in formula (II), X 32 It is S or P.

[0375] In some optional embodiments of the present invention, the positions of the two amino acids Z1 containing -SH in the side chain in the structure represented by formula (II) are respectively one of the following combinations:

[0376] i and i+3, i is 17;

[0377] i and i+4, i is 10;

[0378] i and i+7, i is 10, 14, 17 or 21; or

[0379] i and i+11, i is 10 or 17.

[0380] In some optional embodiments of the present invention, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (II) are 14 and 21 respectively.

[0381] In some optional embodiments of the present invention, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (II) are 17 and 20 respectively.

[0382] In some optional embodiments of the present invention, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (II) are 10 and 14 respectively.

[0383] In some optional embodiments of the present invention, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (II) are 10 and 17 respectively.

[0384] In some optional embodiments of the present invention, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (II) are 17 and 24 respectively.

[0385] In some optional embodiments of the present invention, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (II) are 21 and 28, respectively.

[0386] In some optional embodiments of the present invention, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (II) are 10 and 21 respectively.

[0387] In some optional embodiments of the present invention, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (II) are 17 and 28 respectively.

[0388] In some optional embodiments of the present invention, in the structure represented by formula (II), the two amino acids Z1 are each independently selected from C, C, αMeC, HoC, Hoc, Pen or N-Me-C.

[0389] In some optional embodiments of the present invention, in the structure represented by formula (II), the two amino acids Z1 are each independently selected from C, C, αMeC or HoC.

[0390] In some optional embodiments of the present invention, in the structure shown in formula (II), both amino acids Z1 are C.

[0391] In some optional embodiments of the present invention, in the structure shown in formula (II), both amino acids Z1 are c.

[0392] In some optional embodiments of the present invention, in the structure shown in formula (II), both amino acids Z1 are αMeC.

[0393] In some optional embodiments of the present invention, in the structure shown in formula (II), both amino acids Z1 are HoC.

[0394] According to an embodiment of the present invention, the polypeptide represented by formula (I) or its derivative has a structure represented by formula (III):

[0395] X1-Aib-X3GTX6TSDYSX 12 X 13 CCX 15 X 16 X 17 X 18 X 19 X 20 CCFX 23 X 24 X 25 LLX 28 X 29 X 30 PSSGX 35 PPPS (III).

[0396] In some optional embodiments of the present invention, in the structure represented by formula (III), X1 is Y or H.

[0397] In some optional embodiments of the present invention, in the structure represented by formula (III), X3 is Q or H, preferably H.

[0398] In some optional embodiments of the present invention, in the structure represented by formula (III), X6 is F or F(2-F), preferably F.

[0399] In some optional embodiments of the present invention, in the structure shown in formula (III), X 12 It is K or I, preferably I.

[0400] In some optional embodiments of the present invention, in the structure shown in formula (III), X 13 It is Y or L, preferably Y.

[0401] In some optional embodiments of the present invention, in the structure shown in formula (III), X 15 It is D or E, preferably E.

[0402] In some optional embodiments of the present invention, in the structure shown in formula (III), X 16 It is K or E, preferably K.

[0403] In some optional embodiments of the present invention, in the structure shown in formula (III), X 17 is R, K or Q, preferably R.

[0404] In some optional embodiments of the present invention, in the structure shown in formula (III), X 18 is A, R or Y, preferably Y.

[0405] In some optional embodiments of the present invention, in the structure shown in formula (III), X 19 A or Q, preferably A.

[0406] In some optional embodiments of the present invention, in the structure shown in formula (III), X 20 It is Q, K or Aib, preferably Aib.

[0407] In some optional embodiments of the present invention, in the structure shown in formula (III), X 24 It is Q or E, preferably Q.

[0408] In some optional embodiments of the present invention, in the structure shown in formula (III), X 25 It is W or Y, preferably W.

[0409] In some optional embodiments of the present invention, in the structure shown in formula (III), X 28 A, D or E, preferably E.

[0410] In some optional embodiments of the present invention, in the structure shown in formula (III), X 35 A or Q, preferably A.

[0411] In some optional embodiments of the present invention, X1 is Y or H; X3 is Q or H; X6 is F or F(2-F); 12 K or I; X 13 Y or L; X 15 D or E; X 16 K or E; X 17 R, K or Q; X 18 A, R or Y; X 19 A or Q; X 20 Q, K or Aib; X 23 V or I; X 24 Q or E; X 25 W or Y; X 28 A, D or E; X 29 G or H; X 30 G or H; X 35 It is A or Q.

[0412] In some optional embodiments of the present invention, X1 is Y or H, X3 is H; X6 is F or F(2-F), X 12 I; X 13 is Y; X15 E; X 16 K; X 17 R; X 18 is Y; X 19 A; X 20 Aib;X 23 V or I; X 24 Q; X 25 W; X 28 E; X 29 G or H; X 30 G or H; X 35 It is A.

[0413] According to an embodiment of the present invention, the polypeptide represented by formula (I) or its derivative has a structure represented by formula (IV):

[0414] X1X2X3GT-F(2-F)-TSDYX 11 IX 13 LDKCAX 19 CAFIEYLLX 28 GGPSSGAPPPS (IV).

[0415] In some optional embodiments of the present invention, in the structure represented by formula (IV), X1 is Y or H, preferably Y.

[0416] In some optional embodiments of the present invention, in the structure represented by formula (IV), X2 is Aib.

[0417] In some optional embodiments of the present invention, in the structure represented by formula (IV), X3 is Q or H, preferably Q.

[0418] In some optional embodiments of the present invention, in the structure shown in formula (IV), X 13 It is L or αMeL, preferably αMeL.

[0419] In some optional embodiments of the present invention, in the structure shown in formula (IV), X 19 It is Q or H, preferably Q.

[0420] In some optional embodiments of the present invention, in the structure shown in formula (IV), X 28 A or E, preferably A.

[0421] In some optional embodiments of the present invention, X1 is Y or H, X2 is Aib, s, Ac4c or V, X3 is Q or H, X 11 is S or αMeS, X 13 is L or αMeL, X 19 Q or H, X 28A or E.

[0422] In some optional embodiments of the present invention, X1 is Y; X2 is Aib; X3 is Q; X 11 is S or αMeS; X 13 is αMeL; X 19 Q; X 28 It is A.

[0423] According to an embodiment of the present invention, the polypeptide represented by formula (I) or its derivative has a structure represented by formula (V):

[0424] X1-Aib-X3GTX6TSDYSX 12 X 13 LX 15 KCX 18 X 19 X 20 X 21 FX 23 CX 25 LLX 28 GGPSSGAPPPS (V).

[0425] In some optional embodiments of the present invention, in the structure represented by formula (V), X1 is Y or H.

[0426] In some optional embodiments of the present invention, in the structure represented by formula (V), X3 is Q or H.

[0427] In some optional embodiments of the present invention, in the structure represented by formula (V), X6 is F or F(2-F), preferably F.

[0428] In some optional embodiments of the present invention, in the structure shown in formula (V), X 12 It is K or I.

[0429] In some optional embodiments of the present invention, in the structure shown in formula (V), X 13 It is Y, L or A, preferably Y or L.

[0430] In some optional embodiments of the present invention, in the structure shown in formula (V), X 15 It is D or E, preferably D.

[0431] In some optional embodiments of the present invention, in the structure shown in formula (V), X 18 A or Y.

[0432] In some optional embodiments of the present invention, in the structure shown in formula (V), X 19 It is A or Q.

[0433] In some optional embodiments of the present invention, in the structure shown in formula (V), X 20 is Q, Aib, H or R, preferably Q or Aib.

[0434] In some optional embodiments of the present invention, in the structure shown in formula (V), X 21 It is D, A or L, preferably D or A.

[0435] In some optional embodiments of the present invention, in the structure shown in formula (V), X 25 W or Y.

[0436] In some optional embodiments of the present invention, in the structure shown in formula (V), X 28 A or E, preferably E.

[0437] In some optional embodiments of the present invention, X1 is Y or H, X3 is Q or H, X6 is F or F(2-F), X 12 K or I, X 13 Y, L or A, X 15 D or E, X 18 A or Y, X 19 A or Q, X 20 is Q, Aib, H or R, X 21 is D, A or L, X 25 W or Y, X 28 A or E.

[0438] In some optional embodiments of the present invention, X1 is Y or H; X3 is Q or H; X6 is F; X 12 K or I; X 13 Y or L; X 15 D; X 18 A or Y; X 19 A or Q; X 20 Q or Aib; X 21 D or A; X 25 W or Y; X 28 For E.

[0439] According to an embodiment of the present invention, the polypeptide represented by formula (I) or its derivative has a structure represented by formula (VI):

[0440] Y-Aib-QGTFTSDYSILLDKZ1AQH-Aib-FIEYLLZ1GGPSSGAPPPS (VI).

[0441] In some optional embodiments of the present invention, two Z1 are each independently selected from C or HoC.

[0442] In some optional embodiments of the present invention, both Z1 are C.

[0443] In some optional embodiments of the present invention, both Z1 are HoCs.

[0444] According to an embodiment of the present invention, the polypeptide represented by formula (I) or its derivative has a structure represented by formula (VII):

[0445] X1X2X3GTX6TX8DX 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 Z1X 22 X 23 X 24 X 25 LX 27 Z1GGPX 32 SX 34 X 35 PPPS (VII).

[0446] In some optional embodiments of the present invention, in the structure represented by formula (VII), X1 is Y or H.

[0447] In some optional embodiments of the present invention, in the structure represented by formula (VII), X2 is Aib, s or Ac4c.

[0448] In some optional embodiments of the present invention, in the structure shown in formula (VII), X 10 It is Y, L or 4-Pal, preferably Y or 4-Pal.

[0449] In some optional embodiments of the present invention, in the structure shown in formula (VII), X 11 For S.

[0450] In some optional embodiments of the present invention, in the structure shown in formula (VII), X 12 It is K or I.

[0451] In some optional embodiments of the present invention, in the structure shown in formula (VII), X 13 It is Y, L, αMeL, Q, Aib or Iva, preferably Y, L, αMeL, Q or Iva.

[0452] In some optional embodiments of the present invention, in the structure shown in formula (VII), X 14is L, K(Ac), HoL, Npg or Tle.

[0453] In some optional embodiments of the present invention, in the structure shown in formula (VII), X 15 It is D or E.

[0454] In some optional embodiments of the present invention, in the structure shown in formula (VII), X 16 is K(Ac), K, αMeK or E.

[0455] In some optional embodiments of the present invention, in the structure shown in formula (VII), X 17 is R, K, K(Ac), Q or I.

[0456] In some optional embodiments of the present invention, in the structure shown in formula (VII), X 18 is A, R or Y, preferably Y or A.

[0457] In some optional embodiments of the present invention, in the structure shown in formula (VII), X 19 It is A, Q or Aib.

[0458] In some optional embodiments of the present invention, in the structure shown in formula (VII), X 20 It is Q, K, Aib, H, a or C, preferably Aib, a, H or Q.

[0459] In some optional embodiments of the present invention, in the structure shown in formula (VII), X 22 It is F or HoF, preferably F.

[0460] In some optional embodiments of the present invention, in the structure shown in formula (VII), X 24 It is Q or E.

[0461] In some optional embodiments of the present invention, in the structure shown in formula (VII), X 25 W or Y.

[0462] In some optional embodiments of the present invention, in the structure shown in formula (VII), X 32 It is S or P, preferably S.

[0463] In some optional embodiments of the present invention, in the structure shown in formula (VII), X 35 A or K, preferably A.

[0464] In some optional embodiments of the present invention, in the structure represented by formula (VII), two Z1 are independently selected from C, C, HoC or αMeC.

[0465] In some optional embodiments of the present invention, in the structure represented by formula (VII), both Z1 are C.

[0466] In some optional embodiments of the present invention, in the structure represented by formula (VII), both Z1 are c.

[0467] In some optional embodiments of the present invention, in the structure represented by formula (VII), both Z1 are HoC.

[0468] In some optional embodiments of the present invention, in the structure represented by formula (VII), both Z1 are αMeC.

[0469] In some optional embodiments of the present invention, X1 is Y or H; X2 is Aib, s or Ac4c; X3 is Q, H or Dab(Ac); X6 is F, F(2-F) or αMeF; X8 is S, HoS or αMeS; X 10 Y, L or 4-Pal; X 11 S; X 12 K or I; X 13 is Y, L, αMeL, Q, Aib or Iva; X 14 is L, K(Ac), HoL, Npg or Tle; X 15 D or E; X 16 is K(Ac), K, αMeK or E; X 17 is R, K, K(Ac), Q or I; X 18 A, R or Y; X 19 A, Q or Aib; X 20 is Q, K, Aib, H, a or C; X 21 is C, C, HoC or αMeC; X 22 F or HoF; X 23 V or I; X 24 Q or E; X 25 W or Y; X 27 L, K or I; X 28 is C, C, HoC or αMeC; X 32 S or P; X 34 G or Aib; X 35 It is A or K.

[0470] In some optional embodiments of the present invention, X1 is Y or H; X2 is Aib, s or Ac4c; X3 is Q, H or Dab(Ac); X6 is F, F(2-F) or αMeF; X8 is S, HoS or αMeS; X 10 Y or 4-Pal; X 11 S; X 12 K or I; X13 is Y, L, αMeL, Q or Iva; X 14 is L, K(Ac), HoL, Npg or Tle; X 15 D or E; X 16 is K(Ac), K, αMeK or E; X 17 is R, K, K(Ac), Q or I; X 18 is Y or A; X 19 A, Q or Aib; X 20 is Q, K, Aib, H, a or C; X 21 is C, C, HoC or αMeC; X 22 F; X 23 V or I; X 24 Q or E; X 25 W or Y; X 27 L, K or I; X 28 is C, C, HoC or αMeC; X 34 G or Aib; X 32 S; X 35 It is A.

[0471] According to an embodiment of the present invention, the polypeptide represented by formula (I) or its derivative has a structure represented by formula (VIII):

[0472] YX2QGTX6TSDYSIX 13 LDX 16 X 17 AQX 20 X 21 FIEYLLX 28 GGPSSGAPPPS (VIII).

[0473] In some optional embodiments of the present invention, in the structure represented by formula (VIII), X2 is Aib or Ac4c.

[0474] In some optional embodiments of the present invention, in the structure represented by formula (VIII), X6 is F(2-F) or F.

[0475] In some optional embodiments of the present invention, in the structure shown in formula (VIII), X 13 It is αMeL, Q or L.

[0476] In some optional embodiments of the present invention, in the structure shown in formula (VIII), X 16 is αMeK or K.

[0477] In some optional embodiments of the present invention, in the structure shown in formula (VIII), X 17is K(Ac) or K.

[0478] In some optional embodiments of the present invention, in the structure shown in formula (VIII), X 20 It is Aib or K.

[0479] In some optional embodiments of the present invention, in the structure shown in formula (VIII), X 21 It is K or A.

[0480] In some optional embodiments of the present invention, in the structure shown in formula (VIII), X 28 It is K or A.

[0481] In some optional embodiments of the present invention, the positions of the two amino acids Z2 whose side chains contain -NH2 in the structure represented by formula (VIII) are 17 and 20, or 21 and 28, respectively.

[0482] In some optional embodiments of the present invention, the positions of the two amino acids Z2 containing -NH2 in the side chains in the structure represented by formula (VIII) are 17 and 20 respectively.

[0483] In some optional embodiments of the present invention, the positions of the two amino acids Z2 containing -NH2 in the side chains in the structure represented by formula (VIII) are 21 and 28 respectively.

[0484] In some optional embodiments of the present invention, in the structure represented by formula (VIII), the two amino acids Z2 are each independently selected from K, k, αMeK, HoK, Dap, Dab, Orn or N-Me-K, preferably K or Orn.

[0485] In some optional embodiments of the present invention, in the structure represented by formula (VIII), both amino acids Z2 are K.

[0486] In some optional embodiments of the present invention, in the structure shown in formula (VIII), both amino acids Z2 are Orn.

[0487] According to an embodiment of the present invention, the polypeptide represented by formula (I) or its derivative has a structure represented by formula (IX):

[0488] Y-Aib-QGTX6TSDYSI-αMeL-LDX 16 -K(Ac)-AQ-Aib-Z2FIEYLLZ2GGPSSGAPPPS (IX).

[0489] In some optional embodiments of the present invention, in the structure represented by formula (IX), X6 is F(2-F).

[0490] In some optional embodiments of the present invention, in the structure shown in formula (IX), X 16 is αMeK or K.

[0491] In some optional embodiments of the present invention, in the structure shown in formula (IX), two Z2 are independently selected from K or Orn;

[0492] In some optional embodiments of the present invention, in the structure shown in formula (IX), both Z2 are K;

[0493] In some optional embodiments of the present invention, in the structure represented by formula (IX), both Z2 are Orn.

[0494] According to an embodiment of the present invention, the polypeptide represented by formula (I) or its derivative has a structure represented by formula (X):

[0495] YX2QGTX6TSDYSIX 13 LDKKAQKAFIEYLLAGGPSSGAPPPS (X).

[0496] In some optional embodiments of the present invention, in the structure represented by formula (X), X2 is Aib or Ac4c.

[0497] In some optional embodiments of the present invention, in the structure represented by formula (X), X6 is F(2-F) or F.

[0498] In some optional embodiments of the present invention, in the structure shown in formula (X), X 13 It is αMeL, Q or L.

[0499] According to an embodiment of the present invention, the polypeptide represented by formula (I) or its derivative has at least one of the following structures:

[0500] Y-Aib-QGTFTSDYSKYCDKRAAQCFVQWLLAGGPSSGAPPPS;

[0501] Y-Aib-QGTFTSDYSKYCDEKRAKCFVQWLLDHPSSGQPPPS;

[0502] Y-Aib-QGTFTSDCSKYCDERAAQDFVQWLLAGGPSSGAPPPS;

[0503] Y-Aib-QGTFTSDCSKYLDECAAQDFVQWLLAGGPSSGAPPPS;

[0504] <h2 style=";text-align:left;direction:ltr">Y-Aib-QGTFTSDCSKYLDERAAQCFVQWLLAGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0505] <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDYSIYCEKKYAQCFVQWLLAGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0506] <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDYSIYCEKRYAQCFVQWLLAGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0507] <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDYSIYCEKRYA-Aib-CFVQWLLEGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0508] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSKYLDKCAAQDFVCWLLAGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0509] <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDYSKYLDKCYAQDFVCWLLEGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0510] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSILLDKCAQHAFICYLLEGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0511] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSILLDKCAQ-Aib-AFICYLLEGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0512] <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDYSRALEKCAARLFICWLLEGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0513] <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDYSKYLE-K(Ac)-KYA-Aib-CFVQWLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0514] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0515] <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDLSKL-K(Ac)-EEQRQ-Aib-CFIEWLKCGGPPS-Aib-KPPPK;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0516] <h2 style=";text-align:left;direction:ltr"> H-Aib-QGTFTSDLSKQ-K(Ac)-DEQRAKCFIEWLICGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0517] <h2 style=";text-align:left;direction:ltr">H-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0518] <h2 style=";text-align:left;direction:ltr"> (3-iodo-Y)-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0519] <h2 style=";text-align:left;direction:ltr"> (4-Pal)-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0520] <h2 style=";text-align:left;direction:ltr"> (4-amino-F)-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0521] <h2 style=";text-align:left;direction:ltr"> Ys-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0522] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-αMeF-TSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0523] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFT-HoS-DYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0524] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-HoL-DK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0525] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-Npg-DK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0526] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-Tle-DK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0527] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEWLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0528] <h2 style=";text-align:left;direction:ltr">Y-Aib-QGTFTSDYSILLDK-K(Ac)-AQ-Aib-CFIEWLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0529] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-LDKQAQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0530] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-a-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0531] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQHCFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0532] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQQCFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0533] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-A-Aib-QCFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0534] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-LDKRAQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0535] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-LEK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0536] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-L-Aad-KK(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0537] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSD-4-Pal-SI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0538] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFT-αMeS-DYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0539] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0540] <h2 style=";text-align:left;direction:ltr"> Y-Aib-Dab(Ac)-GTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0541] <h2 style=";text-align:left;direction:ltr"> Y-Aib-HGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0542] <h2 style=";text-align:left;direction:ltr"> Y-Ac4c-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0543] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSILLDKCAQH-Aib-FIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0544] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSILLDK-HoC-AQH-Aib-FIEYLL-HoC-GGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0545] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDYSILLDKCAQQAFICYLLAGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0546] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDYSILLDKQAQQCFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0547] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDYSI-Aib-LDK-K(Ac)-AQQCFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0548] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDYSILCDKQAQQCFIEYLLAGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0549] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDYSILLD-αMeK-K(Ac)-AQQCFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0550] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDYSILLD-αMeK-K(Ac)-AQ-Aib-CFIEYLICGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0551] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDYSI-Iva-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0552] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDY-αMeS-ILLD-αMeK-K(Ac)-AQQCFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0553] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LD-αMeK-K(Ac)-AQQCFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0554] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LD-αMeK-K(Ac)-AQQC-HoF-IEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0555] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKCAQCAFIEYLLAGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0556] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDYSI-Iva-LDKCAQCAFIEYLLAGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0557] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDY-αMeS-I-αMeL-LD-αMeK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0558] <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDY-αMeS-I-αMeL-LD-αMeK-CAQCAFIEYLLAGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0559] <h2 style=";text-align:left;direction:ltr"> H-Aib-HGT-F(2-F)-TSDYSIYLE-K(Ac)-KYA-Aib-CFVQWLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0560] <h2 style=";text-align:left;direction:ltr"> H-Aib-HGT-F(2-F)-TSDYSIQ-K(Ac)-EEIAQ-Aib-CFIEWLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0561] <h2 style=";text-align:left;direction:ltr"> H-Aib-HGT-F(2-F)-TSDYSIY-K(Ac)-EERAQ-Aib-CFIEWLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0562] <h2 style=";text-align:left;direction:ltr"> H-Aib-HGT-F(2-F)-TSDYSI-Iva-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;<h2 style=";text-align:left;direction:ltr">

[0563] Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKCAHCAFIEYLLAGGPSSGAPPPS;

[0564] Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKCA-K(Ac)-CAFIEYLLAGGPSSGAPPPS;

[0565] Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKCAQCAFIEYLLAGGPSSGAPPPS;

[0566] H-Aib-HGT-F(2-F)-TSDYSI-αMeL-LDKCAQCAFIEYLLAGGPSSGAPPPS;

[0567] Ys-QGT-F(2-F)-TSDYSI-αMeL-LDKCAQCAFIEYLLAGGPSSGAPPPS;

[0568] Y-Aib-QGTFTSDSDYSILLDKQAQQCFIEYLLCGGPSSGAPPPS;

[0569] Y-Ac4c-QGT-F(2-F)-TSDYSILLDKCAQCAFIEYLLEGGPSSGAPPPS;

[0570] Y-Ac4c-QGT-F(2-F)-TSDYSILLDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;

[0571] H-Ac4c-HGT-F(2-F)-TSDYSIQLEEIAQ-Aib-CFIEYLLCGGPSSGAPPPS?

[0572] Y-Aib-QGTFTSDSDYSILLDK-K(Ac)-AQ-Aib-c-FIEYLL-c-GGPSSGAPPPS\

[0573] Y-Aib-QGTFTSDSDYSILLDK-K(Ac)-AQ-Aib-Hoc-FIEYLL-Hoc-GGPSSGAPPPS;

[0574] Y-Aib-QGTFTSDYSILLDK-K(Ac)-AQ-Aib-αMeC-FIEYLL-αMeC-GGPSSGAPPPS;

[0575] Y-Aib-QGT-F(2-F)-TSDYSIQLDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS;

[0576] Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LD-αMeK-K(Ac)-AQ-Aib-KFIEYLLKGGPSSGAPPPS;

[0577] Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-KFIEYLLKGGPSSGAPPPS;

[0578] Y-Aib-QGTFTSDYSILLDK-K(Ac)-AQ-Aib-Orn-FIEYLL-Orn-GGPSSGAPPPS;

[0579] Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKKAQKAFIEYLLAGGPSSGAPPPS;

[0580] Y-Aib-QGT-F(2-F)-TSDYSIQLDKKAQKAFIEYLLAGGPSSGAPPPS;

[0581] Y-Aib-QGTFTSDYSILLDKKAQKAFIEYLLAGGPSSGAPPPS;

[0582] Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKKAQKAFIEYLLAGGPSSGAPPPS.

[0583] It should be noted that the “-” between amino acids in the above polypeptide represents an amide bond; for example, the “-” in “Y-Aib-Q” represents an amide bond.

[0584] Herein, "(3-iodo-Y)" refers to 3-iodo-Y, "(4-Pal)" refers to 4-Pal, and the aforementioned "(4-amino-F)" refers to 4-amino-F. The "-" in F(2-F), (3-iodo-Y), (4-Pal), and (4-amino-F) does not indicate an amide bond.

[0585] According to an embodiment of the present invention, a modifying group is further included.

[0586] According to an embodiment of the present invention, the modifying group is connected to one or two amino acids Z1 with -SH side chains, or one or two amino acids Z2 with -NH2 side chains in the polypeptide represented by formula (I) or its derivatives.

[0587] According to an embodiment of the present invention, the modifying group is simultaneously connected to the two amino acids Z1 containing -SH in the side chain of the polypeptide represented by formula (I) or its derivative; or

[0588] The modifying group is simultaneously connected to the two amino acids Z2 containing -NH2 on the side chains in the polypeptide represented by formula (I) or its derivatives.

[0589] According to an embodiment of the present invention, the modifying group is connected to the -SH group of the amino acid C side chain via a sulfur-carbon bond.

[0590] According to an embodiment of the present invention, the modifying group is connected to the ε-amino group of the side chain of amino acid K via an amide bond.

[0591] According to an embodiment of the present invention, the modifying group has a structure shown in formula (XI):

[0592] Among them, R1 is C, N, -C 3～10 Heteroalkylene, -C 6～10 Arylene or -C 5～10 heteroarylene;

[0593] R2 and R3 are each independently optionally replaced by one or more R 1a Substituted -C 1～6 Alkylene-, optionally one or more R 1a Substituted-NH-C(O)-C 1～6 Alkylene- or optionally one or more R 1a Substituted -C 1～6 Alkylene-NH-C(O)-C 1～6 Alkylene-, wherein each R 1a are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy;

[0594] R4 is empty or optionally replaced by one or more R 2a Substituted -C 1～6 Alkylene-NH-C(O)-C 1～6 Alkylene-, wherein each R 2a are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy;

[0595] R5 is H, -C 1～6 Alkoxy or -C 1～6 Alkyl, wherein the -C 1～6 Alkyl and -C 1～6 Each alkoxy group is independently optionally substituted with one or more halogen, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN;

[0596] R6 is optionally replaced by one or more R 3a Substituted -C 1～6 Alkylene-, or optionally one or more R 3a Substituted-(C 1～3 Alkylene-O) m1 -C 1～6 Alkylene-, wherein each R 3a are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy;

[0597] R7 is optionally replaced by one or more R 4a Substituted -C 1～6 Alkylene-, wherein each R 4a are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy;

[0598] R8 is optionally replaced by one or more R 5a Substituted -C 10～20 Alkyl, optionally substituted by one or more R 5a Substituted -C 10～20 Alkylene-R9, optionally replaced by one or more R 5a Substituted -C 5～10 Alkylene-OC 6～10 Arylene-R9, or optionally one or more R 5a Substituted -C 5～10 Alkylene-OC 5～10 Heteroarylene-R9, wherein each R 5a are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6Haloalkyl or -C 1～6 alkoxy;

[0599] R9 is -COOH, -C 3～7 heteroaryl, -S(O)2OH, or -PO(OH)2;

[0600] m1 is any integer from 1 to 6;

[0601] n1 is any integer from 0 to 6;

[0602] n2 is any integer from 1 to 10.

[0603] It should be noted that the “-” in the modifying group in the present invention represents a chemical bond connecting chemical groups, such as a covalent bond between atoms (or atoms in a group) and atoms (or atoms in a group).

[0604] According to an embodiment of the present invention, R1 is C, N, -C 5～7 Heteroalkylene, -C 5～7 Arylene or -C 5～7 Heteroarylene.

[0605] According to an embodiment of the present invention, R1 is N, N, N, N-phenylene or pyridylene.

[0606] According to an embodiment of the present invention, R1 is

[0607] According to an embodiment of the present invention, R2 and R3 are each independently -C 1～6 Alkylene-, or -C 1～6 Alkylene-NH-C(O)-C 1～6 Alkylene-.

[0608] According to an embodiment of the present invention, R2 and R3 are each independently -C 1～3 Alkylene-, or -C 1～3 Alkylene-NH-C(O)-C 1～3 Alkylene-.

[0609] According to an embodiment of the present invention, each n1 is independently 0, 1, 2, 3, 4 or 5.

[0610] According to an embodiment of the present invention, n1 is 0.

[0611] According to an embodiment of the present invention, R4 is empty, or -C 1～6 Alkylene-NH-C(O)-C 1～6 Alkylene-.

[0612] According to an embodiment of the present invention, R4 is empty, or -C 1～3 Alkylene-NH-C(O)-C1～3 Alkylene-.

[0613] According to an embodiment of the present invention, R5 is H, -C 1～3 Alkoxy or -C 1～3 alkyl.

[0614] According to an embodiment of the present invention, R6 is -C 1～6 Alkylene-, -(C 1～3 Alkylene-O) m1 -C 1～6 Alkylene-.

[0615] According to an embodiment of the present invention, R6 is -C 1～3 Alkylene-, -(C 1～3 Alkylene-O) m1 -C 1～3 Alkylene-.

[0616] According to an embodiment of the present invention, m1 is 2, 3, 4 or 5.

[0617] According to an embodiment of the present invention, R7 is -C 1～6 Alkylene-.

[0618] According to an embodiment of the present invention, R7 is -C 2～4 Alkylene-.

[0619] According to an embodiment of the present invention, R8 is -C 10～20 Alkyl, -C 10～20 Alkylene-R9, -C 5～10 Alkylene-OC 6～10 Arylene-R9, or -C 5～10 Alkylene-OC 5～10 Heteroarylene-R9.

[0620] According to an embodiment of the present invention, R8 is -C 10～18 Alkyl, -C 14～18 Alkylene-R9, or -C 7～9 Alkylene-OC 5～7 Arylene-COOH.

[0621] According to an embodiment of the present invention, R9 is -COOH, -C 5～6 heteroaryl, -S(O)2OH, or -PO(OH)2.

[0622] According to an embodiment of the present invention, R9 is -COOH, -S(O)2OH, -PO(OH)2, or

[0623] According to an embodiment of the present invention, n2 is 1, 2 or 3.

[0624] According to an embodiment of the present invention, n2 is 3, 4, 5 or 6.

[0625] According to an embodiment of the present invention, the modifying group represented by formula (XI) has a structure represented by formula (XIa):

[0626] Among them, each R 10 and R 11 Each independently is -C 0～3 Alkylene-;

[0627] R 12 -C 1～6 Alkylene-;

[0628] R8 is -C 10～21 Alkyl, -C 10～21 Alkylene-COOH, -C 10～21 Alkylene-PO(OH)2, -C 10～21 Alkylene-C 5～6 Heteroaryl, or -C 7～10 Alkylene-OC 5～7 Arylene-COOH;

[0629] q1 is 1, 2, 3, or 4;

[0630] q2 is 1, 2, or 3.

[0631] According to an embodiment of the present invention, in the structure shown in formula (XIa), each R 10 and R 11 Each independently is -C 0～3 Alkylene-;

[0632] R 12 -C 1～6 Alkylene-;

[0633] R8 is -C 14～19 Alkyl or -C 10～19 Alkylene-COOH;

[0634] q1 is 1, 2, 3, or 4;

[0635] q2 is 1, 2, or 3.

[0636] According to an embodiment of the present invention, the modifying group represented by formula (XIa) has one of the following structures:

[0637] According to an embodiment of the present invention, the modifying group represented by formula (XI) has a structure represented by formula (XIb):

[0638] Among them, each R 10 ' and R 11 'Each independently -C 0～3 Alkylene-;

[0639] R 12 ' is -C 1～6 Alkylene-;

[0640] R 13 -C 10～20 Alkylene-, preferably -C 14～18 Alkylene-;

[0641] q1' is 1, 2, 3, or 4;

[0642] q2' is 1, 2 or 3.

[0643] According to an embodiment of the present invention, in the structure shown in formula (XIb), each R 10 ' and R 11 'Each independently -C 0～3 Alkylene-;

[0644] R 12 ' is -C 1～6 Alkylene-;

[0645] R 13 -C 14～18 Alkylene-;

[0646] q1' is 1, 2, 3, or 4;

[0647] q2' is 1, 2 or 3.

[0648] According to an embodiment of the present invention, the modifying group represented by formula (XIb) has one of the following structures:

[0649] According to an embodiment of the present invention, the modifying group represented by formula (XI) has a structure represented by formula (XIc):

[0650] Among them, each R 14 Each independently is -C 1～3 Alkylene- or -NH-C(O)-C 1～3 Alkylene-;

[0651] R 15 -C 0～3 Alkylene-or-C(O)-NH-C 1～3 Alkylene-;

[0652] R12 " is -C 1～6 Alkylene-;

[0653] R 13 ' for -C 10～20 Alkylene-, preferably -C 14～18 Alkylene-;

[0654] q1” is 1, 2, 3, or 4;

[0655] q2” is 1, 2, or 3;

[0656] Y1 is C or N.

[0657] According to an embodiment of the present invention, in the structure shown in formula (XIc), each R 14 Each independently is -C 1～3 Alkylene- or -NH-C(O)-C 1～3 Alkylene-;

[0658] R 15 -C 0～3 Alkylene-or-C(O)-NH-C 1～3 Alkylene-;

[0659] R 12 " is -C 1～6 Alkylene-;

[0660] R 13 ' for -C 14～18 Alkylene-;

[0661] q1” is 1, 2, 3, or 4;

[0662] q2” is 1, 2, or 3;

[0663] Y1 is C or N.

[0664] According to an embodiment of the present invention, the modifying group represented by formula (XIc) has one of the following structures:

[0665] According to an embodiment of the present invention, the polypeptide represented by formula (I) or its derivative contains two amino acids Z1 with -SH side chains, and the modification group has a structure represented by formula (XI).

[0666] According to an embodiment of the present invention, the modifying group has a structure shown in formula (XII):

[0667] Among them, R 20 C, N, -C 6～10 Arylene or -C 5～10 heteroarylene;

[0668] R 21 and R 22 Each is independently empty, optionally replaced by one or more R 1b Substituted -C 1～6 Alkylene-, or optionally one or more R 1b Substituted -C 1～6 Oxyalkylene-, wherein each R 1b are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy;

[0669] R 23 Empty, optionally replaced by one or more R 2b Substituted -C 1～6 Alkylene-, optionally substituted by one or more R 2b Substituted-C(O)-C 1～6 Alkylene-, optionally substituted by one or more R 2b Substituted-NH-C(O)-C 1～6 Alkylene-, or optionally one or more R 2b Substituted -C 1～6 Alkylene-C(O)-NH-C 1～6 Alkylene-, wherein each R 2b are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy;

[0670] R 24 is optionally replaced by one or more R 3b Substituted -C 1～6 Alkylene-, or optionally one or more R 3b Substituted-(C 1～3 Alkylene-O) m2 -C 1～6 Alkylene-, wherein each R 3b are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy;

[0671] R 25 H, -C 1～6 Alkoxy or -C 1～6 Alkyl, wherein the -C1～6 Alkyl and -C 1～6 Each alkoxy group is independently optionally substituted with one or more halogen, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN;

[0672] R 26 is optionally replaced by one or more R 4b Substituted -C 1～6 Alkylene-, wherein each R 4b are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy;

[0673] R 27 is optionally replaced by one or more R 5b Substituted -C 10～20 Alkyl, optionally substituted by one or more R 5b Substituted -C 10～20 Alkylene-R 28 , optionally one or more R 5b Substituted -C 5～10 Alkylene-OC 6～10 Arylene-R 28 , or optionally one or more R 5b Substituted -C 5～10 Alkylene-OC 5～10 Heteroarylene-R 28 , where each R 5b are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy;

[0674] R 28 -COOH, -C 3～7 heteroaryl, -S(O)2OH, or -PO(OH)2;

[0675] m2 is any integer from 1 to 6;

[0676] n3 is any integer from 1 to 10;

[0677] n3 is 0, 1, or 2;

[0678] Y2 is empty or NH.

[0679] According to an embodiment of the present invention, R 20 C, N, -C 5～7 Arylene or -C5～7 Heteroarylene.

[0680] According to an embodiment of the present invention, R 20 is C, N, phenylene or pyridylene.

[0681] According to an embodiment of the present invention, R 20 for Preferably

[0682] According to an embodiment of the present invention, R 21 and R 22 Each is independently empty, -C 1～6 Alkylene-, or -C 1～6 Oxyalkylene-.

[0683] According to an embodiment of the present invention, R 21 and R 22 Each is independently empty or -C 1～3 Alkylene-.

[0684] According to an embodiment of the present invention, R 23 Empty, -C 1～6 Alkylene-, -C 1～6 Alkylene-C(O)-NH-C 1～6 Alkylene-, or -C(O)-C 1～6 Alkylene-.

[0685] According to an embodiment of the present invention, R 23 Empty, -C 1～3 Alkylene-, or -C(O)-C 2～4 Alkylene-.

[0686] According to an embodiment of the present invention, R 24 -C 1～6 Alkylene-, or -(C 1～3 Alkylene-O) m2 -C 1～6 Alkylene-.

[0687] According to an embodiment of the present invention, R 24 -C 1～3 Alkylene-, or -(C 1～3 Alkylene-O) m2 -C 1～3 Alkylene-.

[0688] According to an embodiment of the present invention, m2 is 2, 3, 4 or 5.

[0689] According to an embodiment of the present invention, R 25 H, -C 1～6 Alkoxy or -C1～6 alkyl.

[0690] According to an embodiment of the present invention, R 25 H or -C 1～3 alkyl.

[0691] According to an embodiment of the present invention, R 26 -C 1～6 Alkylene-.

[0692] According to an embodiment of the present invention, R 26 -C 1～3 Alkylene-.

[0693] According to an embodiment of the present invention, R 27 -C 10～20 Alkyl, -C 10～20 Alkylene-R 28 、-C 5～10 Alkylene-OC 6～10 Arylene-R 28 , or -C 5～10 Alkylene-OC 5～10 Heteroarylene-R 28 .

[0694] According to an embodiment of the present invention, R 27 -C 10～18 Alkyl, -C 14～18 Alkylene-R 28 , or -C 7～9 Alkylene-OC 5～7 Arylene-COOH.

[0695] According to an embodiment of the present invention, R 28 -COOH, -C 5～6 heteroaryl, -S(O)2OH, or -PO(OH)2.

[0696] According to an embodiment of the present invention, R 28 -COOH, -S(O)2OH, -PO(OH)2, or

[0697] According to an embodiment of the present invention, p is 1, 2 or 3.

[0698] According to an embodiment of the present invention, p is 3, 4, 5 or 6.

[0699] According to an embodiment of the present invention, the modifying group represented by formula (XII) has a structure represented by formula (XIIa):

[0700] Among them, R 27 -C10～20 Alkyl, -C 10～20 Alkylene-COOH, -C 10～20 Alkylene-S(O)2OH, -C 10～20 Alkylene-PO(OH)2, -C 10～20 Alkylene-C 5～6 Heteroaryl, or -C 5～10 Alkylene-OC 6～10 Arylene-COOH;

[0701] Each R 29 Each independently is -C 1～3 Alkylene-;

[0702] R 30 -C(O)-C 1～6 Alkylene-, or -C 1～3 Alkylene-C(O)-NH-C 1～3 Alkylene-;

[0703] R 31 -C 1～6 Alkylene-;

[0704] q3 is 1, 2, 3, or 4;

[0705] q4 is 1, 2, or 3.

[0706] According to an embodiment of the present invention, in the structure represented by formula (XIIa), R 27 -C 12～19 Alkyl, -C 12～19 Alkylene-COOH, or -C 5～10 Alkylene-OC 6～8 Arylene-COOH;

[0707] Each R 29 Each independently is -C 1～3 Alkylene-;

[0708] R 30 -C(O)-C 1～6 Alkylene-, or -C 1～3 Alkylene-C(O)-NH-C 1～3 Alkylene-;

[0709] R 31 -C 1～6 Alkylene-;

[0710] q3 is 1, 2, 3, or 4;

[0711] q4 is 1, 2, or 3.

[0712] According to an embodiment of the present invention, the modifying group represented by formula (XIIa) has one of the following structures:

[0713] According to an embodiment of the present invention, the modifying group represented by formula (XII) has a structure represented by formula (XIIb):

[0714] Among them, R 27 -C 10～20 Alkyl, -C 10～20 Alkylene-COOH, -C 10～20 Alkylene-S(O)2OH, -C 10～20 Alkylene-PO(OH)2, -C 10～20 Alkylene-C 5～6 Heteroaryl, or -C 5～10 Alkylene-OC 6～10 Arylene-COOH;

[0715] Each R 29 'Each independently -C 1～3 Alkylene-;

[0716] R 30 ' for -C 1～6 Alkylene-;

[0717] R 31 ' for -C 1～6 Alkylene-;

[0718] q3' is 1, 2, 3 or 4, preferably 2;

[0719] q4' is 1, 2 or 3, preferably 2.

[0720] According to an embodiment of the present invention, in the structure represented by formula (XIIb), R 27 -C 12～19 Alkyl, or -C 12～19 Alkylene-COOH;

[0721] Each R 29 'Each independently -C 1～3 Alkylene-;

[0722] R 30 ' for -C 1～6 Alkylene-;

[0723] R 31 ' for -C 1～6 Alkylene-;

[0724] q3' is 2;

[0725] q4' is 2.

[0726] According to an embodiment of the present invention, R 27 -C 10～20 Alkylene -COOH or -C 10～20 alkyl.

[0727] According to an embodiment of the present invention, R 27 -C 14～18 Alkylene-COOH.

[0728] According to an embodiment of the present invention, the modifying group represented by formula (XIIb) has one of the following structures:

[0729] According to an embodiment of the present invention, the modifying group represented by formula (XII) has a structure represented by formula (XIIc):

[0730] Among them, R 27 -C 10～20 Alkyl, -C 10～20 Alkylene-COOH, -C 10～20 Alkylene-S(O)2OH, -C 10～20 Alkylene-PO(OH)2, -C 10～20 Alkylene-C 5～6 Heteroaryl, or -C 5～10 Alkylene-OC 6～10 Arylene-COOH;

[0731] R 30 " is -C 1～6 Alkylene-;

[0732] R 31 " is -C 1～6 Alkylene-;

[0733] q3 is 1, 2, 3, or 4;

[0734] q4 is 1, 2, or 3.

[0735] According to an embodiment of the present invention, in the structure represented by formula (XIIc), R 27 -C 10～20 Alkylene -COOH or -C 10～20 alkyl;

[0736] R 30 " is -C 1～6 Alkylene-;

[0737] R 31 " is -C 1～6 Alkylene-;

[0738] q3 is 1, 2, 3, or 4;

[0739] q4 is 1, 2, or 3.

[0740] According to an embodiment of the present invention, in the structure represented by formula (XIIc), R 27 -C 14～18 Alkylene -COOH or -C 10～19 alkyl;

[0741] R 30 " is -C 1～6 Alkylene-;

[0742] R 31 " is -C 1～6 Alkylene-;

[0743] q3 is 1, 2, 3, or 4;

[0744] q4 is 1, 2, or 3.

[0745] According to an embodiment of the present invention, the modifying group represented by formula (XIIc) has one of the following structures:

[0746] According to an embodiment of the present invention, the polypeptide represented by formula (I) or its derivative contains two amino acids Z2 with side chains containing -NH2, and the modification group has a structure represented by formula (XIIc).

[0747] In some optional embodiments of the present invention, the polypeptide represented by formula (I) or its derivative has at least one of the structures shown in Table A below:

[0748] Table A

[0749] It should be noted that the "attachment site of the modification group" in Table A is specifically the X i The position of i in .

[0750] Pharmaceutical compositions, uses and methods

[0751] In a second aspect, the present invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises the polypeptide described in the first aspect, or its derivative, or its pharmaceutically acceptable salt. As previously mentioned, the polypeptide, its derivative, or its pharmaceutically acceptable salt exhibits strong agonist activity against the three receptor targets of GLP-1R, GCGR, and GIPR, effectively controlling blood sugar and reducing body weight. Thus, drugs containing the polypeptide, its derivative, or its pharmaceutically acceptable salt can effectively prevent or treat metabolic disorders, bone-related diseases, cardiovascular diseases, and neurodegenerative diseases.

[0752] According to an embodiment of the present invention, the composition further comprises a pharmaceutically acceptable excipient.

[0753] In the third aspect of the present invention, the present invention proposes a use of the polypeptide or its derivatives or pharmaceutically acceptable salts described in the first aspect or the pharmaceutical composition described in the second aspect in the preparation of a drug, wherein the drug is used to treat or prevent at least one of metabolic disorder-related diseases, bone-related diseases, cardiovascular diseases and neurodegenerative diseases.

[0754] According to the embodiments of the present application, the present invention proposes a use of the polypeptide or its derivatives or pharmaceutically acceptable salts described in the first aspect or the pharmaceutical composition described in the second aspect in treating or preventing at least one of metabolic disorder-related diseases, bone-related diseases, cardiovascular diseases and neurodegenerative diseases.

[0755] According to the embodiments of the present application, the present invention proposes a polypeptide or its derivatives or their pharmaceutically acceptable salts as described in the first aspect or the pharmaceutical composition as described in the second aspect, for treating or preventing at least one of metabolic disorder-related diseases, bone-related diseases, cardiovascular diseases and neurodegenerative diseases.

[0756] According to an embodiment of the present invention, the metabolic disorder-related diseases include at least one of obesity, diabetes, dyslipidemia-related diseases, fatty liver disease, metabolic syndrome, metabolic liver disease, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease.

[0757] According to an embodiment of the present invention, the neurodegenerative disease includes at least one of Alzheimer's disease and Parkinson's disease.

[0758] In a fourth aspect, the present invention provides a method for preventing and / or treating metabolic disorders, bone diseases, cardiovascular diseases, and / or neurodegenerative diseases. According to an embodiment of the present invention, the method comprises administering a pharmaceutically acceptable amount of the polypeptide or derivative thereof or a pharmaceutically acceptable salt thereof described in the first aspect, or the pharmaceutical composition described in the second aspect, to a subject. The method of the present invention is effective in preventing and / or treating metabolic disorders, bone diseases, cardiovascular diseases, and / or neurodegenerative diseases.

[0759] According to an embodiment of the present invention, the metabolic disorder-related diseases include at least one of obesity, diabetes, dyslipidemia-related diseases, fatty liver disease, metabolic syndrome, metabolic liver disease, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease.

[0760] According to an embodiment of the present invention, the neurodegenerative disease includes at least one of Alzheimer's disease and Parkinson's disease.

[0761] The effective amount of the polypeptide or derivative thereof, or pharmaceutical composition of the present invention may vary depending on the mode of administration and the severity of the disease to be treated. The preferred effective amount can be determined by one of ordinary skill in the art based on various factors (e.g., through clinical trials). Such factors include, but are not limited to: pharmacokinetic parameters of the active ingredient, such as bioavailability, metabolism, and half-life; the severity of the disease to be treated, the patient's weight, the patient's immune status, the route of administration, and the like. For example, depending on the urgency of the treatment, several divided doses may be administered daily, or the dose may be proportionally reduced.

[0762] The polypeptides or derivatives thereof, or pharmaceutical compositions of the present invention can be incorporated into drugs suitable for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). These drugs can be prepared in various forms. For example, liquid, semisolid and solid dosage forms, including but not limited to liquid solutions (e.g., injection solutions and infusion solutions) or lyophilized powders. Typical drugs are in the form of injection solutions or infusion solutions. The aforementioned polypeptides or derivatives thereof, or pharmaceutical compositions can be administered by intravenous infusion or injection or intramuscular or subcutaneous injection.

[0763] Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific technology or conditions are not indicated, the technology or conditions described in the literature in this area or the product instructions are used.The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained by commercial purchase.

[0764] Example 1: Preparation of a polypeptide or its derivatives

[0765] 1. The linear peptides in peptides 1 to 83 (abbreviated as TG01 to TG83) in Table A were synthesized using the classic Fmoc-tBu solid phase synthesis method. X peptide synthesizer was prepared, and the reaction conditions were as follows:

[0766] (1) Resin swelling: Add Rink Amide MBHA resin to DCM, react with N2 gas at room temperature for 1 hour, filter, and wash the resin with DMF 2-3 times.

[0767] (2) Removal of Fmoc protecting group: Add DMF solution containing 20% ​​piperidine to the above resin, react under N2 bubbling at room temperature for 10 minutes, filter, and repeat the above operation until complete deprotection, and wash the resin with DMF 2-3 times.

[0768] (3) Amino acid coupling: The materials were added in a reaction ratio of resin: amino acid: DIC: Oxyma Pure = 1:5:5:5. The reactants, DIC, and Oxyma Pure were pre-dissolved in DMF and reacted at room temperature with N2 bubbling for 10 minutes. The mixture was then transferred to a resin reaction tank and reacted at room temperature with N2 bubbling for 1-3 hours. After the reaction, the resin was filtered and washed with DMF 2-3 times. After the synthesis, the resin was washed with DCM 2-3 times and vacuum dried to obtain the peptide resin.

[0769] The above method is applicable to include but not limited to the following amino acids (D or L type) or synthetic reagents: Fmoc-AEEA-OH, Fmoc-Aad(tBu)-OH, Fmoc-Ac4c-OH, Fmoc-Aib-OH, Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Dab(Ac)-OH, Fmoc-Dap(Ac)-OH, Fmoc-Gly-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Iva-OH, Fmoc-Leu-OH, Fmoc-Lys(Ac)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Lys(Alloc)-OH, Fmoc-Lys(ivDde)-OH, Fmoc-Met-OH, Fmoc-Nal-OH, Fmoc-Nle-OH, Fmoc-Orn(Boc)-OH, Fmoc-Pal-OH, Fmoc-Pro-OH, Fmoc-Phe-OH, Fmoc-Phe(2-F)-OH, Fmoc-Phe(3-F)-OH, Fmoc-Phe(4-F)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Tle-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Val-OH, Fmoc-α-methyl-Leu-OH, Fmoc-α-methyl-Lys(Boc)-OH, Fmoc-α-methyl-Phe-OH, Fmoc-α-methyl-Phe(2-F)-OH, Fmoc-AEEA-OH, Fmoc-Glu-OtBu, Fmoc-Asp-OtBu, Fmoc-Ida(Allyl)-OH, Boc-L-His(Trt)-OH, Boc-L-Tyr(tBu)-OH, Myristic acid, Myristic acid, Stearic acid, Arachidic acid, Docosanoic acid, 18-(tert-butoxy)-18-oxooctadecanoic acid, 20-(tert-Butoxy)-20-oxoicosanoic acid, etc.

[0770] 2. Linear peptide cleavage and drying: Prepare peptide cleavage solution according to the volume ratio of TFA:TIPS:H2O:EDT=95:2:2:1. Add cleavage solution (10mL / g resin) to the dried peptide resin and shake it on a shaker for 3 hours. Filter the resin residue and add 10 volumes of cold MTBE to the filtrate. Cool the resulting suspension at -20°C for 1 hour and then centrifuge at 3500rpm. Wash the precipitate with cold MTBE 3-5 times and vacuum dry to obtain the crude peptide.

[0771] 3. Purification of linear peptides: The solvent was prepared according to the volume ratio of mobile phase A (0.1% TFA-water): mobile phase B (0.1% TFA-acetonitrile) = 1.5:1. The crude peptide was dissolved in the solvent to prepare a storage solution, filtered using a 0.45 micron filter membrane, and gradient eluted using mobile phase A and mobile phase B at a flow rate of 10 mL / min using a C18 reverse phase preparative column (20*250 mm, particle size 5 μm). The target peak was collected and lyophilized to obtain the target peptide compound (i.e., linear peptide).

[0772] 4. The Staple linker (or modification group A) is prepared using the classic Fmoc-tBu solid-phase synthesis method. This step takes Staple-A1 (or modification group A1) as an example. The reaction conditions are as follows (see Figure 1 for the specific process):

[0773] (1) Resin swelling: Fmoc-L-Lys(ivDde)-2CTC resin was added to DCM and reacted under N2 bubbling at room temperature for 1 hour. The mixture was filtered and the resin was washed with DMF 2-3 times.

[0774] (2) Removal of Fmoc protecting group: Add DMF solution containing 20% ​​piperidine to the above resin, react under N2 bubbling at room temperature for 10 minutes, filter, and repeat the above operation until complete deprotection, and wash the resin with DMF 2-3 times.

[0775] (3) Fatty acid chain coupling: feed materials according to the reaction ratio of resin: fatty acid: HATU: DIPEA = 1:5:5:10, dissolve fatty acid mono-tert-butyl ester, HATU and DIPEA in DMF in advance, react at room temperature with N2 bubbling for 10 minutes, then transfer to the resin reaction tank, react at room temperature with N2 bubbling for 1-3 hours, filter after the reaction, and wash the resin with DMF 2-3 times.

[0776] (4) Removal of the ivDde protecting group: Add a DMF solution containing 5% hydrazine to the resin and react under N2 bubbling at room temperature for 10 minutes. Repeat this operation 2-3 times until it is completely removed. Wash the resin with DMF 2-3 times.

[0777] (5) Coupling of amino acids, AEEA, and bromoacetic acid: The materials were added according to the reaction ratio of resin: Fmoc-AA-OH: DIC: Oxyma Pure = 1:5:5:5. The reactants, DIC, and Oxyma Pure were pre-dissolved in DMF and reacted at room temperature with N2 bubbling for 10 minutes. The mixture was then transferred to a resin reaction tank and reacted at room temperature with N2 bubbling for 1-3 hours. After the reaction, the resin was filtered and washed with DMF 2-3 times. After the synthesis, the resin was washed with DCM 2-3 times and vacuum dried to obtain the linker resin.

[0778] Staple linkers can also be selected from the following structures:

[0779] 5. Coupling of linear peptides with Staple linkers:

[0780] 1.0 equivalent of the linear peptide (i.e., the target peptide compound obtained in step 3, peptide 30 (abbreviated as TG30) in Table A is used as an example in this step) and 1.2 equivalents of the Staple linker (i.e., the Staple linker obtained in step 4) were dissolved in a reaction solution with a volume ratio of PBS:acetonitrile = 1:1.5 (final concentration of 1.2 mM). The pH of the reaction solution was adjusted to 8.0 with 10% NaOH aqueous solution and shaken thoroughly on a shaker at room temperature for 3-8 hours until the linear peptide was completely consumed as detected by LC-MS. The reaction solution was neutralized to pH 6.5 with 5% TFA aqueous solution, filtered through a 0.45 μm filter membrane, and gradient eluted using a C18 reverse phase preparative column (20*250 mm, particle size 5 μm) with mobile phase A and mobile phase B at a flow rate of 10 mL / min. The target peak was collected and lyophilized to obtain the target coupling compound (i.e., the peptide derivative). The specific process is shown in Figure 2. The purity and mass spectrometry of each polypeptide derivative were determined. The purity of each polypeptide derivative was greater than 90% by HPLC. The molecular weights of the polypeptides determined by mass spectrometry were basically consistent with the theoretical molecular weight (all within the allowable error range). The molecular weights of some polypeptide molecules are exemplified in this example, see Table 1 for details.

[0781] Table 1: Molecular weight of compounds

[0782] Example 2: Preparation of polypeptide or its derivatives

[0783] 1. The linear peptides in peptides 84 to 94 (abbreviated as TG84 to TG94) in Table A were synthesized using the classic Fmoc-tBu solid phase synthesis method. X peptide synthesizer was prepared, and the reaction conditions were as follows:

[0784] (1) Resin swelling: Add Rink Amide MBHA resin to DCM, react with N2 gas at room temperature for 1 hour, filter, and wash the resin with DMF 2-3 times.

[0785] (2) Removal of Fmoc protecting group: Add DMF solution containing 20% ​​piperidine to the above resin, react under N2 bubbling at room temperature for 10 minutes, filter, and repeat the above operation until complete deprotection, and wash the resin with DMF 2-3 times.

[0786] (3) Amino acid coupling: The materials were added according to the reaction ratio of resin: Fmoc-AA-OH: DIC: Oxyma Pure = 1:5:5:5. Fmoc-AA-OH, DIC and Oxyma Pure were pre-dissolved in DMF and reacted at room temperature with N2 for 10 minutes. Then, they were transferred to the resin reaction tank and reacted at room temperature with N2 for 1-3 hours. After the reaction, the resin was filtered and washed with DMF 2-3 times. The amino acids with N-terminal amino acids such as Boc-L-His(Trt)-OH and Boc-L-Tyr(tBu)-OH were also synthesized using the above method. After the synthesis, the resin was washed with DCM 2-3 times and vacuum dried to obtain a peptide resin containing a linear peptide.

[0787] The above method is applicable to include, but not limited to, the following amino acids (D or L type) or synthetic reagents: Fmoc-AEEA-OH, Fmoc-Aad(tBu)-OH, Fmoc-Ac4c-OH, Fmoc-Aib-OH, Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Dab(Ac)-OH, Fmoc-Dap(Ac)-OH, Fmoc-Gly-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Iva-OH, Fmoc-Leu-OH, Fmoc-Lys(Ac)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Lys(Alloc)-OH, Fmoc-Lys(ivDde)-OH, Fmoc-Met-OH, Fmoc-Nal-OH, Fmoc-Nle-OH, Fmoc-Orn(Boc)-OH, Fmoc-Pal-OH, Fmoc-Pro-OH, Fmoc-Phe-OH, Fmoc-Phe(2-F)-OH, Fmoc-Phe(3-F)-OH, Fmoc-Phe(4-F)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Tle-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Val-OH, Fmoc-α-methyl-Leu-OH, Fmoc-α-methyl-Lys(Boc)-OH, Fmoc-α-methyl-Phe-OH, Fmoc-α-methyl-Phe(2-F)-OH, Fmoc-AEEA-OH, Fmoc-Glu-OtBu, Fmoc-Asp-OtBu, Fmoc-Ida(Allyl)-OH, Boc-L-His(Trt)-OH, Boc-L-Tyr(tBu)-OH, Myristic acid, Stearic acid, Arachidic acid, Docosanoic acid, 18-(tert-butoxy)-18-oxooctadecanoic acid, 20-(tert-Butoxy)-20-oxoicosanoic acid, etc.

[0788] 2. The Staple linker (or modification group B) is connected to the peptide resin containing the linear peptide (TG85) obtained in step 1. The specific steps are as follows (see Figure 3 for the specific process):

[0789] 2.1 Removal of Mtt protecting group from peptide resin: prepare deprotection solution according to the volume ratio of TFA:TIPS:DCM=1:2:97, add Mtt removing solution (10mL / g resin) to the resin, place on a shaker and shake thoroughly for 15 minutes, filter the resin, repeat this process 3-5 times until the color no longer turns bright yellow after the addition of the removing solution, indicating complete removal, and wash the resin 2-3 times with DMF.

[0790] 2.2 Removal of Alloc and Allyl protecting groups on the peptide resin: Add DCM (10 mL / g resin), PhSiH3 (10 equivalents) and Pd(PPh3)4 (0.1 equivalents) to the resin, react with N2 gas at room temperature for 1 hour, filter the resin, repeat the process 1-2 times, and wash the resin with DMF 2-3 times.

[0791] 2.3 On-resin ring closure reaction: To the resin from which the Alloc and Allyl protecting groups had been removed, DMF (10 mL / g resin), PyBOP (5 eq.), HOBt (5 eq.), and DIPEA (10 eq.) were added. The reaction was allowed to proceed under nitrogen bubbling at room temperature for 4 h. The resin was then filtered and the reaction was repeated 1-2 times. The resin was washed with DMF 2-3 times.

[0792] 2.4 Solid-phase side chain introduction: The standard solid-phase synthesis method is used, wherein the side chain has the following structure:

[0793] 3. Cutting and drying: Prepare the peptide cutting solution according to the volume ratio of TFA:TIPS:H2O:EDT=95:2:2:1. Add the cutting solution (10mL / g resin) to the dried resin and shake it on a shaker for 3 hours. Filter the resin residue and add 10 volumes of cold MTBE to the filtrate. Cool the resulting suspension at -20°C for 1 hour and then centrifuge at 3500rpm. Wash the precipitate with cold MTBE 3-5 times and vacuum dry to obtain the crude peptide.

[0794] 4. Peptide Purification: A dissolving solution was prepared at a volume ratio of mobile phase A (0.1% TFA-water): mobile phase B (0.1% TFA-acetonitrile) = 1.5:1. The crude peptide was dissolved in the dissolving solution to prepare a storage solution, filtered through a 0.45 μm filter membrane, and gradient eluted using mobile phase A and mobile phase B at a flow rate of 10 mL / min using a C18 reverse-phase preparative column (20*250 mm, particle size 5 μm). The target peak was collected and lyophilized to obtain the target peptide derivatives, namely polypeptides 84 to 94 (abbreviated as TG84 to TG94). The purity and mass spectrometry of each polypeptide derivative were analyzed. HPLC analysis showed that the purity was greater than 90%. The molecular weights of the polypeptides identified by mass spectrometry were basically consistent with the theoretical molecular weight (all within the allowable error range). The molecular weights of some polypeptide molecules are shown in this example. See Table 2 for details.

[0795] Table 2: Compound molecular weight table

[0796] Test Example 1: In vitro activity assay

[0797] 1. Insulin-stimulating analogs can bind to target receptors on the cell membrane, activate the cAMP response element (CRE), and initiate the expression of downstream luciferase. The expression level is positively correlated with the biological activity of the tested analog. After activation, luciferase substrate is added for chemiluminescence detection, and its luminescence intensity is measured to characterize the biological activity of the test compound. Therefore, the CreLuc method can be used to detect the target peptide derivatives (or polypeptide derivatives, i.e., TG1 to TG94) prepared in Example 1 and Example 2. The specific steps are as follows:

[0798] Construct HEK293 / pGM-CREB-L-Luc / GLP-1R pool, HEK293 / pGM-CREB-L-Luc / GIPR pool, 293HEK / pGM-CREB-L-Luc / GCGR pool stable transfection cell lines. The target peptide derivatives (TG1-TG94) prepared in Example 1 and Example 2 were diluted 5-fold from a maximum of 100nM to prepare a dilution series containing 11 concentration gradients. Tianren-derived GLP-1, GIP, and Glucagon were selected as test positive controls, and a dilution series was prepared for testing in the same manner. The corresponding test cells were digested (1min) and blown off by centrifugation (1000rpm, 5min). After discarding the culture medium, the cells were suspended with freestyle culture medium, centrifuged, collected and counted, and diluted to a cell density of 5×10 5Cells / mL were added to the test wells of a 384-well plate (40 μL / 20,000 cells / well). The corresponding dilution series of the test substance was added using Echo. The cell plate was incubated at 37°C and 5% carbon dioxide for 6 hours, and ONE-GLO (20 μL / well) was added for detection. The plate was placed in the dark for 3 minutes, and the plate was measured using a chemiluminescence microplate reader. The plate was read within 30 minutes and the measurement results were recorded. The activation curve was drawn using GraphPad Prism software to calculate the EC of the target peptide derivative. 50 The results are shown in Table 3. The results show that the polypeptide derivatives of the present invention have binding activity to GLP-1R, GIPR and GCGR.

[0799] Table 3: EC of each target peptide derivative 50 value

[0800] 2. Insulin-stimulating analogs can bind to target receptors on the cell membrane, activate the receptors, and release insulin. The activity of the analyte can be measured using a cAMP detection kit and the HTRF method. Therefore, the target peptide derivatives (or polypeptide derivatives, i.e., TG1 to TG86) prepared in Examples 1 and 2 can be detected using the cAMP method. The specific steps are as follows:

[0801] Construct HEK293 / pGM-CREB-L-Luc / GLP-1pool, HEK293 / pGM-CREB-L-Luc / GIP pool, and HEK293 / pGM-CREB-L-Luc / GCG pool stably transfected cell lines. The target peptide derivatives (TG1-TG86) prepared in Example 1 and Example 2 were diluted 5-fold from a maximum of 100 nM to prepare a dilution series containing 11 concentration gradients. Tianren-derived GLP-1, GIP, and Glucagon were selected as positive controls for the test, and a dilution series was prepared for testing in the same manner. The test cell line was selected and digested with cAMP-specific trypsin, and then 3 mL of serum-free DMEM culture medium was added to suspend by pipetting, and the cells were counted. 5 μL IBMX (prepared in serum-free DMEM medium, 0.5 mM) and test cells (5 μL / 7500 cells / well) were added to a 384-well plate in sequence. After incubation at 37°C and 5% carbon dioxide for 30 minutes, cAMP-d2 (5 μL, 1x) and Anti-cAMP-Cryptate (5 μL, 1x) were added. The plates were left at room temperature for 1 hour. The HTRF values ​​were measured using a chemiluminescence microplate reader and the results were recorded. Activation curves were drawn using GraphPad Prism software to calculate the EC values ​​of the target peptide derivatives. 50The results are shown in Table 4. The results show that the polypeptide derivatives of the present invention have binding activity to GLP-1R, GIPR and GCGR.

[0802] Table 4: EC of each target peptide derivative 50 value

[0803] The methods described in Examples 1 and 2 were used to prepare the polypeptide derivatives disclosed in Patent PCT / CN2022 / 097622, ​​and the CreLuc method was used to prepare the polypeptide derivatives. The results showed that the polypeptide derivatives only had binding activity for two of the GLP-1R, GIPR, and GCCR receptors, and did not have agonist activity for all three receptors simultaneously.

[0804] Test Example 2: In vivo pharmacokinetic evaluation

[0805] The target peptide derivatives (or polypeptide derivatives, i.e.

[0806] The pharmacokinetic behavior of (TG1-TG94) in rodents was tested. The specific steps are as follows:

[0807] The target peptide derivatives (TG1-TG94) were administered as a single subcutaneous (SC) injection (3 mg / kg, 1.5 mg / mL in PBS, 2 mL) or intravenously (IV) injection (1 mg / kg, 0.5 mg / mL in PBS, 2 mL). Whole blood samples were collected from the jugular vein or other appropriate vein at the following time points after administration: SC: 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 168 h; IV: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 168 h. 0.2 mL of blood was collected into labeled EDTA-K2 anticoagulant tubes. After gently inverting the tube to thoroughly mix the anticoagulant (EDTA-K2) with the blood, immediately place on wet ice and centrifuge to separate the plasma as quickly as possible at 4°C, 6800 × g, and 6 minutes. Store the plasma sample at a temperature no higher than -20°C until analysis.

[0808] Under yellow light in an ice-water bath, 300 μL of precipitant containing an internal standard was added to a 96-well plate containing 20 μL of standard curve samples, quality control samples, or unknown samples, with the exception of blank samples. 300 μL of acetonitrile was added to the blank samples. Vortex to mix thoroughly, then centrifuge. 150 μL of the supernatant from the centrifugation was transferred to a new 96-well plate and mixed thoroughly with 150 μL of ultrapure water. These samples were quantitatively analyzed by LC-MS using an XB-C18 (2.1 x 100 mm, 3 μm) chromatograph with gradient elution using the following mobile phases: mobile phase A = 0.1% formic acid in water; mobile phase B = acetonitrile. Pharmacokinetic parameters were calculated using Phoenix WinNonlin software. The results showed that the polypeptide derivatives of the present invention exhibited good in vivo absorption in rats, with high plasma concentrations and prolonged half-lives. The pharmacokinetic parameter results for some of the polypeptide derivatives are shown in Tables 5A and 5B.

[0809] Table 5A: Pharmacokinetic parameters of each target peptide derivative

[0810] Table 5B: Pharmacokinetic parameters of each target peptide derivative

[0811] To test the pharmacokinetic behavior of TG52 in non-rodent animals, the specific steps are as follows:

[0812] Adult male cynomolgus monkeys were administered a single subcutaneous and intravenous injection of the target peptide derivative TG52 (0.2 mg / kg, in PBS). Whole blood samples were collected from the jugular vein or other appropriate vein at the following time points: SC: 0 min, 30 min, 1 h, 3 h, 7 h, 24 h, 48 h, 72 h, 120 h, 168 h, 216 h, and 264 h; IV: 0 min, 5 min, 30 min, 1 h, 3 h, 7 h, 24 h, 48 h, 72 h, 120 h, 168 h, 216 h, and 264 h. 0.2 mL of blood was collected and placed in labeled EDTA-K2 anticoagulant tubes. After gentle inversion to thoroughly mix the anticoagulant (EDTA-K2) with the blood, the tubes were immediately placed on wet ice and centrifuged as quickly as possible at 4°C, 6800 × g, and 6 min to separate plasma. The plasma samples were stored in a refrigerator at a temperature not exceeding -20°C until analysis. The drug content in the blood samples was analyzed using the analytical method described above.

[0813] Table 5C: Pharmacokinetic parameters of TG52 in cynomolgus monkeys

[0814] Test Example 3: In vivo pharmacodynamics study

[0815] 23-26 week old DIO male C57BL / 6J mice were taken, with a body weight of 45-55g and a blood glucose range of 8-12mmol / L. The DIO mice were randomly divided into groups, with 6 mice in each group placed in a cage for adaptive feeding for 1 week, during which they were kept on a high-fat diet and had free access to water. After the animals were pre-adapted, the basal blood glucose and body weight values ​​of each mouse were tested before administration (Day 0). Then, according to the experimental groups, the solvent control (Vehicle), Tirzepatide (10nmol / kg) and three doses of the compound of the present invention TG52 (3nmol / kg, 10nmol / kg, 30nmol / kg) were given by subcutaneous injection (sc). After the administration, normal high-fat diet and water were given. On Days 1, 2, 3, 4, 5, 6, and 7 after administration, the blood glucose level, body weight, and total daily food intake of each mouse group were measured. The changes in blood glucose, body weight (% of the starting value), and total daily food intake of each mouse group were calculated, and the curves were plotted. The results are shown in Figures 4 to 6.

[0816] Test Example 4: Study on Anti-enzymatic Stability

[0817] The stability of the target peptide derivatives (or polypeptide derivatives, i.e., (TG1 to TG94)) and Retatrutide (positive control) prepared in Examples 1 and 2 were tested in artificial gastric fluid (SGF) and artificial small intestinal fluid (SIF), respectively. The specific steps are as follows:

[0818] The target peptide derivatives (TG1-TG94) and Retatrutide (positive control) to be tested were dissolved in PBS to prepare a stock solution (60 μM), and 15 μL was diluted with 285 μL of commercial artificial gastric juice (SGF) and incubated in a 37°C water bath. Equal amounts of solution (30 μL) were extracted at 0 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, and 8 h, and the reaction was neutralized with 0.2 M Na2CO3 aqueous solution (30 μL). The remaining peptide amount was analyzed by LC-MS, and the relative percentage of the peptide amount at different times corresponding to the 0 min time was calculated. The degradation curve was drawn using GraphPad Prism, and the half-life (T) of the target peptide derivative in SGF was calculated. 1 / 2 ).

[0819] The test compound was dissolved in PBS to prepare a stock solution (60 uM), and 15 μL was diluted with 285 μL of commercial artificial gastric fluid (SGF) and incubated in a 37°C water bath. Equal amounts of solution (30 μL) were extracted at 0 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, and 8 h, respectively. The reaction was neutralized with 10% TFA-water solution (30 μL). The remaining peptide amount was analyzed by LC-MS, and the relative percentage of the peptide amount at different times corresponding to the 0 min time was calculated. The degradation curve was drawn using GraphPad Prism, and the half-life (T) of each target peptide derivative in SIF was calculated. 1 / 2 The results showed that all target peptide derivatives had good stability against enzymatic degradation. The stability test results of TG52 and Retatrutide (positive control) in artificial gastric fluid are shown in Figure 7.

[0820] Test Example 5: Comparison of serum albumin binding capacity

[0821] To further illustrate that the agonist of the present application can provide stronger serum albumin binding after cyclization, the binding of semaglutide and the target peptide derivative TG052 to serum albumin was tested based on step 1 of test example 1 of the present application (the only difference from step 1 of test example 1 is the addition of 10% FBS to the cell culture system), and the steps are as follows:

[0822] Construct a HEK293 / pGM-CREB-L-Luc / GLP-1R pool stably transfected cell line. TG052 and the positive control Semaglutide were diluted 5-fold from a maximum of 100nM to prepare a dilution series containing 11 concentration gradients. The corresponding test cells were digested (1min) and blown off by centrifugation (1000rpm, 5min). After discarding the culture medium, the cells were suspended with freestyle culture medium, centrifuged, collected and counted, and diluted to a cell density of 5×10 using freestyle culture medium (ie, 0% FBS) and culture medium containing 10% FBS. 5 Cells / mL were added to the detection wells of a 384-well plate (40 μL / 20,000 cells / well). The corresponding dilution series of the test substance was added using Echo. The cell plate was cultured at 37°C and 5% carbon dioxide for 6 hours, and ONE-GLO (20 μL / well) was added for detection. The plate was placed in the dark for 3 minutes, and the plate was measured using a chemiluminescence microplate reader. The plate was read within 30 minutes and the measurement results were recorded. GraphPad Prism software was used to draw the activation curve and calculate the EC values ​​of the target peptide under 0% and 10% FBS culture conditions. 50 The specific test results are shown in Figure 8 and Table 6.

[0823] Table 6

[0824] As shown above, compared to the single-side fatty acid-modified positive control Semaglutide (i.e., linear agonist), the activity of the target peptide derivative TG052 of the present application decreased more significantly in the presence of 10% FBS (Fold), indicating that TG052 has stronger binding affinity to FBS and serum albumin. Therefore, this further demonstrates that compared to linear agonists (such as the positive control Semaglutide), the cyclic agonists of the present application (such as TG052) bind more to FBS and have stronger binding ability to TG052.

[0825] Test Example 6: Comparison of in vivo drug efficacy

[0826] This test example compares the therapeutic effects of the target peptide derivative of the present application (TG052) and commercially available linear agonists (Glucagon and Retatrutide) in a DIO mouse model and a non-alcoholic steatohepatitis (NASH) mouse model.

[0827] 4.1 23-26 week old DIO male C57BL / 6J mice weighing 45-55 g and with a blood glucose range of 8-12 mmol / L were randomly divided into groups of 6 mice per cage and housed for 1 week on a high-fat diet with free access to water. After animal pre-acclimation, basal blood glucose and body weight were measured before dosing (Day 0). Subsequently, mice were administered subcutaneously (sc) with vehicle control, Tirzepatide (10 nmol / kg), Retatrutide (10 mg / kg), and the present compound TG52 (10 nmol / kg), according to experimental grouping. 23-26-week-old normal male C57BL / 6J mice were used as healthy controls (Lean controls) and administered with vehicle. Following dosing, they were fed a normal high-fat diet and water. Subcutaneous dosing was continued every three days (Q3D) for 21 consecutive days. All animals were euthanized on Day 22, and blood and organ samples were collected for analysis. The insulin content in the blood of each mouse was measured using a commercially available insulin detection kit. The liver tissue of each mouse was fixed with 4% paraformaldehyde (4% PFA), embedded in paraffin, and sectioned to obtain liver tissue sections. The liver tissue of each mouse was stained with Oil Red O to obtain stained slides, and the fat content in the liver tissue was also calculated. The specific test results are shown in Figures 9 and 10.

[0828] As shown in FIG9 , compared with the positive control drugs Retatrutide and Tirzepatide, the target peptide derivative (TG052) of the present application can more effectively improve the insulin resistance state of obese mice and reduce blood insulin levels.

[0829] As shown in Figure 10, compared with the positive control drugs Retatrutide and Tirzepatide, the target peptide derivative (TG052) of the present application can more significantly and effectively eliminate fat accumulation in the liver of obese mice and improve the liver metabolic state.

[0830] 4.2 18-20 week old DIO male C57BL / 6J mice were fed a high-fat diet (HFD) for 10 weeks and then divided into three groups of six for testing. These groups included a control group (given vehicle + carbon tetrachloride), a TG52 group (given TG52 10 nmol / kg + carbon tetrachloride), and a Tirzepatide group (given Tirzepatide 10 nmol / kg + carbon tetrachloride). A healthy control group was also established. 18-20 week old normal male C57BL / 6J mice were fed a normal diet for 10 weeks and then tested (given vehicle + vehicle). All four groups were dosed every three days (Q3D) for 8 weeks. After euthanasia, liver tissue was obtained for testing. Liver tissues from each mouse were fixed with 4% paraformaldehyde (4% PFA), embedded in paraffin, and sliced ​​to obtain liver tissue sections. Hematoxylin-eosin (H&E) staining was then performed. Commercially available antibodies were used to stain target proteins (fibronectin and α-SMA) to obtain stained sections. Finally, statistical analysis was performed on each stained section to obtain quantitative analysis results (Figure 11, right). The specific test results are shown in Figure 11.

[0831] As shown in Figure 11, compared with the positive control drug Tirzepatide, the target peptide derivative (TG052) of the present application can more significantly and effectively improve the liver inflammation state, more significantly reverse the liver fibrosis state, and significantly reduce the level of liver fibrosis markers.

[0832] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0833] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A polypeptide or its derivative or a pharmaceutically acceptable salt thereof, characterized in that: The polypeptide or its derivative has a structure shown in formula (I): X1X2X3GTX6X7X8DX 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 LX 27 X 28 X 29 X 30 PX 32 SX 34 X 35 P PPX 39 (I); wherein X1 is Y, H, 3-iodo-Y, 4-Pal or 4-amino-F; X2 is Aib, s, or Ac4c; X3 is Q, H or Dab(Ac); X6 is F, F(2-F) or αMeF; X8 is S, HoS or αMeS; X 10 is Z2, Y, Z1, L or 4-Pal; X 11 is S or αMeS; X 12 is K, R or I; X 13 is Z2, Z1, Y, L, A, αMeL, Q, Aib, or Iva; X 14 is Z2, Z1, L, K(Ac), HoL, Npg or Tle; X 15 is D, E or Aad; X 16 For K, E, K(Ac), αMeK; X 17 is R, Z2, Z1, K(Ac), Q or I; X 18 is Z2, Z1, A, R or Y; X 19 is A, Q, Aib, H or K(Ac); X 20 is Q, Z2, Aib, H, R, a or Z1; X 21 is Z1, D, A, L, Z2 or Aib; X 22 is F or HoF; X 23 V or I; X 24 is Z2, Q, Z1 or E; X 25 is Z2, Z1, W or Y; X 27 is L, K or I; X 28 is A, D, E, Z1 or Z2; X 29 is G or H; X 30 is G or H; X 32 is Z2, Z1, S or P; X 34 is G or Aib; X 35 A, Q or K; X 39 is S or K; In the structure represented by formula (I), two sites in any of the following groups are independently selected from amino acids Z1 having -SH in the side chain, or in the structure represented by formula (I), two sites in any of the following groups are independently selected from amino acids Z2 having -NH2 in the side chain: 1)i and i+3; 2)i and i+4; 3) i and i+7; or 4)i and i+11; Wherein, i is 10, 14, 17 or 21; The two amino acids Z1 containing -SH on the side chains are each independently selected from C, C, αMeC, HoC, Hoc, Pen or N-Me-C; The two amino acids Z2 containing -NH2 on their side chains are each independently selected from K, k, αMeK, HoK, Dap, Dab, Orn or N-Me-K.

2. The polypeptide or its derivative or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (I) are respectively i and i+3, i and i+4, i and i+7, or i and i+11, and i is 10, 14, 17 or 21; Optionally, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (I) are respectively i and i+3, i is 10, 14, 17 or 21, preferably i is 17; Optionally, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (I) are respectively i and i+4, i is 10, 14, 17 or 21, preferably i is 10; Optionally, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (I) are respectively i and i+7, i is 10, 14, 17 or 21, preferably i is 14, 17 or 21; Optionally, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (I) are respectively i and i+11, i is 10, 14, 17 or 21, preferably i is 10 or 17; Optionally, the positions of the two amino acids Z2 containing -NH2 in the side chains in the structure represented by formula (I) are respectively i and i+3, i and i+4, i and i+7, or i and i+11, and i is 10, 14, 17 or 21; Optionally, the positions of the two amino acids Z2 containing -NH2 in the side chains in the structure represented by formula (I) are respectively i+3, or i and i+7, and i is 17 or 21; Optionally, the positions of the two amino acids Z2 whose side chains contain -NH2 in the structure represented by formula (I) are 17 and 20, or 21 and 28, respectively.

3. The polypeptide or its derivative or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: X1 is Y or H; Optionally, X2 is Aib or Ac4c; Optionally, X3 is Q or H; Optionally, X6 is F or F(2-F); Optionally, X6 is F(2-F); Optionally, X 10 is Y, C, L or 4-Pal; Optionally, X 10 Y, L or 4-Pal; Optionally, X 10 Y or 4-Pal; Optionally, X 11 is S or αMeS; Optionally, X 12 is K or I; Optionally, X 13 is Y, L, A, αMeL, Q, Aib or Iva; Optionally, X 13 is Y, L, αMeL, Q, Aib or Iva; Optionally, X 13 is Y, L, αMeL, Q or Iva; Optionally, X 13 is L or αMeL; Optionally, X 13 is Y, L or A; Optionally, X 13 is αMeL, Y or Iva; Optionally, X 13 is αMeL, Q or L; Optionally, X 13 is Y or L; Optionally, X 14 is L, K(Ac), HoL, Npg or Tle; Optionally, X 14 is C, L, K(Ac), HoL, Npg or Tle; Optionally, X 15 is D or E; Optionally, X 16 is K or E; Optionally, X 16 is E, K, αMeK or K(Ac); Optionally, X 16 is K or αMeK; Optionally, X 17 is C, Q, K(Ac), R or I; Optionally, X 17 is R, K, K(Ac), Q or I; Optionally, X 17 is K(Ac) or K; Optionally, X 17 is C or K(Ac); Optionally, X 17 is R, K or Q; Optionally, X 18 is A, R or Y; Optionally, X 18 is A or Y; Optionally, X 19 A, Q or Aib; Optionally, X 19 is Q or A; Optionally, X 19 is Q or H; Optionally, X 20 is Q, K, Aib, H, a or C; Optionally, X 20 is Aib, Q, H, C or a; Optionally, X 20 is Q, Aib, H or R; Optionally, X 20 is Q, K or Aib; Optionally, X 20 is Aib or Q; Optionally, X 20 is Aib or K; Optionally, X 21 is C, D, A, L or Aib; Optionally, X 21 is D, A or C; Optionally, X 21 is D, A or L; Optionally, X 21 It is K or A; Optionally, X 21 D or C; Optionally, X 22 is F or HoF; Optionally, X 23 I or V; Optionally, X 24 is Q, C or E; Optionally, X 24 is E, C or Q; Optionally, X 24 is E or C; Optionally, X 24 is Q or E; Optionally, X 25 is W or Y; Optionally, X 28 is A, D, E, C or HoC; Optionally, X 28 is A, D or E; Optionally, X 28 A or E; Optionally, X 28 is E or C; Optionally, X 28 It is K or A; Optionally, X 32 is S or P; Optionally, X 35 A or Q; Optionally, X 35 It is A or K.

4. The polypeptide or its derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The polypeptide represented by formula (I) or its derivative has the structure represented by formula (Ia): X1X2X3GTX6TSDX 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 FX 23 X 24 X 25 LLX 28 GGPSSGAPPPS (Ia); Optionally, the positions of the two amino acids Z1 containing -SH in the side chains in the structure represented by formula (Ia) are 14 and 21, 17 and 24, 21 and 28, or 17 and 20, respectively; Optionally, the positions of the two amino acids Z2 containing -NH2 in the side chains in the structure represented by formula (Ia) are 21 and 28, or 17 and 20, respectively; Optionally, the polypeptide represented by formula (I) or its derivative has a structure represented by formula (Ib): X1X2X3GTX6TSDYX 11 X 12 X 13 LDX 16 X 17 X 18 X 19 X 20 X 21 FX 23 X 24 X 25 LLX 28 GGPSSGAPPPS (Ib); Optionally, the positions of the two amino acids Z1 having -SH in the side chains in the structure represented by formula (Ib) are 17 and 24, or 21 and 28, respectively.

5. The polypeptide or its derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The polypeptide represented by formula (I) or its derivative has the structure represented by formula (II): X1X2X3GTX6X7X8DX 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 FX 23 X 24 X 25 LX 27 X 28 X 29 X 30 PX 32 SX 34 X 35 PPPX 39 (II); Optionally, the positions of the two amino acids Z1 containing -SH on the side chains in the structure represented by formula (II) are respectively one of the following combinations: i and i+3, i is 17; i and i+4, i is 10; i and i+7, i is 10, 14, 17 or 21; or i and i+11, i is 10 or 17; Optionally, the polypeptide represented by formula (I) or its derivative has a structure represented by formula (III): X1-Aib-X3GTX6TSDYSX 12 X 13 Z1X 15 X 16 X 17 X 18 X 19 X 20 Z1FX 23 X 24 X 25 LLX 28 X 29 X 30 PSSGX 35 PPPS (III); Optionally, the polypeptide represented by formula (I) or its derivative has a structure represented by formula (IV): X1X2X3GT-F(2-F)-TSDYX 11 IX 13 LDKZ1AX 19 Z1AFIEYLLX 28 GGPSSGAPPPS (IV); Optionally, the polypeptide represented by formula (II) or its derivative has a structure represented by formula (V): X1-Aib-X3GTX6TSDYSX 12 X 13 LX 15 KCX 18 X 19 X 20 X 21 FX 23 CX 25 LLX 28 GGPSSGAPPPS (V)； Optionally, the polypeptide represented by formula (I) or its derivative has a structure represented by formula (VI): Y-Aib-QGTFTSDYSILLDKZ1AQH-Aib-FIEYLLZ1GGPSSGAPPPS (VI); Optionally, two Z1 are each independently selected from C or HoC; Optionally, both Z1 are C; Optionally, both Z1 are HoC; Optionally, the polypeptide represented by formula (I) or its derivative has a structure represented by formula (VII): X1X2X3GTX6TX8DX 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 Z1X 22 X 23 X 24 X 25 LX 27 Z1GGPX 32 SX 34 X 35 PPPS (VII); Optionally, two Z1 are each independently selected from C, C, HoC or αMeC; Optionally, both Z1 are C; Optionally, both Z1 are c; Optionally, both Z1 are HoC; Optionally, both Z1 are αMeC.

6. The polypeptide or its derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The polypeptide represented by formula (I) or its derivative has the structure represented by formula (VIII): YX2QGTX6TSDYSIX 13 LDX 16 X 17 AQX 20 X 21 FIEYLLX 28 GGPSSGAPPPS (VIII); Optionally, the positions of the two amino acids Z2 containing -NH2 in the side chains in the structure represented by formula (VIII) are 17 and 20, or 21 and 28, respectively; Optionally, the polypeptide represented by formula (I) or its derivative has a structure represented by formula (IX): <h2 style=";text-align:left;direction:ltr">Y-Aib-QGTX6TSDYSI-αMeL-LDX<h2 style=";text-align:left;direction:ltr"> 16 <h2 style=";text-align:left;direction:ltr"> -K(Ac)-AQ-Aib-Z2FIEYLLZ2GGPSSGAPPPS (IX); Optionally, two Z2 are each independently selected from K or Orn; Optionally, both Z2 are K; Optionally, both Z2 are Orn; Optionally, the polypeptide represented by formula (I) or its derivative has a structure represented by formula (X): YX2QGTX6TSDYSIX 13 LDKKAQKAFIEYLLAGGPSSGAPPPS (X)。 7. The polypeptide or its derivative or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The polypeptide represented by formula (I) or its derivative has at least one of the following structures: Y-Aib-QGTFTSDYSKYCDKRAAQCFVQWLLAGGPSSGAPPPS; Y-Aib-QGTFTSDYSKYCDEKRAKCFVQWLLDHPSSGQPPPS; <h2 style=";text-align:left;direction:ltr">Y-Aib-QGTFTSDCSKYCDERAAQDFVQWLLAGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDCSKYLDECAAQDFVQWLLAGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDCSKYLDERAAQCFVQWLLAGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDYSIYCEKKYAQCFVQWLLAGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDYSIYCEKRYAQCFVQWLLAGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDYSIYCEKRYA-Aib-CFVQWLLEGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSKYLDKCAAQDFVCWLLAGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDYSKYLDKCYAQDFVCWLLEGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSILLDKCAQHAFICYLLEGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSILLDKCAQ-Aib-AFICYLLEGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDYSRALEKCAARLFICWLLEGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDYSKYLE-K(Ac)-KYA-Aib-CFVQWLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDLSKL-K(Ac)-EEQRQ-Aib-CFIEWLKCGGPPS-Aib-KPPPK; <h2 style=";text-align:left;direction:ltr"> H-Aib-QGTFTSDLSKQ-K(Ac)-DEQRAKCFIEWLICGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> H-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> (3-iodo-Y)-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> (4-Pal)-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> (4-amino-F)-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr">Ys-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-αMeF-TSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFT-HoS-DYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-HoL-DK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-Npg-DK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-Tle-DK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEWLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSILLDK-K(Ac)-AQ-Aib-CFIEWLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-LDKQAQ-Aib-CFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-a-CFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQHCFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQQCFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-LDK-K(Ac)-A-Aib-QCFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-LDKRAQ-Aib-CFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-LEK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSI-αMeL-L-Aad-KK(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; Y-Aib-QGTFTSD-4-Pal-SI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; Y-Aib-QGTFT-αMeS-DYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; Y-Aib-Dab(Ac)-GTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; Y-Aib-HGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; Y-Ac4c-QGTFTSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; Y-Aib-QGTFTSDYSILLDKCAQH-Aib-FIEYLLCGGPSSGAPPPS; Y-Aib-QGTFTSDYSILLDK-HoC-AQH-Aib-FIEYLL-HoC-GGPSSGAPPPS; Y-Aib-QGT-F(2-F)-TSDYSILLDKCAQQAFICYLLAGGPSSGAPPPS; Y-Aib-QGT-F(2-F)-TSDYSILLDKQAQQCFIEYLLCGGPSSGAPPPS; Y-Aib-QGT-F(2-F)-TSDYSI-Aib-LDK-K(Ac)-AQQCFIEYLLCGGPSSGAPPPS; Y-Aib-QGT-F(2-F)-TSDYSILCDKQAQQCFIEYLLAGGPSSGAPPPS; Y-Aib-QGT-F(2-F)-TSDYSILLD-αMeK-K(Ac)-AQQCFIEYLLCGGPSSGAPPPS; Y-Aib-QGT-F(2-F)-TSDYSILLD-αMeK-K(Ac)-AQ-Aib-CFIEYLICGGPSSGAPPPS; Y-Aib-QGT-F(2-F)-TSDYSI-Iva-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; Y-Aib-QGT-F(2-F)-TSDY-αMeS-ILLD-αMeK-K(Ac)-AQQCFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr">Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LD-αMeK-K(Ac)-AQQCFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LD-αMeK-K(Ac)-AQQC-HoF-IEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKCAQCAFIEYLLAGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDYSI-Iva-LDKCAQCAFIEYLLAGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDY-αMeS-I-αMeL-LD-αMeK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDY-αMeS-I-αMeL-LD-αMeK-CAQCAFIEYLLAGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> H-Aib-HGT-F(2-F)-TSDYSIYLE-K(Ac)-KYA-Aib-CFVQWLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> H-Aib-HGT-F(2-F)-TSDYSIQ-K(Ac)-EEIAQ-Aib-CFIEWLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> H-Aib-HGT-F(2-F)-TSDYSIY-K(Ac)-EERAQ-Aib-CFIEWLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> H-Aib-HGT-F(2-F)-TSDYSI-Iva-LDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKCAHCAFIEYLLAGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKCA-K(Ac)-CAFIEYLLAGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKCAQCAFIEYLLAGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> H-Aib-HGT-F(2-F)-TSDYSI-αMeL-LDKCAQCAFIEYLLAGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Ys-QGT-F(2-F)-TSDYSI-αMeL-LDKCAQCAFIEYLLAGGPSSGAPPPS; <h2 style=";text-align:left;direction:ltr"> Y-Aib-QGTFTSDYSILLDKQAQQCFIEYLLCGGPSSGAPPPS; Y-Ac4c-QGT-F(2-F)-TSDYSILLDKCAQCAFIEYLLEGPGPSSGAPPPS; Y-Ac4c-QGT-F(2-F)-TSDYSILLDK-K(Ac)-AQ-Aib-CFIEYLLCGPSSGAPPPS; H-Ac4c-HGT-F(2-F)-TSDYSIQLEEIAQ-Aib-CFIEYLLCGPSSGAPPPS; Y-Aib-QGTFTSDYSILLDK-K(Ac)-AQ-Aib-c-FIEYLL-c-GGPSSGAPPPS; Y-Aib-QGTFTSDYSILLDK-K(Ac)-AQ-Aib-Hoc-FIEYLL-Hoc-GGPSSGAPPPS; Y-Aib-QGTFTSDYSILLDK-K(Ac)-AQ-Aib-αMeC-FIEYLL-αMeC-GGPSSGAPPPS; Y-Aib-QGT-F(2-F)-TSDYSIQLDK-K(Ac)-AQ-Aib-CFIEYLLCGGPSSGAPPPS; Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LD-αMeK-K(Ac)-AQ-Aib-KFIEYLLKGGPSSGAPPPS; Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDK-K(Ac)-AQ-Aib-KFIEYLLKGGPSSGAPPPS; Y-Aib-QGTFTSDYSILLDK-K(Ac)-AQ-Aib-Orn-FIEYLL-Orn-GGPSSGAPPPS; Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKKAQKAFIEYLLAGGPSSGAPPPS; Y-Aib-QGT-F(2-F)-TSDYSIQLDKKAQKAFIEYLLAGGPSSGAPPPS; Y-Aib-QGTFTSDYSILLDKKAQKAFIEYLLAGGPSSGAPPPS; Y-Aib-QGT-F(2-F)-TSDYSI-αMeL-LDKKAQKAFIEYLLAGGPSSGAPPPS.

8. The polypeptide or its derivative or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: further comprising a modifying group; Optionally, the modifying group is connected to one or two amino acids Z1 having -SH in the side chain, or one or two amino acids Z2 having -NH2 in the side chain, in the polypeptide represented by formula (I) or its derivative; Optionally, the modifying group is simultaneously connected to two amino acids Z1 containing -SH on the side chains in the polypeptide represented by formula (I) or its derivatives; or The modifying group is simultaneously connected to the two amino acids Z2 containing -NH2 on the side chains in the polypeptide represented by formula (I) or its derivative; Optionally, the modifying group is connected to the -SH of the amino acid C side chain via a sulfur-carbon bond; or The modifying group is connected to the ε-amino group of the amino acid K side chain via an amide bond.

9. The polypeptide or its derivative or pharmaceutically acceptable salt thereof according to claim 8, characterized in that: The modifying group has a structure shown in formula (XI): Where R1 is C, N, -C 3～10 Heteroalkylene, -C 6～10 Arylene or -C 5～10 heteroarylene; R2 and R3 are each independently optionally replaced by one or more R 1a Replaced-C 1～6 Alkylene-, optionally one or more R 1a Substituted-NH-C(O)-C 1～6 Alkylene- or optionally one or more R 1a Replaced-C 1～6 Alkylene-NH-C(O)-C 1～6 Alkylene-, wherein each R 1a are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 Alkoxy; R4 is empty or optionally replaced by one or more R 2a Replaced-C 1～6 Alkylene-NH-C(O)-C 1～6 Alkylene-, wherein each R 2a are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 Alkoxy; R5 is H, -C 1～6 Alkoxy or -C 1～6 Alkyl, wherein the -C 1～6 Alkyl and -C 1～6 The alkoxy groups are each independently optionally substituted with one or more halogen, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN; R6 is optionally replaced by one or more R 3a Replaced-C 1～6 Alkylene-, or optionally one or more R 3a Replaced-(C 1～3 Alkylene-O) m1 -C 1～6 Alkylene-, wherein each R 3a are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 Alkoxy; R7 is optionally replaced by one or more R 4a Replaced-C 1～6 Alkylene-, wherein each R 4a are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 Alkoxy; R8 is optionally replaced by one or more R 5a Replaced-C 10～20 Alkyl, optionally with one or more R 5a Replaced-C 10～20 Alkylene-R9, optionally with one or more R 5a Replaced-C 5～10 Alkylene-OC 6～10 Arylene-R9, or optionally one or more R 5a Replaced-C 5～10 Alkylene-OC 5～10 Heteroarylene-R9, wherein each R 5a are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 Alkoxy; R9 is -COOH, -C 3～7 heteroaryl, -S(O)2OH, or -PO(OH)2; m1 is any integer from 1 to 6; n1 is any integer from 0 to 6; n2 is any integer from 1 to 10.

10. The polypeptide or its derivative or pharmaceutically acceptable salt thereof according to claim 9, characterized in that: R1 is C, N, -C 5～7 Heteroalkylene, -C 5～7 Arylene or -C 5～7 heteroarylene; Optionally, R1 is N, phenylene or pyridylene; Optionally, R1 is Optionally, R2 and R3 are each independently -C 1～6 Alkylene-, or -C 1～6 Alkylene-NH-C(O)-C 1～6 Alkylene-; Optionally, R2 and R3 are each independently -C 1～3 Alkylene-, or -C 1～3 Alkylene-NH-C(O)-C 1～3 Alkylene-; Optionally, each n1 is independently 0, 1, 2, 3, 4 or 5; Optionally, n1 is 0; Optionally, R4 is empty, or -C 1～6 Alkylene-NH-C(O)-C 1～6 Alkylene-; Optionally, R4 is empty, or -C 1～3 Alkylene-NH-C(O)-C 1～3 Alkylene-; Optionally, R5 is H, -C 1～3 Alkoxy or -C 1～3 alkyl; Optionally, R6 is -C 1～6 Alkylene-, -(C 1～3 Alkylene-O) m1 -C 1～6 Alkylene-; Optionally, R6 is -C 1～3 Alkylene-, -(C 1～3 Alkylene-O) m1 -C 1～3 Alkylene-; Optionally, m1 is 2, 3, 4 or 5; Optionally, R7 is -C 1～6 Alkylene-; Optionally, R7 is -C 2～4 Alkylene-; Optionally, R8 is -C 10～20 Alkyl, -C 10～20 Alkylene-R9, -C 5～10 Alkylene-OC 6～10 Arylene-R9, or -C 5～10 Alkylene-OC 5～10 Heteroarylene-R9; Optionally, R8 is -C 10～18 Alkyl, -C 14～18 Alkylene-R9, or -C 7～9 Alkylene-OC 5～7 Arylene-COOH; Optionally, R9 is -COOH, -C 5～6 heteroaryl, -S(O)2OH, or -PO(OH)2; Optionally, R9 is -COOH, -S(O)2OH, -PO(OH)2, or Optionally, n2 is 1, 2 or 3; Optionally, n2 is 3, 4, 5 or 6; Optionally, the modifying group represented by formula (XI) has a structure represented by formula (XIa): Among them, each R 10 and R 11 Each independently is -C 0～3 Alkylene-; R 12 For -C 1～6 Alkylene-; R8 is -C 10～21 Alkyl, or -C 10～21 Alkylene-COOH, preferably -C 14～19 Alkyl or -C 10～18 Alkylene-COOH; q1 is 1, 2, 3, or 4; q2 is 1, 2, or 3; Optionally, the modifying group represented by formula (XIa) has the structure shown below: Optionally, the modifying group represented by formula (XI) has a structure represented by formula (XIb): Among them, each R 10 ' and R 11 'Each independently -C 0～3 Alkylene-;' R 12 'For -C 1～6 Alkylene-; R 13 For -C 10～20 Alkylene-, preferably -C 14～18 Alkylene-; q1' is 1, 2, 3 or 4; q2' is 1, 2 or 3; Optionally, the modifying group represented by the formula (XIb) has the structure shown below: Optionally, the modifying group represented by formula (XI) has a structure represented by formula (XIc): Among them, each R 14 Each independently is -C 1～3 Alkylene-or-NH-C(O)-C 1～3 Alkylene-; R 15 For -C 0～3 Alkylene-or-C(O)-NH-C 1～3 Alkylene-; R 12 " for -C 1～6 Alkylene-; R 13 'For -C 10～20 Alkylene-, preferably -C 14～18 Alkylene-; q1” is 1, 2, 3 or 4; q2” is 1, 2 or 3; Y1 is C or N; Optionally, the modifying group represented by formula (XIc) has the structure shown below: Optionally, the polypeptide represented by formula (I) or its derivative contains two amino acids Z1 whose side chains contain -SH, and the modification group has a structure represented by formula (XI).

11. The polypeptide or its derivative or pharmaceutically acceptable salt thereof according to claim 8, characterized in that: The modifying group has a structure shown in formula (XII): Among them, R 20 C, N, -C 6～10 Arylene or -C 5～10 heteroarylene; R 21 and R 22 Each is independently empty, optionally replaced by one or more R 1b Replaced-C 1～6 Alkylene-, or optionally one or more R 1b Replaced-C 1～6 Oxyalkylene-, wherein each R 1b are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 Alkoxy; R 23 Empty, optionally replaced by one or more R 2b Replaced-C 1～6 Alkylene-, optionally with one or more R 2b Substituted -C(O)-C 1～6 Alkylene-, optionally with one or more R 2b Substituted-NH-C(O)-C 1～6 Alkylene-, or optionally one or more R 2b Replaced-C 1～6 Alkylene-C(O)-NH-C 1～6 Alkylene-, wherein each R 2b are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 Alkoxy; R 24 is optionally replaced by one or more R 3b Replaced-C 1～6 Alkylene-, or optionally one or more R 3b Replaced-(C 1～3 Alkylene-O) m2 -C 1～6 Alkylene-, wherein each R 3b are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 Alkoxy; R 25 H, -C 1～6 Alkoxy or -C 1～6 Alkyl, wherein the -C 1～6 Alkyl and -C 1～6 The alkoxy groups are each independently optionally substituted with one or more halogen, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN; R 26 is optionally replaced by one or more R 4b Replaced-C 1～6 Alkylene-, wherein each R 4b are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 Alkoxy; R 27 is optionally replaced by one or more R 5b Replaced-C 10～20 Alkyl, optionally with one or more R 5b Replaced-C 10～20 Alkylene-R 28 , optionally one or more R 5b Replaced-C 5～10 Alkylene-OC 6～10 Arylene-R 28 , or optionally one or more R 5b Replaced-C 5～10 Alkylene-OC 5～10 Heteroarylene-R 28 , where each R 5b are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 Alkoxy; R 28 -COOH, -C 3～7 heteroaryl, -S(O)2OH, or -PO(OH)2; m2 is any integer from 1 to 6; n3 is any integer from 1 to 10; n3 is 0, 1 or 2; Y2 is empty or NH.

12. The polypeptide or its derivative or pharmaceutically acceptable salt thereof according to claim 11, characterized in that: R 20 C, N, -C 5～7 Arylene or -C 5～7 heteroarylene; Optionally, R 20 is C, N, phenylene or pyridylene; Optionally, R 20 for Preferably Optionally, R 21 and R 22 Each is independently empty, -C 1～6 Alkylene-, or -C 1～6 Oxyalkylene-; Optionally, R 21 and R 22 Each is independently empty or -C 1～3 Alkylene-; Optionally, R 23 Empty, -C 1～6 Alkylene-, -C 1～6 Alkylene-C(O)-NH-C 1～6 Alkylene-, or -C(O)-C 1～6 Alkylene-; Optionally, R 23 Empty, -C 1～3 Alkylene-, or -C(O)-C 2～4 Alkylene-; Optionally, R 24 For -C 1～6 Alkylene-, or -(C 1～3 Alkylene-O) m2 -C 1～6 Alkylene-; Optionally, R 24 For -C 1～3 Alkylene-, or -(C 1～3 Alkylene-O) m2 -C 1～3 Alkylene-; Optionally, m2 is 2, 3, 4 or 5; Optionally, R 25 H, -C 1～6 Alkoxy or -C 1～6 alkyl; Optionally, R 25 H or -C 1～3 alkyl; Optionally, R 26 For -C 1～6 Alkylene-; Optionally, R 26 For -C 1～3 Alkylene-; Optionally, R 27 For -C 10～20 Alkyl, -C 10～20 Alkylene-R 28 , -C 5～10 Alkylene-OC 6～10 Arylene-R 28 , or -C 5～10 Alkylene-OC 5～10 Heteroarylene-R 28 ; Optionally, R 27 For -C 10～18 Alkyl, -C 14～18 Alkylene-R 28 , or -C 7～9 Alkylene-OC 5～7 Arylene-COOH; Optionally, R 28 -COOH, -C 5～6 heteroaryl, -S(O)2OH, or -PO(OH)2; Optionally, R 28 -COOH, -S(O)2OH, -PO(OH)2, or Optionally, p is 1, 2 or 3; Optionally, p is 3, 4, 5 or 6; Optionally, the modifying group represented by formula (XII) has a structure represented by formula (XIIa): Among them, each R 29 Each independently is -C 1～3 Alkylene-; R 30 -C(O)-C 1～6 Alkylene-, or -C 1～3 Alkylene-C(O)-NH-C 1～3 Alkylene-; R 31 For -C 1～6 Alkylene-; q3 is 1, 2, 3 or 4; q4 is 1, 2 or 3; Optionally, R 27 For -C 10～20 Alkylene -COOH or -C 10～20 Alkyl, preferably -C 14～18 Alkylene -COOH or -C 10～19 alkyl; Optionally, the modifying group represented by formula (XIIa) has the structure shown below: Optionally, the modifying group represented by formula (XII) has a structure represented by formula (XIIb): Among them, each R 29 'Each independently -C 1～3 Alkylene-; R 30 'For -C 1～6 Alkylene-; R 31 'For -C 1～6 Alkylene-; q3' is 1, 2, 3 or 4, preferably 2; q4' is 1, 2 or 3, preferably 2; Optionally, R 27 For -C 10～20 Alkylene -COOH or -C 10～20 Alkyl, preferably -C 14～18 Alkylene-COOH; Optionally, the modifying group represented by formula (XIIb) has the structure shown below: Optionally, the modifying group represented by formula (XII) has a structure represented by formula (XIIc): Among them, R 30 " for -C 1～6 Alkylene-; R 31 " for -C 1～6 Alkylene-; q3 is 1, 2, 3 or 4; q4 is 1, 2 or 3; Optionally, R 27 For -C 10～20 Alkylene -COOH or -C 10～20 Alkyl, preferably -C 14～18 Alkylene -COOH or -C 10～19 alkyl; Optionally, the modifying group represented by formula (XIIc) has the structure shown below: Optionally, the polypeptide represented by formula (I) or its derivative contains two amino acids Z2 whose side chains contain -NH2, and the modification group has the structure represented by formula (XII).

13. A polypeptide derivative or a pharmaceutically acceptable salt thereof, characterized in that: The polypeptide derivative has any structure shown in Table A: Table A 14. A pharmaceutical composition, characterized in that The polypeptide or its derivative or their pharmaceutically acceptable salts according to any one of claims 1 to 12, or the polypeptide derivative or their pharmaceutically acceptable salts according to claim 13; Optionally, it further includes a pharmaceutically acceptable excipient or carrier.

15. The polypeptide or derivative thereof or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, the polypeptide derivative or pharmaceutically acceptable salt thereof according to claim 13, or the pharmaceutical composition according to claim 14, for the treatment or prevention of disease; and / or Use in the preparation of a medicament for treating or preventing a disease; and / or Use in the treatment or prevention of disease; in, The disease comprises at least one of a metabolic disorder-related disease, a bone-related disease, a cardiovascular disease, and a neurodegenerative disease; Optionally, the metabolic disorder-related disease comprises at least one of obesity, diabetes, dyslipidemia-related diseases, fatty liver disease, metabolic syndrome, metabolic liver disease, nonalcoholic steatohepatitis and nonalcoholic fatty liver disease; Optionally, the neurodegenerative disease comprises at least one of Alzheimer's disease and Parkinson's disease.

16. A method for treating or preventing a disease, characterized in that: include: Administering a pharmaceutically acceptable dose of the polypeptide or derivative thereof or pharmaceutically acceptable salts thereof according to any one of claims 1 to 12, the polypeptide derivative or pharmaceutically acceptable salts thereof according to claim 13, or the pharmaceutical composition according to claim 14 to a subject; Wherein, the disease includes at least one of metabolic disorder-related diseases, bone-related diseases, cardiovascular diseases and neurodegenerative diseases; Optionally, the metabolic disorder-related disease comprises at least one of obesity, diabetes, dyslipidemia-related diseases, fatty liver disease, metabolic syndrome, metabolic liver disease, nonalcoholic steatohepatitis and nonalcoholic fatty liver disease; Optionally, the neurodegenerative disease comprises at least one of Alzheimer's disease and Parkinson's disease.

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