Polypeptide or analogue thereof and application thereof

Abstract

The invention discloses a polypeptide or a derivative thereof or a pharmaceutically acceptable salt thereof, the polypeptide or the derivative thereof or the pharmaceutically acceptable salt thereof has a structure (U-X1SHX4SX6X7X8X9X10X11X12X13X14X15X16X18X19X20DX22PX24TDVGAGSX32-NH2) as shown in a formula (I) and a modification group, the structure as shown in the formula (I) contains two amino acids Z1 or two amino acids Z2, the positions of the two amino acids Z1 or the two amino acids Z2 are Xi and Xi + 7 respectively, i is any integer between 6 and 13, and X is any integer between 6 and 13. The modification group is connected with the two amino acids Z1 or the two amino acids Z2 through covalent bonds. The polypeptide or the derivative thereof has certain activation activity on amylin receptors and calcitonin receptors at the same time, has a long in-vivo half-life period through modification of side chain modification groups so as to support low-dose and low-frequency administration, and can be used for preventing or treating metabolic related diseases.

Description

Technical Field

[0001] The present invention belongs to the technical field of biopharmaceuticals, and particularly relates to a polypeptide or its analog and its application. More particularly, it relates to a polypeptide or its derivative or a pharmaceutically acceptable salt thereof that simultaneously has activation activity on amylin receptor (AMYR) and calcitonin receptor (CTR), a pharmaceutical composition, and their uses. Background Art

[0002] The continuous increase in the prevalence of obesity and type 2 diabetes (T2DM) has led to a lack of effective means. At the same time, obesity and T2D patients are often accompanied by a high risk of inducing cardiovascular diseases and the influence of other metabolic complications, which makes the safe use of drugs complicated. In addition to changes in diet and lifestyle, current bariatric surgery can effectively relieve obesity and T2DM. However, the surgery is accompanied by risks and irreversible physical changes. Therefore, there is a need to develop novel and more effective drug treatment methods to achieve blood glucose control and weight management.

[0003] Amylin is a pancreatic hormone composed of 37 amino acids, which is secreted by pancreatic islet β cells together with insulin and plays a role in satiety, gastric emptying, and glucagon secretion. Amylin controls satiety signals by directly acting on the amylin receptor (AMYR) in the brain. Currently, three amylin receptor subtypes are known to exist, namely Amy1R, Amy2R, and Amy3R. Studies have shown that Amy1R is related to lipid metabolism, while Amy3R is responsible for blood glucose regulation. Amylin is also an effective inhibitor of gastric emptying and can further inhibit glucagon secretion through a central mechanism.

[0004] Calcitonin is a 32 - amino acid peptide secreted by thyroid C cells. Calcitonin acts on the calcitonin receptor (CTR) and plays a role in reducing blood calcium by inhibiting osteoclasts and promoting renal calcium excretion.

[0005] Studies have shown that co - activation of the amylin receptor and the calcitonin receptor has a positive metabolic promoting effect, which can effectively reduce blood glucose levels and body weight. Developing long - acting dual agonists of the amylin receptor and the calcitonin receptor is expected to provide an effective drug for treating metabolic diseases, including obesity, type 2 diabetes, non - alcoholic fatty liver (NASH), dyslipidemia, etc. Currently, no long - acting dual agonists of the amylin receptor and the calcitonin receptor (DACRA) have been approved. Therefore, there is an urgent need to develop a polypeptide or its analog that can simultaneously have activation activity on the amylin receptor (AMYR) and the calcitonin receptor (CTR). Summary of the Invention

[0006] The present invention aims to solve at least one of the technical problems existing in the prior art to at least a certain extent. To this end, the present invention provides a polypeptide or an analogue thereof, which has activation activity for amylin receptor (AMYR) and calcitonin receptor (CTR) simultaneously.

[0007] The present invention is completed based on the following findings of the inventors:

[0008] Some long-acting amylin analogues are in the clinical research stage and show certain advantages in the treatment of metabolic diseases. Pramlintide is an amylin analogue, which is approved for combination use with insulin treatment to improve insulin sensitivity in diabetic patients and assist in reducing blood glucose. However, the in vivo half-life of this drug is less than 1 hour, so patients need to inject it multiple times daily with meals, causing inconvenience. Moreover, due to its structural characteristics, amylin analogues are prone to fibrotic aggregation in vivo and in vitro, resulting in harsh storage conditions and potential immunogenic risks.

[0009] Salmon calcitonin (sCT) is used in diseases such as hypercalcemia, osteoporosis, and Paget's disease. Recent studies have shown that calcitonin also has other metabolic benefits, such as affecting insulin sensitivity, reducing gastric emptying rate, and promoting satiety. However, its in vivo half-life is short and it needs to be administered subcutaneously multiple times a day, resulting in poor patient compliance. And sCT has poor stability and is prone to aggregation and precipitation, causing immunogenic reactions, and there are safety problems.

[0010] The development of polypeptide drugs is often hindered by short half-life, low bioavailability, etc. Patients often receive higher doses of therapeutic drugs more frequently, which may lead to reduced compliance, increased costs, and increased risk of side effects. Therefore, it is necessary to develop therapeutic agents with an extended half-life.

[0011] Based on this, the method of the present invention introduces residues containing -SH or -NH 2 side chains (including but not limited to cysteine (C or c) or lysine (K or k)) at two points of mutation in the polypeptide chain, and performs side chain dual-site fixation modification through macrocyclization reaction to lock the advantageous binding conformation of the target polypeptide. Compared with traditional polypeptide drugs, this strategy can reduce the tendency of aggregation and fibrosis, which is beneficial to further improving the stability and receptor binding activity of the target polypeptide.

[0012] Therefore, in one aspect of the present invention, the present invention proposes 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 or a pharmaceutically acceptable salt thereof has the structure shown in formula (I):

[0013] U-X1 SHX 4 SX 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 DX 22 PX 24 TDVGAGSX 32 -NH 2 (I);

[0014] wherein each U is independently hydrogen, acetyl, or benzoyl;

[0015] X 1 is A or K; X 4 is L or αMeL; X 6 is Z 1 、Z 2 or T; X 7 is Z 1 、Z 2 or A; X 8 is Z 1 、Z 2 or V; X 9 is Z 1 、Z 2 or L; X 10 is Z 1 、Z 2 or G; X 11 is Z 1 、Z 2 、homoR, Orn or R; X 12 is Z 1 、Z 2 or L; X 13 is Z 1 、Z 2 or S; X 14 is Z 1 、Z 2 or A; X 15 is Z 1 、Z 2 or E; X 16 is Z 1 、Z 2 or L; X 17 is Z 1 、Z 2 or H; X18 is Z 1 、Z 2 、K, αMeK or Orn; X 19 is Z 1 、Z 2 or L; X 20 is Z 1 、Z 2 or Aib; X 22 is Y or αMeF; X 24 is R, N-Me-R, homoR, norR, Q or r; X 32 is P, Hyp, cis-P(4-NH 2 )、trans-P(4-NH 2 ) or p;

[0016] The structure shown in formula (I) contains two amino acids Z 1 or contains two amino acids Z 2 , and the two amino acids Z 1 or the two amino acids Z 2 are located at X i and X i+7 respectively, and i is any integer between 6 and 13;

[0017] Each amino acid Z 1 is independently selected from C, c, αMeC, HoC, Hoc, Pen or N-Me-C;

[0018] Each amino acid Z 2 is independently selected from K, k, Dap, Dab, Orn, HomoK, N-Me-K, N-Me-k, αMeK, αMek.

[0019] The polypeptide or its derivative or their pharmaceutically acceptable salts (referred to as polypeptide or its analogs) according to the embodiments of the present invention are dual agonist polypeptide analogs, which can simultaneously have a certain balanced or unbalanced activation activity on amylin receptor (AMYR) and calcitonin receptor (CTR). It can be used for preventing or treating metabolic syndrome, such as T2DM, obesity, hyperlipidemia, NAFLD and NASH; it also has other potential therapeutic applications for diseases, such as Alzheimer's disease (AD), related symptoms or diseases of alcohol or drug addiction, etc.

[0020] In a second aspect of the present invention, 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 a pharmaceutically acceptable salt thereof as described in the first aspect. As can be seen from the foregoing, the polypeptide or its derivative or a pharmaceutically acceptable salt thereof (hereinafter referred to as the polypeptide or its analog) is a dual agonist polypeptide analog, which can simultaneously have a certain balanced or unbalanced activation activity on the amylin receptor (AMYR) and the calcitonin receptor (CTR). Thus, a drug containing the polypeptide or its derivative or a pharmaceutically acceptable salt thereof can effectively prevent or treat diseases related to the amylin receptor and / or the calcitonin receptor.

[0021] In a third aspect of the present invention, the present invention provides a combined drug or a drug kit. According to an embodiment of the present invention, the combined drug or the drug kit comprises: the polypeptide or its derivative or a pharmaceutically acceptable salt thereof as described in the first aspect, or the pharmaceutical composition as described in the second aspect as a first active ingredient; and a second active ingredient; wherein the second active ingredient comprises a drug for preventing and / or treating diseases. The combined drug or the drug kit according to the embodiment of the present invention can further improve the therapeutic effect on diseases related to the amylin receptor and / or the calcitonin receptor.

[0022] In a fourth aspect of the present invention, the present invention provides the use of the polypeptide or its derivative or a pharmaceutically acceptable salt thereof as described in the first aspect, the pharmaceutical composition as described in the second aspect, or the combined drug or the drug kit as described in the third aspect in the preparation of a drug for treating or preventing diseases related to the amylin receptor and / or the calcitonin receptor.

[0023] The additional aspects and advantages of the present invention will be partially given in the following description, partially become apparent from the following description, or be understood through the practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The above and / or additional aspects and advantages of the present invention will become apparent and be readily understood from the description of the embodiments in conjunction with the following drawings, wherein:

[0025] Figure 1 FIG. 18 is a schematic diagram of the synthesis process of the Staple linker in Example 1 of the present invention;

[0026] Figure 2 FIG. 22 is a graph showing the binding activity results of different polypeptide derivatives to AMY3R in Test Example 1 of the present invention;

[0027] Figure 3 FIG. 26 is a graph showing the binding activity results of different polypeptide derivatives to CTR in Test Example 1 of the present invention;

[0028] FIG. 4 is a PK curve graph of different polypeptide derivatives in rats in Test Example 2 of the present invention;

[0029] Figure 5 This is the PK curve of different polypeptide derivatives in cynomolgus monkeys in Test Example 2 of the present invention;

[0030] Figure 6 This is the result of the changes in body weight and food intake after a single dose of the polypeptide derivative in SD rats in Test Example 3 of the present invention;

[0031] Figure 7 This is the result of the changes in body weight and food intake after a single dose of the polypeptide derivative in the DIO mouse model in Test Example 4 of the present invention. The positive control drug is Cagrilintide;

[0032] Figure 8 This is the result of the changes in body weight and food intake after a single dose of the combination of the polypeptide derivative and Semaglutide in the DIO mouse model in Test Example 5 of the present invention. The positive control drug is the same dose of Cagrilintide or the same dose of Semaglutide;

[0033] Figure 9 This is the result of the changes in body weight, blood glucose and food intake after continuous administration of the polypeptide derivative in the ZDF rat model in Test Example 6 of the present invention;

[0034] Figure 10 This is the result of the aggregation precipitation stability test of the polypeptide derivative in Test Example 9 of the present invention. The positive control is salmon calcitonin. Detailed implementation mode

[0035] The embodiments of the present invention will be described in detail below. The embodiments described below are exemplary and are only used to explain the present invention and should not be construed as a limitation of the present invention.

[0036] It should be noted that the terms "first" and "second" are only used for descriptive purposes and cannot be construed as indicating or implying relative importance or implicitly indicating the quantity of the indicated technical features. Thus, features defined with "first" and "second" may explicitly or implicitly include one or more of such features. Further, in the description of the present invention, unless otherwise specified, the meaning of "plurality" is two or more.

[0037] Detailed description of the present invention

[0038] Definitions and general terms

[0039] In this article, the term "comprising" or "including" is an open expression, that is, it includes the content specified by the present invention, but does not exclude other aspects of the content.

[0040] As used herein, the term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other ingredients contained in a polypeptide or its derivative and / or the mammalian subject being treated therewith. Preferably, "pharmaceutically acceptable" as used in the present invention means approved by a federal regulatory agency or a national government or listed in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals, particularly in humans.

[0041] As used herein, the term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the polypeptides or their derivatives of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.

[0042] As used herein, amino acids are represented by the conventional single-letter and three-letter codes for natural amino acids, as well as the generally accepted three-letter codes for other α-amino acids. For example, α-aminoisobutyric acid can be represented by either Aib or B. Unless otherwise specified, all amino acid residues in capital letters in the present invention are in the L-configuration, and amino acid residues in lower case letters are in the D-configuration.

[0043] As used herein, the term "Aib" has the structural formula

[0044] As used herein, the term "αMeF" has the structural formula

[0045] As used herein, the term "Orn" has the structural formula

[0046] As used herein, the term "αMeL" has the structural formula

[0047] As used herein, the term "αMeK" has the structural formula

[0048] As used herein, the term "N-Me-R" has the structural formula

[0049] As used herein, the term "Hyp" has the structural formula

[0050] As used herein, the term "homoR" has the structural formula

[0051] As used herein, the term "cis-P(4-NH 2) The structural formula of

[0052] In this text, the term "trans-P(4-NH 2 ) The structural formula of In this text, the structural formula of the term "αMeC" is In this text, the structural formula of the term "HoC" is In this text, the structural formula of the term "Hoc" is In this text, the structural formula of the term "Pen" is In this text, the structural formula of the term "N-Me-C" is In this text, the structural formula of the term "Dab" is In this text, the structural formula of the term "Dap" is In this text, the structural formula of the term "homoK" is In this text, the structural formula of the term "αMek" is

[0053] In this text, the structural formula of the term "N-Me-K" is

[0054] In this text, the terms "optionally", "optional", or "option" generally mean that the subsequent described event or condition may but does not necessarily occur, and this description includes the cases where the event or condition occurs and the cases where the event or condition does not occur.

[0055] In this text, the terms "optionally substituted", "optionally substituted with", and "substituted or unsubstituted" can be used interchangeably. Generally, the term "optionally", whether before or after the term "substituted", means that one or more hydrogen atoms in the given structure are replaced by specific substituents. Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When there are more than one position in the given structural formula that can be substituted by one or more substituents selected from a specific group, then the substituents can be the same or different at each position. The substituents described therein can be, but are not limited to, F, Cl, Br, CN, OH, NH 2 , NO 2 etc.

[0056] In this text, the term "one or more" (for example, in the definition of the substituents of the compounds (modifying groups) of the general formula of the present invention) means "one, two, three, four, or five, especially one, two, three, or four, more especially one, two, or three, even more especially one or two".

[0057] In addition, it should be noted that, unless otherwise explicitly specified, in the present invention, the description methods "each... independently is", "... each independently is" and "... independently is" can be interchanged and should be understood in a broad sense. It can either mean that among different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0058] In this text, the term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.

[0059] In this text, the minimum and maximum carbon atom contents in a hydrocarbon group are indicated by a prefix. For example, the prefix C a～b means containing "a" to "b" carbon atoms. Exemplarily, "C 1～n " refers to a straight-chain or branched-chain saturated / unsaturated carbon chain containing 1, 2, 3, 4, 5,..., or n carbon atoms; further understanding, "C 1～n " should be interpreted as any sub-range included therein. For example, in C 1～20 , it includes 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 .

[0060] In this text, the general structural formula of the term "alkyl" is An alkylene group can be a straight-chain alkyl group or a branched-chain alkyl group. Exemplarily, the term "C 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.

[0061] In this text, the structural general formula of the term "alkylene" is The alkylene can be a straight-chain alkylene or a branched-chain alkylene. Exemplarily, the term "C 1～20 alkylene" refers to an alkylene having 1 to 20 carbon atoms; the term "C 1～6 alkylene" refers to an alkylene having 1 to 6 carbon atoms.

[0062] In this text, the term "C 1～6 alkoxy" refers to a C 1～6 alkyl containing the formula "-O-alkyl", where the term "alkyl" is defined as 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 said "C 1～6 alkoxy" can contain 1, 2, 3, 4, or 5 carbon atoms ("C 1～5 alkoxy"), preferably, it can contain 1, 2, 3, or 4 carbon atoms ("C 1～4 alkoxy").

[0063] In this text, the term "oxoalkylene" refers to the group formed by removing one hydrogen atom from "oxoalkyl".

[0064] In this text, the term "aryl" refers to a carbocyclic system containing monocyclic, bicyclic, and tricyclic rings, where at least one ring system is aromatic, and each ring system contains a ring composed of 3 - 10 atoms. The aryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the aryl group. The term "aryl" can be used interchangeably with the terms "aromatic ring" or "aromatic cycle". The aryl group can include phenyl, indenyl, naphthyl, and anthracenyl. The said aryl group is optionally substituted by one or more substituents described in this disclosure.

[0065] In this text, the term "arylene" refers to the group formed by removing one hydrogen atom from "aryl".

[0066] In this text, the term "heteroaryl" refers to a carbocyclic system containing monocyclic, bicyclic, and tricyclic rings that contains at least one heteroatom, where at least one ring system is aromatic. Among them, the heteroatom refers to nitrogen atom, oxygen atom, sulfur atom, etc. It usually represents a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of multiple ring atoms, which contains 1, 2, or 3 ring heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon.

[0067] In this text, the term "heteroarylene" refers to the group formed by removing one hydrogen atom from "heteroaryl".

[0068] In the description of the groups of the present invention is used to describe the position of group substitution.

[0069] In this text, the structural formula of the term "-NH-CO-" or "-NH-C(=O)-" is

[0070] In this text, "pharmaceutical composition" can refer to the treatment of diseases and can also be used in in vitro cell culture experiments. When used for the treatment of diseases, the term "pharmaceutical composition" generally refers to a unit dosage form, which can be any type of preparation and can be prepared by any of the methods well-known in the pharmaceutical field. All methods include the step of combining the active ingredient with excipients constituting one or more accessory ingredients. Generally, the composition is prepared by uniformly and sufficiently combining the active polypeptide or its derivative or the resuscitator with a liquid excipient, a finely divided solid excipient or both.

[0071] In the chemical structure of the ligand or compound described in the present disclosure, the bond represents an unspecified configuration. If there are chiral isomers in the chemical structure, the bond can be or simultaneously include both configurations. Although all the above structural formulas are drawn in certain isomeric forms for simplicity, the present disclosure can include all isomers, such as: tautomers, rotamers, geometric isomers, diastereomers, racemates and enantiomers.

[0072] In this text, the term "pharmaceutically acceptable excipients" can include any solvent, including but not limited to pharmaceutically acceptable carriers, stabilizers, dispersants, cosolvents, plasticizers, solid excipients, diluents or other liquid excipients, etc., suitable for a particular target dosage form. Except for the range where any conventional excipients are incompatible with the polypeptide or its derivative, pharmaceutical composition or drug containing them of the present invention, such as any adverse biological effects produced or any harmful interactions with any other components of the pharmaceutically acceptable composition, their uses are also within the scope contemplated by the present invention.

[0073] Except for any conventional excipients, the range where they are incompatible with the polypeptide or its derivative, pharmaceutical composition or drug containing them of the present invention, such as any adverse biological effects produced or any harmful interactions with any other components of the pharmaceutically acceptable composition, their uses are also within the scope contemplated by the present invention.

[0074] The pharmaceutical compositions of the present disclosure include formulations suitable for parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the pharmaceutical art. The amount of the active ingredient that may be combined with the excipient substances to produce a single dosage form is generally the amount of the polypeptide or its derivative that produces a therapeutic effect.

[0075] As used herein, the term "agonist" refers to a substance (ligand) that activates the receptor type.

[0076] As used herein, the term "treatment" refers to achieving the desired pharmacological and / or physiological effect. The effect may be prophylactic in terms of completely or partially preventing a disease or its symptoms, and / or may be therapeutic in terms of partially or completely curing a disease and / or an adverse effect caused by the disease. "Treatment" as used herein covers diseases of mammals, particularly humans, including: (a) preventing the occurrence of a disease or disorder in an individual who is susceptible to the disease but has not been diagnosed with the disease; (b) inhibiting a disease, such as arresting the development of the disease; or (c) alleviating a disease, such as reducing the symptoms associated with the disease. "Treatment" as used herein covers any administration of a medicament containing a polypeptide or its derivative to an individual to treat, cure, alleviate, improve, reduce or inhibit a disease of the individual, including but not limited to administering a medicament containing the polypeptide or its derivative described herein to an individual in need thereof.

[0077] As used herein, the term "non-alcoholic fatty liver disease (NAFLD)" generally refers to a clinicopathological syndrome characterized by excessive intrahepatic fat deposition excluding that caused by alcohol and other definite liver-damaging factors, 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.

[0078] Detailed description of the polypeptide or its analogs of the present invention and their applications

[0079] The present invention provides a polypeptide or its derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition and their uses, which will be described in detail below respectively.

[0080] Polypeptide or its derivative or a pharmaceutically acceptable salt thereof

[0081] In one aspect of the present invention, there is provided a polypeptide or its derivative or a pharmaceutically acceptable salt thereof. According to an embodiment of the present invention, the polypeptide or its derivative or a pharmaceutically acceptable salt thereof has the structure shown in formula (I):

[0082] U-X 1 SHX 4 SX 6 X 7 X 8X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 DX 22 PX 24 TDVGAGSX 32 -NH 2 (I);

[0083] wherein each U is independently hydrogen, acetyl, or benzoyl;

[0084] X 1 is A or K; X 4 is L or αMeL; X 6 is Z 1 、Z 2 or T; X 7 is Z 1 、Z 2 or A; X 8 is Z 1 、Z 2 or V; X 9 is Z 1 、Z 2 or L; X 10 is Z 1 、Z 2 or G; X 11 is Z 1 、Z 2 、homoR, Orn or R; X 12 is Z 1 、Z 2 or L; X 13 is Z 1 、Z 2 or S; X 14 is Z 1 、Z 2 or A; X 15 is Z 1 、Z 2 or E; X 16 is Z 1 、Z 2 or L; X 17 is Z 1 、Z 2 or H; X 18 is Z 1 、Z 2 、K, αMeK or Orn; X 19is Z 1 、Z 2 or L; X 20 is Z 1 、Z 2 or Aib; X 22 is Y or αMeF; X 24 is R, N-Me-R, homoR, norR, Q or r; X 32 is P, Hyp, cis-P(4-NH 2 )、trans-P(4-NH 2 ) or p;

[0085] The structure shown in formula (I) contains two amino acids Z 1 or contains two amino acids Z 2 , the two amino acids Z 1 or two amino acids Z 2 are located at X i and X i+7 , and i is any integer between 6 and 13;

[0086] Each amino acid Z 1 is independently selected from C, c, αMeC, HoC, Hoc, Pen or N-Me-C;

[0087] Each amino acid Z 2 is independently selected from K, k, Dap, Dab, Orn, HomoK, N-Me-K, N-Me-k, αMeK, αMek.

[0088] The polypeptide or its derivative or their pharmaceutically acceptable salts (referred to as polypeptide or its analogs) according to the embodiments of the present invention are dual agonist polypeptide analogs, which can simultaneously have a certain balanced or unbalanced activation activity on the amylin receptor (AMYR) and the calcitonin receptor (CTR). It can be used for the prevention or treatment of metabolic syndrome, such as T2DM, obesity, hyperlipidemia, NAFLD and NASH; it also has other potential therapeutic applications for diseases, such as Alzheimer's disease (AD), symptoms or diseases related to alcohol or drug addiction, etc.

[0089] Furthermore, by modifying the two amino acids Z 1 or the two amino acids Z 2 of the above polypeptide or its analogs, it can have a longer in vivo half-life to support low-dose and low-frequency administration.

[0090] It should be noted that in this article, without special explanation, U refers to a hydrogen or its substituent group in the -NH 1 of amino acid X 2 . When U is hydrogen, X 1-NH of 2 is -NH 2 itself; when U is an acetyl group (i.e., Ac), X 1 -NH of 2 is -NHAc; when U is a benzoyl group (i.e., Bzl), X 1 -NH of 2 is -NH(Bzl).

[0091] It should be noted that in this article, without special explanation, -NH of X 32 -NH of 2 refers to that the -OH in -COOH of X 32 is replaced by -NH 2 , that is, -CONH 2 .

[0092] According to an embodiment of the present invention, the positions of the two amino acids Z 1 or the two amino acids Z 2 are one of the following groups: X 6 and X 13 , X 7 and X 14 , X 8 and X 15 , X 9 and X 16 , X 10 and X 17 , X 11 and X 18 , X 12 and X 19 , X 13 and X 20 .

[0093] According to an embodiment of the present invention, the positions of the two amino acids Z 1 or the two amino acids Z 2 are X 8 and X 15 respectively.

[0094] According to an embodiment of the present invention, the two amino acids Z 1 or the two amino acids Z 2 are each independently selected from K, c or C.

[0095] According to an embodiment of the present invention, X 1 is A or K.

[0096] According to an embodiment of the present invention, X 1 is A.

[0097] According to an embodiment of the present invention, X 4 is L.

[0098] According to an embodiment of the present invention, X 6 is K, c, C or T.

[0099] According to an embodiment of the present invention, X 6 is C or T.

[0100] According to an embodiment of the present invention, X 6 is T.

[0101] According to an embodiment of the present invention, X 7 is K, c, C or A.

[0102] According to an embodiment of the present invention, X 7 is C or A.

[0103] According to an embodiment of the present invention, X 7 is A.

[0104] According to an embodiment of the present invention, X 8 is C, V, c, HoC, Pen, αMeC, N-Me-C, K, Orn, k or Dab.

[0105] According to an embodiment of the present invention, X 8 is K, c, C or V.

[0106] According to an embodiment of the present invention, X 8 is C, V or K.

[0107] According to an embodiment of the present invention, X 8 is C or V.

[0108] According to an embodiment of the present invention, X 8 is V.

[0109] According to an embodiment of the present invention, X 9 is K, c, C or L.

[0110] According to an embodiment of the present invention, X 9 is C or L.

[0111] According to an embodiment of the present invention, X 9 is L.

[0112] According to an embodiment of the present invention, X 10 is K, c, C or G.

[0113] According to an embodiment of the present invention, X 10 is C or G.

[0114] According to an embodiment of the present invention, X 10 is G.

[0115] According to an embodiment of the present invention, X 11 is K, c, C, homoR, Orn or R.

[0116] According to an embodiment of the present invention, X 11 is K, C, homoR, Orn or R.

[0117] According to an embodiment of the present invention, X 11 is K, C, homoR or R.

[0118] According to an embodiment of the present invention, X 11 is C, homoR or R.

[0119] According to an embodiment of the present invention, X 11 is homoR or R.

[0120] According to an embodiment of the present invention, X 12 is K, c, C or L.

[0121] According to an embodiment of the present invention, X 12 is C or L.

[0122] According to an embodiment of the present invention, X 12 is L.

[0123] According to an embodiment of the present invention, X 13 is K, c, C or S.

[0124] According to an embodiment of the present invention, X 13 is C or S.

[0125] According to an embodiment of the present invention, X 13 is S.

[0126] According to an embodiment of the present invention, X 14 is K, c, C or A.

[0127] According to an embodiment of the present invention, X 14 is C or A.

[0128] According to an embodiment of the present invention, X 14 is A.

[0129] According to an embodiment of the present invention, X 15 is C, E, c, HoC, Pen, αMeC, αMeK, N-Me-C, K, Orn, k or Dab.

[0130] According to an embodiment of the present invention, X 15 is K, c, C or E.

[0131] According to an embodiment of the present invention, X 15is K, C or E.

[0132] According to an embodiment of the present invention, X 15 is C or E.

[0133] According to an embodiment of the present invention, X 15 is C.

[0134] According to an embodiment of the present invention, X 16 is K, c, C or L.

[0135] According to an embodiment of the present invention, X 16 is C or L.

[0136] According to an embodiment of the present invention, X 16 is L.

[0137] According to an embodiment of the present invention, X 17 is K, c, C or H.

[0138] According to an embodiment of the present invention, X 17 is C or H.

[0139] According to an embodiment of the present invention, X 17 is H.

[0140] According to an embodiment of the present invention, X 18 is c, K, C, k, αMeK or Orn.

[0141] According to an embodiment of the present invention, X 18 is K, C, k, αMeK or Orn.

[0142] According to an embodiment of the present invention, X 18 is C, K or αMeK.

[0143] According to an embodiment of the present invention, X 18 is K or αMeK.

[0144] According to an embodiment of the present invention, X 19 is K, c, C or L.

[0145] According to an embodiment of the present invention, X 19 is C or L.

[0146] According to an embodiment of the present invention, X 21 is L.

[0147] According to an embodiment of the present invention, X 20 is K, c, C or Aib.

[0148] According to an embodiment of the present invention, X 20 is C or Aib.

[0149] According to an embodiment of the present invention, X 20 is Aib.

[0150] According to an embodiment of the present invention, X 22 is Y.

[0151] According to an embodiment of the present invention, X 23 is P.

[0152] According to an embodiment of the present invention, X 24 is R, N-Me-R, homoR, norR, r or Q.

[0153] According to an embodiment of the present invention, X 24 is R, N-Me-R, homoR, norR or Q.

[0154] According to an embodiment of the present invention, X 24 is R, N-Me-R or Q.

[0155] According to an embodiment of the present invention, X 29 is A.

[0156] According to an embodiment of the present invention, X 32 is P or Hyp.

[0157] According to an embodiment of the present invention, the structure shown in formula (I) has the following structure: U-X 1 SHX 4 STX 7 X 8 LGX 11 LX 13 X 14 X 15 LHX 18 LX 20 DX 22 X 23 X 24 TDVGAGSX 32 -NH 2 (Ia).

[0158] In some alternative embodiments of the present invention, in the structure shown in formula (Ia), X 1 is A or K.

[0159] In some alternative embodiments of the present invention, in the structure shown in formula (Ia), X 4 is L or αMeL.

[0160] In some alternative embodiments of the present invention, in the structure shown in formula (Ia), X 7 is C or A.

[0161] In some alternative embodiments of the present invention, in the structure represented by formula (Ia), X 8 is C or V.

[0162] In some alternative embodiments of the present invention, in the structure represented by formula (Ia), X 11 is homoR, C or R.

[0163] In some alternative embodiments of the present invention, in the structure represented by formula (Ia), X 13 is C or S.

[0164] In some alternative embodiments of the present invention, in the structure represented by formula (Ia), X 14 is C or A.

[0165] In some alternative embodiments of the present invention, in the structure represented by formula (Ia), X 15 is C or E.

[0166] In some alternative embodiments of the present invention, in the structure represented by formula (Ia), X 18 is C, K, k, αMeK or Orn.

[0167] In some alternative embodiments of the present invention, in the structure represented by formula (Ia), X 20 is C or Aib.

[0168] In some alternative embodiments of the present invention, in the structure represented by formula (Ia), X 22 is Y or αMeF.

[0169] In some alternative embodiments of the present invention, in the structure represented by formula (Ia), X 23 is P or K.

[0170] In some alternative embodiments of the present invention, in the structure represented by formula (Ia), X 24 is R, N-Me-R, homoR, norR or Q.

[0171] In some alternative embodiments of the present invention, in the structure represented by formula (Ia), X 32 is P or Hyp.

[0172] According to an embodiment of the present invention, the structure represented by formula (I) has the following structure: U-X 1 SHX 4 STAX 8 LGX 11 LSAX 15 LHX 18 L-Aib-DX 22 PX 24TDVGAGSX 32 -NH 2 (Ib).

[0173] In some alternative embodiments of the present invention, in the structure shown in formula (Ib), X 1 is A or K.

[0174] In some alternative embodiments of the present invention, in the structure shown in formula (Ib), X 4 is L or αMeL.

[0175] In some alternative embodiments of the present invention, in the structure shown in formula (Ib), X 8 is C, V, c, HoC, Pen, αMeC, N-Me-C, K, Orn, k or Dab.

[0176] In some alternative embodiments of the present invention, in the structure shown in formula (Ib), X 11 is homoR, C, K, Orn or R.

[0177] In some alternative embodiments of the present invention, in the structure shown in formula (Ib), X 15 is C, E, c, HoC, Pen, αMeC, αMeK, N-Me-C, K, Orn, k or Dab.

[0178] In some alternative embodiments of the present invention, in the structure shown in formula (Ib), X 18 is C, K, αMeK or Orn.

[0179] In some alternative embodiments of the present invention, in the structure shown in formula (Ib), X 22 is Y or αMeF.

[0180] In some alternative embodiments of the present invention, in the structure shown in formula (Ib), X 24 is R, N-Me-R, homoR, norR, r or Q.

[0181] In some alternative embodiments of the present invention, in the structure shown in formula (Ib), X 32 is P or Hyp.

[0182] According to an embodiment of the present invention, the structure shown in formula (I) has the following structure: U-ASHX 4 STX 7 X 8 LGX 1 1 X 12 X 13 X 14 X 15LX 17 X 18 X 19 X 20 DX 22 PX 24 TDVGAGSX 32 -NH 2 (II).

[0183] In some alternative embodiments of the present invention, in the structure shown in formula (II), X 4 is L or αMeL.

[0184] In some alternative embodiments of the present invention, in the structure shown in formula (II), X 7 is C or A.

[0185] In some alternative embodiments of the present invention, in the structure shown in formula (II), X 8 is C, K or V.

[0186] In some alternative embodiments of the present invention, in the structure shown in formula (II), X 11 is homoR, C, K or R.

[0187] In some alternative embodiments of the present invention, in the structure shown in formula (II), X 12 is L or C.

[0188] In some alternative embodiments of the present invention, in the structure shown in formula (II), X 13 is C or S.

[0189] In some alternative embodiments of the present invention, in the structure shown in formula (II), X 14 is C or A.

[0190] In some alternative embodiments of the present invention, in the structure shown in formula (II), X 15 is K, C or E.

[0191] In some alternative embodiments of the present invention, in the structure shown in formula (II), X 17 is C or H.

[0192] In some alternative embodiments of the present invention, in the structure shown in formula (II), X 18 is C, K, αMeK or Orn.

[0193] In some alternative embodiments of the present invention, in the structure shown in formula (II), X 19 is C or L.

[0194] In some alternative embodiments of the present invention, in the structure shown in formula (II), X20 is C or Aib.

[0195] In some alternative embodiments of the present invention, in the structure shown in formula (II), X 22 is Y or αMeF.

[0196] In some alternative embodiments of the present invention, in the structure shown in formula (II), X 24 is R, N-Me-R or Q.

[0197] In some alternative embodiments of the present invention, in the structure shown in formula (II), X 32 is P or Hyp.

[0198] According to an embodiment of the present invention, the structure shown in formula (I) has the following structure: U-ASHX 4 STAX 8 LGX 11 LX 13 AX 15 LHX 18 LX 20 DX 22 PX 24 TDVGAGSX 32 -NH 2 (IIa).

[0199] In some alternative embodiments of the present invention, in the structure shown in formula (IIa), X 4 is L or αMeL.

[0200] In some alternative embodiments of the present invention, in the structure shown in formula (IIa), X 8 is C, K or V.

[0201] In some alternative embodiments of the present invention, in the structure shown in formula (IIa), X 11 is homoR, C, K or R.

[0202] In some alternative embodiments of the present invention, in the structure shown in formula (IIa), X 13 is C or S.

[0203] In some alternative embodiments of the present invention, in the structure shown in formula (IIa), X 15 is K, C or E.

[0204] In some alternative embodiments of the present invention, in the structure shown in formula (IIa), X 18 is C, K, αMeK or Orn.

[0205] In some alternative embodiments of the present invention, in the structure shown in formula (IIa), X 20 is C or Aib.

[0206] In some alternative embodiments of the present invention, in the structure shown in formula (IIa), X 22 is Y or αMeF.

[0207] In some alternative embodiments of the present invention, in the structure shown in formula (IIa), X 24 is R, N-Me-R or Q.

[0208] In some alternative embodiments of the present invention, in the structure shown in formula (IIa), X 32 is P or Hyp.

[0209] According to an embodiment of the present invention, the structure shown in formula (I) has the following structure: U-ASHLSTAX 8 LGX 11 LSAX 15 LHX 18 L-Aib-DYPX 24 TDVGAGSX 32 -NH 2 (IIb).

[0210] In some alternative embodiments of the present invention, in the structure shown in formula (IIb), X 8 is C, K or V.

[0211] In some alternative embodiments of the present invention, in the structure shown in formula (IIb), X 11 is homoR, C or R.

[0212] In some alternative embodiments of the present invention, in the structure shown in formula (IIb), X 15 is K, C or E.

[0213] In some alternative embodiments of the present invention, in the structure shown in formula (IIb), X 18 is C, K or αMeK.

[0214] In some alternative embodiments of the present invention, in the structure shown in formula (IIb), X 24 is R, N-Me-R or Q.

[0215] In some alternative embodiments of the present invention, in the structure shown in formula (IIb), X 32 is P or Hyp.

[0216] According to an embodiment of the present invention, the structure shown in formula (I) has the following structure: U-ASHLSTACLGX11 LSACLHX 18 L-Aib-DYPX 24 TDVGAGSX 32 -NH 2 (III).

[0217] In some alternative embodiments of the present invention, in the structure shown in formula (III), X 11 is homoR or R.

[0218] In some alternative embodiments of the present invention, in the structure shown in formula (III), X 18 is K or αMeK.

[0219] In some alternative embodiments of the present invention, in the structure shown in formula (III), X 24 is R, N-Me-R or Q.

[0220] In some alternative embodiments of the present invention, in the structure shown in formula (III), X 32 is P or Hyp.

[0221] According to an embodiment of the present invention, the structure shown in formula (I) has at least one of the following structures:

[0222] U-ASHLSCAVLGRLCAELHKL-Aib-DYPRTDVGAGSP-NH 2 ;

[0223] U-ASHLSTCVLGRLSCELHKL-Aib-DYPRTDVGAGSP-NH 2 ;

[0224] U-ASHLSTACLGRLSACLHKL-Aib-DYPRTDVGAGSP-NH 2 ;

[0225] U-ASHLSTAVCGRLSAECHKL-Aib-DYPRTDVGAGSP-NH 2 ;

[0226] U-ASHLSTAVLCRLSAELCKL-Aib-DYPRTDVGAGSP-NH 2 ;

[0227] U-ASHLSTAVLGCLSAELHCL-Aib-DYPRTDVGAGSP-NH 2 ;

[0228] U-ASHLSTAVLGRCSAELHKC-Aib-DYPRTDVGAGSP-NH 2 ;

[0229] U-ASHLSTAVLGRLCAELHKLCDYPRTDVGAGSP-NH 2 ;

[0230] U-ASHLSTACLGRLSACLH-Orn-L-Aib-D-(αMeF)-PRTDVGAGS-Hyp-NH 2 ;

[0231] U-ASH-(αMeL)-STACLGRLSACLHKL-Aib-D-(αMeF)-P-(N-Me-R)-TDVGAGSP-NH 2 ;

[0232] U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYP-(N-Me-R)-TDVGAGS-Hyp-NH 2 ;

[0233] U-ASHLSTACLG-homoR-LSACLH-(αMeK)-L-Aib-DYP-(N-Me-R)-TDVGAGSP-NH 2 ;

[0234] U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYP-homoR-TDVGAGS-Hyp-NH 2 ;

[0235] U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYP-norR-TDVGAGS-Hyp-NH 2 ;

[0236] U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH 2 ;

[0237] U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYP-r-TDVGAGS-Hyp-NH 2 ;

[0238] U-ASHLSTAVLGCLSAELHCL-Aib-DYPQTDVGAGS-Hyp-NH 2 ;

[0239] U-KSHLSTACLGRLSACLH-(αMeK)-L-Aib-DYP-(N-Me-R)-TDVGAGS-Hyp-NH 2 ;

[0240] U-KSHLSTAVLGCLSAELHCL-Aib-DYPQTDVGAGS-Hyp-NH 2 ;

[0241] U-KSHLSTA-c-LGRLSA-c-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH 2 ;

[0242] U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYPQTDVGAGS-(cis-P(4-NH 2 ))-NH 2 ;

[0243] U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYPQTDVGAGS-(trans-P(4-NH 2 ))-NH 2 ;

[0244] U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYPQTDVGAGS-p-NH 2 ;

[0245] U-ASHLSTACLG-homoR-LSACLH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH 2 ;

[0246] U-ASHLSTACLG-Orn-LSA CLH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH 2 ;

[0247] U-ASHLSTA-HoC-LGRLSA-HoC-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH 2 ;

[0248] U-ASHLSTA-Pen-LGRLSA-Pen-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH 2 ;

[0249] U-ASHLSTA-(αMeC)-LGRLSA-(αMeC)-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH 2 ;

[0250] U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH 2 ;

[0251] U-ASHLSTA-(N-Me-C)-LGRLSA-(N-Me-C)-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH 2 ;

[0252] U-ASHLSTAKLGRLSAKLH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH 2 ;

[0253] U-ASHLSTAVLGKLSAELHKL-Aib-DYPQTDVGAGS-Hyp-NH 2 ;

[0254] U-ASHLSTA-Orn-LGRLSA-Orn-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH 2 ;

[0255] U-ASHLSTA-Dab-LGRLSA-Dab-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH 2 ;

[0256] Each U is independently selected from H, acetyl, and benzoyl.

[0257] It should be noted that in the polypeptide in the structure shown by the above formula (I), the "-" between amino acids represents an amide bond; exemplarily, the "-" in "L-Aib-D" represents an amide bond.

[0258] According to an embodiment of the present invention, in the structure shown by the formula (I), U is hydrogen.

[0259] According to an embodiment of the present invention, in the structure shown by the formula (I), U is acetyl.

[0260] According to an embodiment of the present invention, in the structure shown by the formula (I), U is benzoyl.

[0261] According to an embodiment of the present invention, the structure represented by the formula (I) has at least one of the following table structures:

[0262]

[0263] It should be noted that in the tables herein, when a polypeptide encodes multiple polypeptides in Table A or Table B, that is, the polypeptide in the table has the same main peptide chain as multiple polypeptides in Table A or Table B, the only difference being the absence of the side chain of the modifying group. For example, "1-21 (AMY-021, AMY-038)" means that the 1-21 polypeptide in the above table has the same main peptide chain as AMY-021 and AMY-038 in Table A, but the 1-21 polypeptide does not contain the side chain of the modifying group; the same as "1-15 (AMY-015, AMY-016, AMY-017, AMY-018)".

[0264] According to an embodiment of the present invention, the polypeptide or its derivative or a pharmaceutically acceptable salt thereof further comprises a modifying group.

[0265] According to an embodiment of the present invention, the modifying group is connected to two of the amino acids Z in the polypeptide or its derivative represented by the formula (I) 1 or two amino acids Z 2 are connected.

[0266] According to an embodiment of the present invention, the modifying group is connected to the -SH of the side chain of the amino acid Z 1 through a sulfur-carbon bond.

[0267] According to an embodiment of the present invention, the modifying group is connected to the -NH 2 of the side chain of the amino acid Z 2 through an amide bond.

[0268] In an alternative embodiment of the present invention, the modifying group is connected to the -SH of the side chain of amino acid C through a sulfur-carbon bond.

[0269] In an alternative embodiment of the present invention, the modifying group is connected to the ε-amino of the side chain of amino acid K through an amide bond.

[0270] According to an embodiment of the present invention, the modifying group has the structure represented by the formula (IV):

[0271]

[0272] Wherein, R 1 is C, N, -C 3～10 heteroalkylidene, -C 3～10 arylidene or -C 3～10 heteroarylidene;

[0273] R2 and R 3 each independently is optionally a -C 1a alkylene- optionally substituted by one or more R 1～6 groups, an -NH-C(O)-C 1a alkylene- optionally substituted by one or more R 1～6 groups, or a -C 1a alkylene-NH-C(O)-C 1～6 alkylene- optionally substituted by one or more R 1～6 groups, where each R 1a is independently halogen, -OH, -SH, -NH 2 , -NO 2 , -CN, phenyl, -C 1～6 alkyl, -C 1～6 haloalkyl or -C 1～6 alkoxy;

[0274] R 4 is empty or is an -C 2a alkylene-NH-C(O)-C 1～6 alkylene- optionally substituted by one or more R 1～6 groups, where each R 2a is independently halogen, -OH, -SH, -NH 2 , -NO 2 , -CN, phenyl, -C 1～6 alkyl, -C 1～6 haloalkyl or -C 1～6 alkoxy;

[0275] R 5 is H, -C 1～6 alkoxy or -C 1～6 alkyl, where the -C 1～6 alkyl and -C 1～6 alkoxy are each independently optionally substituted by one or more halogen, -OH, -C(O)OH, -C(O)-, -SH, -NH 2 , -NO 2 , -CN;

[0276] R 6 is an -C 3a alkylene- optionally substituted by one or more R 1～6 groups, or an -(C 3a alkylene-O) 1～3 -C m1 alkylene- optionally substituted by one or more R 1～6 groups, where each R 3a is independently halogen, -OH, -SH, -NH 2 , -NO2 、 -CN, phenyl, -C 1～6 alkyl, -C 1～6 haloalkyl or -C 1～6 alkoxy;

[0277] R 7 is optionally substituted by one or more R 4a substituted -C 1～6 alkylene-, wherein each R 4a is independently halogen, -OH, -SH, -NH 2 , -NO 2 , -CN, phenyl, -C 1～6 alkyl, -C 1～6 haloalkyl or -C 1～6 alkoxy;

[0278] R 8 is optionally substituted by one or more R 5a substituted -C 10～20 alkyl, optionally substituted by one or more R 5a substituted -C 10～20 alkylene-R 9 , optionally substituted by one or more R 5a substituted -C 5～10 alkylene-O-C 3～10 arylene-R 9 , or optionally substituted by one or more R 5a substituted -C 5～10 alkylene-O-C 3～10 heteroarylene-R 9 , wherein each R 5a is independently halogen, -OH, -SH, -NH 2 , -NO 2 , -CN, phenyl, -C 1～6 alkyl, -C 1～6 haloalkyl or -C 1～6 alkoxy;

[0279] R 9 is -COOH, -C 3～7 heteroaryl, -S(O) 2 OH, or -PO(OH) 2 ;

[0280] m1 is any integer from 1 to 6;

[0281] n1 is any integer from 0 to 6;

[0282] n2 is any integer from 1 to 10.

[0283] It should be noted that in the present invention, the "-" in the modifying group represents the chemical bond connecting chemical groups, such as the covalent bond between atoms (or atoms in the group) and atoms (or atoms in the group).

[0284] According to an embodiment of the present invention, R 1 is C, N, -C 5～7 subalkylene, -C 5～7 arylene or -C 5～7 heteroarylene.

[0285] According to an embodiment of the present invention, R 1 is N, , phenylene or pyridinylene.

[0286] According to an embodiment of the present invention, R 1 is

[0287] According to an embodiment of the present invention, R 2 and R 3 are each independently -C 1～6 alkylene-, or -C 1～6 alkylene-NH-C(O)-C 1～6 alkylene-.

[0288] According to an embodiment of the present invention, R 2 and R 3 are each independently -C 1～3 alkylene-, or -C 1～3 alkylene-NH-C(O)-C 1～3 alkylene-.

[0289] According to an embodiment of the present invention, each n1 is independently 0, 1, 2, 3, 4 or 5.

[0290] According to an embodiment of the present invention, n1 is 0.

[0291] According to an embodiment of the present invention, R 4 is empty, or -C 1～6 alkylene-NH-C(O)-C 1～6 alkylene-.

[0292] According to an embodiment of the present invention, R 4 is empty, or -C 1～3 alkylene-NH-C(O)-C 1～3 alkylene-.

[0293] According to an embodiment of the present invention, R 5 is H, -C 1～3 alkoxy or -C 1～3 alkyl.

[0294] According to an embodiment of the present invention, R 6 is -C 1～6 alkylene-, -(C 1～3 alkylene-O) m1 -C 1～6 alkylene-.

[0295] According to an embodiment of the present invention, R 6 is -C 1～3 alkylene-, -(C 1～3 alkylene-O) m1 -C 1～3 alkylene-.

[0296] According to an embodiment of the present invention, m1 is 2, 3, 4 or 5.

[0297] According to an embodiment of the present invention, R 7 is -C 1～6 alkylene-.

[0298] According to an embodiment of the present invention, R 7 is -C 2～4 alkylene-.

[0299] According to an embodiment of the present invention, R 8 is -C 10～20 alkyl, -C 10～20 alkylene-R 9 、-C 5～10 alkylene-O-C 3～10 arylene-R 9 、or -C 5～10 alkylene-O-C 3～10 heteroarylene-R 9 .

[0300] According to an embodiment of the present invention, R 8 is -C 10～18 alkyl, -C 14～18 alkylene-R 9 、or -C 7～9 alkylene-O-C 5～7 arylene-COOH.

[0301] According to an embodiment of the present invention, R 9 is -COOH, -C 5～6 heteroaryl, -S(O) 2 OH, or -PO(OH) 2 .

[0302] According to an embodiment of the present invention, R 9 is -COOH, -S(O) 2 OH, -PO(OH) 2 、or

[0303] According to an embodiment of the present invention, n2 is 1, 2 or 3.

[0304] According to an embodiment of the present invention, n2 is 3, 4, 5 or 6.

[0305] According to an embodiment of the present invention, the modifying group represented by formula (IV) has the structure represented by formula (IVa):

[0306]

[0307] Wherein each R 10 and R 11 are each independently -C 0～3 alkylene-;

[0308] R 12 is -C 1～6 alkylene-;

[0309] R 8 is -C 10～21 alkyl, or -C 10～21 alkylene-COOH, preferably -C 14～19 alkyl or -C 10～18 alkylene-COOH;

[0310] q1 is 1, 2, 3 or 4;

[0311] q2 is 1, 2 or 3.

[0312] According to an embodiment of the present invention, the modifying group represented by formula (IVa) has one of the following structures:

[0313]

[0314]

[0315]

[0316]

[0317] According to an embodiment of the present invention, the modifying group represented by formula (IV) has the structure represented by formula (IVb):

[0318]

[0319] Wherein each R 10 ’ and R 11 ’ are each independently -C 0～3 alkylene-;’

[0320] R12 is -C 1～6 alkylene-;

[0321] R 13 is -C 10～20 alkylene-, preferably -C 14～18 alkylene-;

[0322] q1' is 1, 2, 3 or 4;

[0323] q2' is 1, 2 or 3.

[0324] According to an embodiment of the present invention, the modifying group represented by the formula (IVb) has one of the following structures:

[0325]

[0326] According to an embodiment of the present invention, the modifying group represented by the formula (IV) has the structure represented by the formula (IVc):

[0327]

[0328] wherein each R 14 is independently -C 1～3 alkylene- or -NH-C(O)-C 1～3 alkylene-;

[0329] R 15 is -C 0～3 alkylene- or -C(O)-NH-C 1～3 alkylene-;

[0330] R 12 ” is -C 1～6 alkylene-;

[0331] R 13 ’ is -C 10～20 alkylene-, preferably -C 14～18 alkylene-;

[0332] q1” is 1, 2, 3 or 4;

[0333] q2” is 1, 2 or 3;

[0334] Y 1 is C or N.

[0335] According to an embodiment of the present invention, the modifying group represented by the formula (IVc) has one of the following structures:

[0336]

[0337]

[0338] According to an embodiment of the present invention, two of the amino acids Z are contained in the polypeptide or its derivative represented by the formula (I). 1 , and the modifying group has a structure represented by the formula (IV).

[0339] According to an embodiment of the present invention, the modifying group has a structure represented by the formula (V):

[0340]

[0341] wherein, R 20 is C, N, -C 3～10 arylene or -C 3～10 heteroarylene;

[0342] R 21 and R 22 are each independently empty, -C 1b alkylene optionally substituted with one or more R 1～6 s, or -C 1b alkyleneoxy optionally substituted with one or more R 1～6 s, wherein each R 1b is independently halogen, -OH, -SH, -NH 2 , -NO 2 , -CN, phenyl, -C 1～6 alkyl, -C 1～6 haloalkyl or -C 1～6 alkoxy;

[0343] R 23 is empty, -C 2b alkylene optionally substituted with one or more R 1～6 s, -C(O)-C 2b alkylene optionally substituted with one or more R 1～6 s, -NH-C(O)-C 2b alkylene optionally substituted with one or more R 1～6 s, or -C 2b alkylene-C(O)-NH-C 1～6 alkylene optionally substituted with one or more R 1～6 s, wherein each R 2b is independently halogen, -OH, -SH, -NH 2 , -NO 2 , -CN, phenyl, -C 1～6 alkyl, -C 1～6 haloalkyl or -C 1～6 alkoxy;

[0344] R 24is optionally a -C 3b alkylene group, or optionally a -C 1～6 alkylene group, or optionally a -C 3b alkylene group, or optionally a -C 1～3 alkylene-O) m2 -C 1～6 alkylene group, where each R 3b is independently halogen, -OH, -SH, -NH 2 , -NO 2 , -CN, phenyl, -C 1～6 alkyl, -C 1～6 haloalkyl or -C 1～6 alkoxy;

[0345] R 25 is H, -C 1～6 alkoxy or -C 1～6 alkyl, where the -C 1～6 alkyl and -C 1～6 alkoxy are each independently optionally substituted by one or more halogen, -OH, -C(O)OH, -C(O)-, -SH, -NH 2 , -NO 2 , -CN;

[0346] R 26 is optionally a -C 4b alkylene group, where each R 1～6 is independently halogen, -OH, -SH, -NH 4b , -NO 2 , -CN, phenyl, -C 2 , -C 1～6 alkyl, -C 1～6 haloalkyl or -C 1～6 alkoxy;

[0347] R 27 is optionally a -C 5b alkyl, optionally a -C 10～20 alkyl, optionally a -C 5b alkylene-R 10～20 , optionally a -C 28 alkylene-O-C 5b arylene-R 5～10 , or optionally a -C 3～10 alkylene-O-C 28 heteroarylene-R 5b , where each R 5～10 is independently halogen, -OH, -SH, -NH 3～10 , -NO 28 , -CN, phenyl, -C 5bIndependently being halogen, -OH, -SH, -NH 2 , -NO 2 , -CN, phenyl, -C 1～6 alkyl, -C 1～6 haloalkyl or -C 1～6 alkoxy;

[0348] R 28 is -COOH, -C 3～7 heteroaryl, -S(O) 2 OH, or -PO(OH) 2 ;

[0349] m2 is any integer from 1 to 6;

[0350] n3 is any integer from 1 to 10;

[0351] n3 is 0, 1 or 2;

[0352] Y 2 is empty or NH.

[0353] According to an embodiment of the present invention, R 20 is C, N, -C 5～7 arylene or -C 5～7 heteroarylene.

[0354] According to an embodiment of the present invention, R 20 is C, N, phenylene or pyridinylene.

[0355] According to an embodiment of the present invention, R 20 is preferably

[0356] According to an embodiment of the present invention, R 21 and R 22 each independently is empty, -C 1～6 alkylene-, or -C 1～6 oxyalkylene-.

[0357] According to an embodiment of the present invention, R 21 and R 22 each independently is empty or -C 1～3 alkylene-.

[0358] According to an embodiment of the present invention, R 23 is empty, -C 1～6 alkylene-, -C 1～6 alkylene-C(O)-NH-C 1～6 alkylene-, or -C(O)-C 1～6 alkylene-.

[0359] According to an embodiment of the present invention, R 23 is empty, -C 1～3 alkylene-, or -C(O)-C 2～4 alkylene-.

[0360] According to an embodiment of the present invention, R 24 is -C 1～6 alkylene-, or -(C 1～3 alkylene-O) m2 -C 1～6 alkylene-.

[0361] According to an embodiment of the present invention, R 24 is -C 1～3 alkylene-, or -(C 1～3 alkylene-O) m2 -C 1～3 alkylene-.

[0362] According to an embodiment of the present invention, m2 is 2, 3, 4 or 5.

[0363] According to an embodiment of the present invention, R 25 is H, -C 1～6 alkoxy or -C 1～6 alkyl.

[0364] According to an embodiment of the present invention, R 25 is H or -C 1～3 alkyl.

[0365] According to an embodiment of the present invention, R 26 is -C 1～6 alkylene-.

[0366] According to an embodiment of the present invention, R 26 is -C 1～3 alkylene-.

[0367] According to an embodiment of the present invention, R 27 is -C 10～20 alkyl, -C 10～20 alkylene-R 28 -, -C 5～10 alkylene-O-C 3～10 arylene-R 28 -, or -C 5～10 alkylene-O-C 3～10 heteroarylene-R 28 .

[0368] According to an embodiment of the present invention, R 27 is -C 10～18 alkyl, -C 14～18 alkylene-R 28 , or -C7～9 Alkylene-O-C 5～7 Arylene-COOH.

[0369] According to an embodiment of the present invention, R 28 is -COOH, -C 5～6 heteroaryl, -S(O) 2 OH, or -PO(OH) 2 .

[0370] According to an embodiment of the present invention, R 28 is -COOH, -S(O) 2 OH, -PO(OH) 2 , or

[0371] According to an embodiment of the present invention, p is 1, 2 or 3.

[0372] According to an embodiment of the present invention, p is 3, 4, 5 or 6.

[0373] According to an embodiment of the present invention, the modifying group represented by formula (V) has the structure represented by formula (Va):

[0374]

[0375] Wherein each R 29 is independently -C 1～3 alkylene-;

[0376] R 30 is -C(O)-C 1～6 alkylene-, or -C 1～3 alkylene-C(O)-NH-C 1～3 alkylene-;

[0377] R 31 is -C 1～6 alkylene-;

[0378] q3 is 1, 2, 3 or 4;

[0379] q4 is 1, 2 or 3.

[0380] According to an embodiment of the present invention, in formula (Va), R 27 is -C 10～20 alkylene-COOH or -C 10～20 alkyl, preferably -C 14～18 alkylene-COOH or -C 10～19 alkyl.

[0381] According to an embodiment of the present invention, the modifying group represented by formula (Va) has the following structure:

[0382]

[0383]

[0384] According to an embodiment of the present invention, the modifying group represented by formula (V) has the structure represented by formula (Vb):

[0385]

[0386] wherein each R 29 ’ is independently -C 1～3 alkylene-;

[0387] R 30 ’ is -C 1～6 alkylene-;

[0388] R 31 ’ is -C 1～6 alkylene-;

[0389] q3’ is 1, 2, 3 or 4, preferably 2;

[0390] q4’ is 1, 2 or 3, preferably 2.

[0391] According to an embodiment of the present invention, in formula (Vb), R 27 is -C 10～20 alkylene-COOH or -C 10～20 alkyl, preferably -C 14～18 alkylene-COOH. According to an embodiment of the present invention, the modifying group represented by formula (Vb) has the following structure:

[0392]

[0393] According to an embodiment of the present invention, the modifying group represented by formula (V) has the structure represented by formula (Vc):

[0394]

[0395] wherein R 30 ” is -C 1～6 alkylene-;

[0396] R 31 ” is -C 1～6 alkylene-;

[0397] q3 is 1, 2, 3 or 4;

[0398] q4 is 1, 2 or 3.

[0399] According to an embodiment of the present invention, in formula (Vc), R 27-C 10～20 alkylene-COOH or -C 10～20 alkyl, preferably -C 14～18 alkylene-COOH or -C 10～19 alkyl.

[0400] According to an embodiment of the present invention, the modifying group represented by formula (Vc) has the structure shown below:

[0401]

[0402] According to an embodiment of the present invention, two of the amino acids Z in the polypeptide or its derivative represented by formula (I) 2 , and the modifying group has the structure shown by formula (V).

[0403] According to an embodiment of the present invention, the polypeptide derivative has any of the structures shown in the following table:

[0404]

[0405]

[0406] According to an embodiment of the present invention, the polypeptide derivative has any of the structures shown in Table A or Table B:

[0407] Table A

[0408]

[0409] It should be noted that based on Table A, the two amino acids to which the modifying group is connected in polypeptides AMY-001 to AMY-020 and AMY-023 to AMY-036 are both replaced with K, and the modifying group is replaced with the modifying group shown by formula (V) (such as B1). The resulting polypeptide sequences have properties similar to those of polypeptides AMY-001 to AMY-020 and AMY-023 to AMY-036 in Table A. Based on this, the present invention does not show all of them, and they are all within the scope of protection of this application. The present invention only exemplarily shows some polypeptides. For details, see Table B, and for specific activity data, see the examples and test examples of the present invention.

[0410] Table B

[0411]

[0412] It should be noted that the "connection site of the modifying group" in Table A and Table B is specifically the position of i in X in the structure represented by formula (I) of the present invention i in.

[0413] Pharmaceutical composition, combination drug or medicine kit

[0414] In a second aspect of the present invention, 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 a pharmaceutically acceptable salt thereof as described in the first aspect. As can be seen from the foregoing, the polypeptide or its derivative or a pharmaceutically acceptable salt thereof (hereinafter referred to as the polypeptide or its analog) is a dual agonist polypeptide analog, which can simultaneously have a certain balanced or unbalanced activation activity on the amylin receptor (AMYR) and the calcitonin receptor (CTR). Thus, a drug containing the polypeptide or its derivative or a pharmaceutically acceptable salt thereof can effectively prevent or treat diseases related to the amylin receptor and / or the calcitonin receptor.

[0415] According to an embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient or carrier.

[0416] In a third aspect of the present invention, the present invention provides a combination drug or a drug kit. According to an embodiment of the present invention, the combination drug or the drug kit comprises: the polypeptide or its derivative or a pharmaceutically acceptable salt thereof as described in the first aspect, or the pharmaceutical composition as described in the second aspect as the first active ingredient; and a second active ingredient; wherein the second active ingredient comprises a drug for preventing and / or treating a disease. The combination drug or the drug kit according to the embodiment of the present invention can further improve the therapeutic effect on diseases related to the amylin receptor and / or the calcitonin receptor.

[0417] According to an embodiment of the present invention, the disease comprises preventing and / or treating diseases related to the amylin receptor and / or the calcitonin receptor.

[0418] According to an embodiment of the present invention, the diseases related to the amylin receptor and / or the calcitonin receptor include at least one of lipodystrophy, glucose metabolism disorder, cardiovascular disease, brain system disease, mental system disease or nervous system disease.

[0419] According to an embodiment of the present invention, the diseases related to the amylin receptor and / or the calcitonin receptor include at least one of diseases related to metabolic disorders, bone-related diseases, cardiovascular diseases not related to metabolic diseases, related symptoms or diseases of alcohol or drug addiction, and neurodegenerative diseases.

[0420] According to an embodiment of the present invention, the amylin receptor and / or calcitonin receptor-related diseases include at least one of diabetes, hypertension, arteriosclerosis, liver cirrhosis, coronary heart disease, angina pectoris, myocardial infarction, inflammatory bowel disease, dyspepsia, gastrointestinal ulcer, hyperglycemia, impaired glucose tolerance, X syndrome, cognitive impairment, stroke, dyslipidemia-related diseases (hyperlipidemia, dyslipidemia), metabolic syndrome, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, abnormal body weight, obesity, fatty liver disease, diabetic nephrotic syndrome, diabetes-related renal fibrosis, liver fibrosis, Alzheimer's disease, and Parkinson's disease.

[0421] According to an embodiment of the present invention, the amylin receptor and / or calcitonin receptor-related diseases include at least one of cardiovascular diseases, diabetes, and / or obesity.

[0422] According to an embodiment of the present invention, the drug is selected from at least one of drugs for cardiovascular diseases, diabetes, and / or obesity.

[0423] According to an embodiment of the present invention, the drug is selected from at least one of adrenergic receptor blockers, HMG-CoA reductase inhibitors, angiotensin receptor antagonists, angiotensin-converting enzyme inhibitors, calcium channel blockers, endothelin antagonists, renin inhibitors, diuretics, aldosterone receptor blockers, endothelin receptor blockers, aldosterone synthase inhibitors, CETP inhibitors, relaxin, PCSK9 inhibitors, BNP and NEP inhibitors, GLP-1 analogs, insulin, sulfonylurea drugs, biguanide drugs, meglitinide drugs, glucosidase inhibitors, DPP IV inhibitors, and SGLT2 inhibitors.

[0424] According to an embodiment of the present invention, the GLP-1 analog drugs include at least one of semaglutide, exenatide, liraglutide, dulaglutide, tirzepatide, and retatrutide.

[0425] According to an embodiment of the present invention, the sodium-glucose cotransporter 2 (SGLT2) inhibitor hypoglycemic drugs include at least one of dapagliflozin and empagliflozin.

[0426] According to an embodiment of the present invention, the biguanides include metformin.

[0427] Uses and methods

[0428] In a fourth aspect of the present invention, there is provided the use of the polypeptide or its derivative or a pharmaceutically acceptable salt thereof as described in the first aspect, the pharmaceutical composition as described in the second aspect, or the combination drug or kit as described in the second aspect in the preparation of a drug for treating or preventing amylin receptor- and / or calcitonin receptor-related diseases.

[0429] According to an embodiment of the present invention, the amylin receptor- and / or calcitonin receptor-related diseases include lipodystrophy, glucose metabolism disorder, cardiovascular diseases, brain system diseases, mental system diseases or nervous system diseases.

[0430] According to an embodiment of the present invention, the amylin receptor- and / or calcitonin receptor-related diseases include at least one of metabolic disorder-related diseases, bone-related diseases, cardiovascular diseases not related to metabolic diseases, related symptoms or diseases of alcohol or drug addiction, and neurodegenerative diseases.

[0431] According to an embodiment of the present invention, the amylin receptor- and / or calcitonin receptor-related diseases include at least one of diabetes, hypertension, arteriosclerosis, liver cirrhosis, coronary heart disease, angina pectoris, myocardial infarction, inflammatory bowel disease, dyspepsia, gastrointestinal ulcer, hyperglycemia, impaired glucose tolerance, X syndrome, cognitive impairment, stroke, dyslipidemia-related diseases (hyperlipidemia, dyslipidemia), metabolic syndrome, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, abnormal body weight, obesity, fatty liver disease, diabetic nephrotic syndrome, diabetes-related renal fibrosis, liver fibrosis, Alzheimer's disease and Parkinson's disease.

[0432] In a fifth aspect of the present invention, there is provided a method for preventing and / or treating amylin receptor- and / or calcitonin receptor-related diseases. According to an embodiment of the present invention, the method includes: administering to a subject a pharmaceutically acceptable amount of the polypeptide or its derivative or a pharmaceutically acceptable salt thereof as described in the first aspect, the pharmaceutical composition as described in the second aspect, or the combination drug or kit as described in the second aspect. As can be seen from the foregoing, the polypeptide or its derivative or a pharmaceutically acceptable salt thereof (hereinafter referred to as the polypeptide or its analog) is a dual agonist polypeptide analog, which can simultaneously have a certain balanced or unbalanced activation activity on the amylin receptor (AMYR) and the calcitonin receptor (CTR). Thus, the method of the present invention can effectively prevent and / or treat amylin receptor- and / or calcitonin receptor-related diseases.

[0433] According to an embodiment of the present invention, the amylin receptor- and / or calcitonin receptor-related diseases include at least one of metabolic disorder-related diseases, bone-related diseases, cardiovascular diseases not related to metabolic diseases, related symptoms or diseases of alcohol or drug addiction, and neurodegenerative diseases.

[0434] According to an embodiment of the present invention, the metabolic disorder-related diseases include at least one of type 2 diabetes, dyslipidemia-related diseases, metabolic syndrome, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, obesity, fatty liver disease, and the like.

[0435] According to an embodiment of the present invention, the neurodegenerative diseases include at least one of Alzheimer's disease and Parkinson's disease.

[0436] The effective amount of the polypeptide or its derivative or their pharmaceutically acceptable salts, or the pharmaceutical composition of the present invention may vary depending on the mode of administration and the severity of the disease to be treated, etc. The selection of the preferred effective amount can be determined by those of ordinary skill in the art according to various factors (e.g., through clinical trials). The factors include but are not limited to: the pharmacokinetic parameters of the active ingredient such as bioavailability, metabolism, half-life, etc.; the severity of the disease to be treated in the patient, the patient's weight, the patient's immune status, the route of administration, etc. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dose may be proportionally reduced.

[0437] The polypeptide or its derivative or their pharmaceutically acceptable salts, or the pharmaceutical composition 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, semi-solid, and solid dosage forms, etc., 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 polypeptide or its derivative or their pharmaceutically acceptable salts, or the pharmaceutical composition can be administered by intravenous infusion or injection or intramuscular or subcutaneous injection.

[0438] The solution of the present invention will be explained below in conjunction with embodiments. Those skilled in the art will understand that the following embodiments are only for illustrating the present invention and should not be regarded as limiting the scope of the present invention. For those not specified in the embodiments regarding specific techniques or conditions, they shall be carried out according to the techniques or conditions described in the literature in the art or according to the product specifications. For the reagents or instruments not specified regarding the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0439] Example 1: Preparation method of polypeptide or its derivative

[0440] 1. The linear peptides in Polypeptide 1 to Polypeptide 20 (abbreviated as AMY-001 to AMY-020) and Polypeptide 23 to Polypeptide 36 (abbreviated as AMY-023 to AMY-031) in Table A were synthesized using the classical Fmoc-tBu solid-phase synthesis method with an X polypeptide synthesizer, and the reaction conditions are as follows:

[0441] (1) Resin swelling: Add Rink Amide MBHA resin into DCM (dichloromethane), and bubble N at room temperature for 1 hour, then filter by suction and wash the resin with DMF 2 - 3 times. 2 Bubble air and react for 1 hour, filter by suction, and wash the resin with DMF 2 - 3 times.

[0442] (2) Removal of Fmoc protecting group: Add a DMF (N,N - dimethylformamide) solution containing 20% (volume percentage, v / v) piperidine to the above resin, and bubble N at room temperature for 10 minutes, then filter by suction. Repeat the above operation until complete de - protection, and wash the resin with DMF 2 - 3 times. 2 Bubble air and react for 10 minutes, filter by suction, repeat the above operation until complete de - protection, and wash the resin with DMF 2 - 3 times.

[0443] (3) Amino acid coupling: Charge according to the reaction ratio of resin: amino acid: DIC: Oxyma Pure = 1:5:5:5 (equivalent ratio). Pre - dissolve the reactants, DIC (N,N’ - diisopropylcarbodiimide) and Oxyma pure (condensation reagent) in DMF, and bubble N at room temperature for 10 minutes, then transfer to the resin reaction tank and bubble N at room temperature for 1 - 3 hours. After the reaction, filter by suction and wash the resin with DMF 2 - 3 times. After the synthesis, wash the resin with DCM 2 - 3 times and dry it under vacuum to obtain the peptide resin. 2 Bubble air and react for 10 minutes, then transfer to the resin reaction tank and bubble N at room temperature for 1 - 3 hours. 2 After the reaction, filter by suction and wash the resin with DMF 2 - 3 times. After the synthesis, wash the resin with DCM 2 - 3 times and dry it under vacuum to obtain the peptide resin.

[0444] The above method is applicable to, including but not limited to, the following amino acids (D or L form) or synthetic reagents: Fmoc-AEEA-OH, Fmoc-Aib-OH, Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gly-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Lys(Alloc)-OH, Fmoc-Orn(Boc)-OH, Fmoc-Pro-OH, Fmoc-Phe-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-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-N-Me-Arg(Pbf)-OH, Fmoc-homoArg(Boc)-OH, Fmoc-cys(Trt)-OH, Fmoc-arg(Pbf)-OH, Fmoc-Pro(4-S-NH-Boc)-OH, Fmoc-Pro(4-R-NH-Boc)-OH, Fmoc-pro-OH, etc.

[0445] 2. Linear peptide cleavage and drying: Prepare a polypeptide cleavage solution according to the volume ratio of TFA (trifluoroacetic acid): TIPS (triisopropylsilylethynyl): H 2 O: EDT (1,2-ethanedithiol) = 95:2:2:1. Add the cleavage solution (10 mL / g resin) to the dried peptide resin, place it on a shaker and shake vigorously for 3 hours, filter the resin residue, add 10 times the volume of cold MTBE (methyl tert-butyl ether) to the filtrate, place the resulting suspension at -20 °C for 1 hour, then centrifuge at 3500 rpm, wash the precipitate with cold MTBE 3 - 5 times, and dry it under vacuum to obtain the crude peptide.

[0446] 3. Purification of linear peptide: Prepare a dissolution solution according to the volume ratio of mobile phase A (0.1% (v / v) TFA (trifluoroacetic acid) - water) : mobile phase B (0.1% (v / v) TFA - acetonitrile) = 1.5 : 1. Dissolve the crude peptide in the dissolution solution to prepare a storage solution, filter it through a 0.45 - micron filter membrane, and use a C18 reversed - phase preparative column (20 * 250 mm, particle size 5 μm) to perform gradient elution with mobile phase A and mobile phase B at a flow rate of 10 mL / min. Collect the target peak and lyophilize to obtain the target peptide compound (i.e., the linear peptide).

[0447] 4. Preparation of the Staple linker (or modification group A) is carried out using the classical Fmoc - tBu solid - phase synthesis method. In this step, taking Staple - A1 (or modification group A1) as an example, the reaction conditions are as follows (for the specific synthesis process, see Figure 1 ):

[0448] (1) Resin swelling: Add Fmoc - L - Lys(ivDde)-2CTC resin to DCM, and bubble with N 2 at room temperature for 1 hour, then perform suction filtration and wash the resin with DMF 2 - 3 times.

[0449] (2) Removal of Fmoc protecting group: Add a DMF solution containing 20% piperidine to the above resin, and bubble with N 2 at room temperature for 10 minutes, then perform suction filtration. Repeat the above operation until complete de - protection, and wash the resin with DMF 2 - 3 times.

[0450] (3) Coupling of fatty acid chain: Feed materials according to the reaction ratio of resin : fatty acid : HATU (2 - (7 - azabenzotriazol - 1 - yl)-N,N,N',N' - tetramethyluronium hexafluorophosphate) : DIPEA (N,N - diisopropylethylamine) = 1 : 5 : 5 : 10 (volume ratio). Pre - dissolve the fatty acid monoter - t - butyl ester, HATU, and DIPEA in DMF, and bubble with N 2 at room temperature for 10 minutes, then transfer it to the resin reaction tank and bubble with N 2 at room temperature for 1 - 3 hours. After the reaction, perform suction filtration and wash the resin with DMF 2 - 3 times.

[0451] (4) Removal of ivDde protecting group: Add a DMF solution containing 5% hydrazine to the resin, and bubble with N 2 at room temperature for 10 minutes. Repeat this operation 2 - 3 times until complete removal, and wash the resin with DMF 2 - 3 times.

[0452] (5) Coupling of amino acid, AEEA and bromoacetic acid: The materials were added according to the reaction equivalent 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 heated at room temperature for 2 h. 2 The reaction was carried out by blowing air for 10 minutes, and then the mixture was transferred to a resin reaction tank and heated at room temperature under N 2 The reaction was carried out by blowing air for 1-3 hours, and after the reaction was completed, the resin was filtered and washed with DMF for 2-3 times. After the synthesis was completed, the resin was washed with DCM for 2-3 times and vacuum dried to obtain the linker resin.

[0453] The structure of the Staple linker can be the above-mentioned modification groups A1 to A22, for example, can be selected from the following structures:

[0454]

[0455]

[0456] 5. Coupling of linear peptides with Staple linkers:

[0457] 1.0 equivalent of linear peptide (i.e., the target peptide compound obtained in step 3, and this step takes polypeptide DAC09 (abbreviated as AMY-008) in Table A as an example) and 1.2 equivalent of Staple linker peptide (i.e., the Staple linker obtained in step 4) were dissolved in a reaction solution of PBS (phosphate buffered saline): acetonitrile = 1:1.5 volume ratio (final concentration of 1.2 mM), and the pH of the reaction solution was adjusted to 8.0 using 10% (volume percentage, v / v) NaOH aqueous solution, and the reaction solution was fully shaken at room temperature on a shaker for 3-8 hours until the linear peptide was completely consumed by LC-MS detection, and the reaction solution was neutralized to pH 8.0 using 5% (volume percentage, v / v) TFA aqueous solution. 6.5, filter with a 0.45 μm filter membrane, use a C18 reverse phase preparative column (20*250 mm, particle size 5 μm) at a flow rate of 10 mL / min using mobile phase A and mobile phase B for gradient elution, collect the target peak, and lyophilize to obtain the target coupling compound (i.e., polypeptide derivatives, AMY-001 to AMY-020, AMY-023 to AMY-031). The specific synthesis process is shown in the following formula:

[0458]

[0459] The purity and mass spectrometry of each polypeptide derivative were also performed. The purity was greater than 90% as determined by HPLC. The molecular weights of the polypeptides determined by mass spectrometry were basically consistent with the theoretical molecular weights (all within the allowable error range). The molecular weights of some polypeptide molecules are shown in this example. See Table 1 for details.

[0460] Table 1

[0461]

[0462] Example 2: Preparation method of polypeptide or its derivative

[0463] 1. The linear peptides in polypeptides 21 to 22 (abbreviated as AMY-021 to AMY-022) and polypeptides 37 to 40 (abbreviated as AMY-037 to AMY-041) in Table A are synthesized by the classical Fmoc-tBu solid-phase synthesis method using an X polypeptide synthesizer, and the reaction conditions are as follows:

[0464] (1) Resin swelling: Add Rink Amide MBHA resin to DCM, and N 2 bubbling reaction for 1 hour at room temperature, filter by suction, and wash the resin with DMF 2 - 3 times.

[0465] (2) Removal of Fmoc protecting group: Add a DMF solution containing 20% (volume percentage, v / v) piperidine to the above resin, and N 2 bubbling reaction for 10 minutes at room temperature, filter by suction, repeat the above operation until complete deprotection, and wash the resin with DMF 2 - 3 times.

[0466] (3) Amino acid coupling: Charge according to the reaction ratio of resin:Fmoc-AA-OH:DIC:Oxyma Pure = 1:5:5:5. Pre-dissolve Fmoc-AA-OH, DIC, and Oxyma pure in DMF, and N 2 bubbling reaction for 10 minutes at room temperature, then transfer to the resin reaction tank, and N 2 bubbling reaction for 1 - 3 hours at room temperature. After the reaction is completed, filter by suction, and wash the resin with DMF 2 - 3 times. The N-terminal amino acids of the sequence are Boc-L-His(Trt)-OH, Boc-L-Tyr(tBu)-OH, etc. The same method is also used for the synthesis of these amino acids. After the synthesis is completed, wash the resin with DCM 2 - 3 times and vacuum dry to obtain a peptide resin containing the linear peptide.

[0467] The above method is applicable to, including but not limited to, the following amino acids (D or L form) or synthetic reagents: Fmoc-AEEA-OH, Fmoc-Aib-OH, Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gly-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Lys(Alloc)-OH, Fmoc-Orn(Boc)-OH, Fmoc-Pro-OH, Fmoc-Phe-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-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-N-Me-Arg(Pbf)-OH, Fmoc-homoArg(Boc)-OH, Fmoc-cys(Trt)-OH, Fmoc-arg(Pbf)-OH, Fmoc-Pro(4-S-NH-Boc)-OH, Fmoc-Pro(4-R-NH-Boc)-OH, Fmoc-pro-OH, etc.

[0468] 2. Linkage of the staple linker (or modification group B) to the peptide resin containing the linear peptide (AMY-022) obtained in step 1. The specific steps are as follows:

[0469]

[0470] 2.1 Deprotection of the Mtt protecting group on the peptide resin: Prepare a deprotection solution according to the volume ratio of TFA:TIPS:DCM = 1:2:97. Add the Mtt deprotection solution (10 mL / g resin) to the resin, place it on a shaker and shake well for 15 minutes. Filter the resin by suction, and repeat this process 3 - 5 times until the deprotection solution no longer shows a bright yellow color indicating complete deprotection. Wash the resin with DMF 2 - 3 times.

[0471] 2.2 Deprotection of the Alloc and Allyl protecting groups on the peptide resin: Add DCM (10 mL / g resin), PhSiH3 (10 equivalents), and Pd(PPh3)4 (0.1 equivalent) to the resin. At room temperature, N 2The reaction was carried out by blowing air for 1 hour, and the resin was filtered by suction. This process was repeated 1-2 times, and the resin was washed with DMF 2-3 times.

[0472] 2.3 Cyclic reaction on peptide resin: DMF (10 mL / g resin), PyBOP (5 equivalents), HOBt (5 equivalents) and DIPEA (10 equivalents) were added to the resin from which the Alloc and Allyl protecting groups were removed. 2 The reaction was carried out by blowing air for 4 hours, and the resin was filtered by suction, and the process was repeated 1-2 times. The resin was washed with DMF 2-3 times.

[0473] 2.4 Solid-phase side chain introduction: According to the standard solid-phase synthesis method, the side chain has the following structure:

[0474]

[0475] In addition, the structure of the Staple linker can be the above-mentioned modification groups B1 to B23.

[0476] 3. Cutting and drying: According to TFA: TIPS: H 2 The peptide cutting solution was prepared in a volume ratio of O:EDT = 95:2:2:1. The cutting solution (10 mL / g resin) was added to the dried resin, and the resin was placed on a shaker for 3 hours. The resin residue was filtered, and 10 times the volume of cold MTBE was added to the filtrate. The resulting suspension was cooled at -20°C for 1 hour, and then centrifuged at 3500 rpm. The precipitate was washed 3-5 times with cold MTBE, and the crude peptide was obtained by vacuum drying.

[0477] 4. Peptide purification: Prepare the dissolving solution according to the volume ratio of mobile phase A (0.1% TFA-water): mobile phase B (0.1% TFA-acetonitrile) = 1.5:1, dissolve the crude peptide in the dissolving solution to prepare the storage solution, filter with a 0.45 micron filter membrane, use a C18 reverse phase preparation column (20*250mm, particle size 5μm) at a flow rate of 10mL / min to use mobile phase A and mobile phase B for gradient elution, collect the target peak, and freeze-dry to obtain the target peptide derivative, namely AMY-021~AMY-022. The purity and mass spectrometry of each polypeptide derivative were identified, among which, after HPLC detection, the purity was greater than 90%; the molecular weight of the polypeptide identified by mass spectrometry was basically consistent with the theoretical molecular weight (all within the error allowable range). The molecular weight of some polypeptide molecules is exemplified in this embodiment, see Table 2 for details.

[0478] Table 2: Molecular weight of compounds

[0479]

[0480] Test Example 1: In vitro activity assay

[0481] 1. In Example 1 and Example 2 of the present invention, the prepared polypeptide derivatives can bind to the target AMYR and CTR receptors on the cell membrane, activate the cAMP response element (CRE), initiate the expression of downstream luciferase, and the expression level is positively correlated with the biological activity of the tested analogs. After activation, the luciferase substrate is added for chemiluminescence detection, and the luminescence intensity is measured to characterize the biological activity of the tested compound. Therefore, the polypeptide derivatives prepared in Example 1 and Example 2 of the present invention are detected, and the specific steps are as follows:

[0482] Construct a stable transfected cell line of HEK293 / pGM-CREB-L-Luc / AMY3R pool. Dilute the polypeptide derivatives (i.e., AMY-001 to AMY-041) prepared in Example 1 and Example 2 by 5-fold starting from the highest concentration of 1000 nM to prepare a dilution series containing 8 - 11 concentration gradients. Select Cagrilintide as the positive control for testing and prepare a dilution series for testing in the same way. Digest the corresponding test cells (1 min), disperse and centrifuge (1000 rpm, 5 min). After discarding the culture medium, resuspend with freestyle medium, centrifuge, collect and count, and then dilute to a cell density of 5 * 10 5 cells / mL and add them to the detection wells of a 384-well plate (40 μL / 20000 cells / well). Use Echo to add the corresponding dilution series of the test substance. Incubate the cell plate at 37 °C and 5% carbon dioxide for 6 hours, then add ONE-GLO (20 μL / well) for detection. Place it in the dark for 3 min, measure with a chemiluminescence microplate reader, read the plate within 30 min, and record the measurement results. Use GraphPad Prism software to plot the activation curve and calculate the EC 50 value of the compound. The results show that the polypeptide derivatives of the present invention have binding activity to AMYR and CTR.

[0483] 2. In Example 1 and Example 2 of the present invention, the prepared polypeptide derivatives can bind to the target AMYR and CTR receptors on the cell membrane, activate the receptors and release cAMP. Therefore, the activity of the test substance can be measured by using a cAMP detection kit and the HTRF (homogeneous time-resolved fluorescence) method. The specific steps are as follows:

[0484] Construct HEK293 / pGM-CREB-L-Luc / AMY3R pool and HEK293 / pGM-CREB-L-Luc / CTR pool stably transfected cell lines. Dilute the polypeptide derivatives (i.e., AMY-001 to AMY-041) prepared in Example 1 and Example 2 5-fold starting from a maximum of 1000 nM to prepare a dilution series containing 8-11 concentration gradients. Select Cagrilintide and sCT as test positive control substances and prepare dilution series for testing in the same manner. Select the test cell lines, digest them with cAMP-specific trypsin, add 3 mL of serum-free DMEM medium and pipette to suspend, and count the cells. Sequentially add 5 μL IBMX (prepared with serum-free DMEM medium, 0.5 mM), test cells (5 μL / 7500 cells / well) to the 384-well plate, incubate at 37 °C and 5% carbon dioxide for 30 minutes, then add cAMP-d2 (5 μL, 1x) and Anti-cAMP-Cryptate (5 μL, 1x), place at room temperature for 1 hour, and measure the HTRF value with a chemiluminescence microplate reader and record the measurement results. Use GraphPad Prism software to plot the activation curve and calculate the IC 50 value, and the results show that the polypeptide derivatives of the present invention have binding activity with AMY3R and CTR. This example exemplarily shows the IC 50 values of some polypeptides, as specifically shown in Table 3, Figure 2 and Figure 3 as shown.

[0485] Table 3: IC 50 values

[0486]

[0487] Test Example 2: Pharmacokinetic Evaluation

[0488] 1. Test the pharmacokinetic behavior of the polypeptide derivatives (i.e., AMY-001 to AMY-041) prepared in Example 1 and Example 2 in SD rats.

[0489] Each polypeptide derivative (i.e., AMY-001 to AMY-041) was administered to male Sprague-Dawley rats by single injection via subcutaneous injection (SC, 3 mg / kg, drug vehicle was PBS, concentration 1.5 mg / mL, administration volume 2 mL) and intravenous injection (IV, 1 mg / kg, drug vehicle was PBS, concentration 0.5 mg / mL, administration volume 2 mL). After administration, whole blood samples were collected from the jugular vein or other suitable veins at selected time points. 0.2 mL of blood was collected into an anticoagulation tube containing labeled EDTA-K2. After gently inverting the tube up and down to fully mix the anticoagulant (EDTA-K2) with the blood, it was immediately placed on wet ice and centrifuged as soon as possible to separate plasma. The centrifugation conditions were set at 4°C, 6800 g, and 6 minutes. The plasma samples were stored in a refrigerator not higher than -20°C for use when analyzed.

[0490] Under the condition of yellow light in an ice-water bath, (1) except for the blank sample, 300 μL of a precipitating agent containing an internal standard was added to a 96-well plate containing 20 μL of a standard curve sample, a quality control sample, or an unknown sample; 300 μL of acetonitrile was added to the blank sample; (2) vortex and mix well; (3) centrifuge; (4) take 150 μL of the supernatant into a new 96-well plate, and then add 150 μL of ultrapure water and mix well. (5) The above samples were quantitatively analyzed using LC-MS analysis. Gradient elution was performed using an XB-C18 (2.1*100 mm, 3 μm) column. The mobile phase used was: mobile phase A = 0.1% (volume percentage, v / v) formic acid - water; mobile phase B = acetonitrile. PhoenixWinNonlin software was used to calculate the pharmacokinetic parameters. It was found that the polypeptide derivatives of the present invention had good absorption in rats, with relatively high blood drug concentrations and long half-lives. The detection results of the pharmacokinetic parameters of some polypeptide derivatives are shown in Table 4 and Figure 4.

[0491] Table 4: PK data of some polypeptide derivatives in rats

[0492]

[0493] 2. Test the pharmacokinetic behavior of the polypeptide derivatives (i.e., AMY-001 to AMY-041) prepared in Test Example 1 and Example 2 in cynomolgus monkeys.

[0494] Each polypeptide derivative (i.e., AMY-001 to AMY-041) was administered as a single injection to adult male cynomolgus monkeys by subcutaneous injection (S.C., 0.2 mg / kg, drug solvent was PBS, concentration 0.2 mg / mL, administration volume 1 mL) and intravenous injection (I.V., 1 mg / kg, drug solvent was PBS, concentration 0.2 mg / mL, administration volume 1 mL). After administration, whole blood samples were collected from the jugular vein or other suitable veins at selected time points. 0.2 mL of blood was collected and placed in an anticoagulant tube containing labeled EDTA-K2. After gently inverting up and down to fully mix the anticoagulant (EDTA-K2) with the blood, it was immediately placed on wet ice and centrifuged as soon as possible to separate plasma. The centrifugation conditions were set at 4 °C, 6800 g, and 6 minutes. The plasma samples were stored in a refrigerator not higher than -20 °C for use when analyzed.

[0495] Under the condition of yellow light in an ice-water bath, (1) except for the blank sample, 300 μL of a precipitating agent containing an internal standard was added to a 96-well plate containing 20 μL of standard curve samples, quality control samples, or unknown samples; 300 μL of acetonitrile was added to the blank sample; (2) vortexed and mixed evenly; (3) centrifuged; (4) 150 μL of the supernatant was taken into a new 96-well plate, and then 150 μL of ultrapure water was added and mixed evenly. (5) The above samples were quantitatively analyzed using LC-MS analysis. Gradient elution was performed using an XB-C18 (2.1 * 100 mm, 3 μm) chromatograph. The mobile phases used were: mobile phase A = 0.1% formic acid - water; mobile phase B = acetonitrile. Phoenix WinNonlin software was used to calculate the pharmacokinetic parameters. It was found that the polypeptide derivatives of the present invention had good absorption in rats in vivo, with relatively high blood drug concentrations and relatively long half-lives. The detection results of the pharmacokinetic parameters of some polypeptide derivatives are shown in Table 5 and Figure 5 as shown.

[0496] Table 5: PK data of some polypeptide derivatives in cynomolgus monkeys

[0497]

[0498] Test Example 3: Changes in body weight and food intake after single-dose administration in wild-type SD rats

[0499] Adult male wild-type SD rats weighing 200-250g were selected for the experiment. The SD rats were randomly divided into groups of 4 rats per group and 2 rats per cage for adaptive feeding for 1 week, during which they maintained a normal diet and free drinking water. After the pre-adaptation of the animals, the basal blood glucose value and body weight of each rat were detected before administration (Day 0), and then the vehicle control (Vehicle) and three doses of the polypeptide derivatives prepared in Example 1 and Example 2 of the present invention (i.e., AMY-001 to AMY-041) (3nmol / kg, 10nmol / kg, 30nmol / kg) were respectively given by subcutaneous injection (sc) according to the experimental grouping, and normal diet and drinking water were given after the administration. The body weight of each rat and the total daily food intake of each group of rats were respectively detected on Day 1, 2, 3, 4, 5, 6, and 7 after administration, and the body weight of each rat (% initial value) and the cumulative food intake change value of each group of rats were calculated, and the curve was drawn. The results showed that the compound of the present invention can reduce the body weight and food intake of rats. The results of AMY-015 are shown in this test example. Figure 6 Test Example 4: Changes in body weight, blood sugar and food intake after continuous administration in DIO rat model

[0500] Adult male Sprague Dawley rats weighing 200-250g were selected for the experiment. They were fed a high-fat diet for 16 weeks and weighed about 600-700g. The rats were randomly divided into groups, 5 rats in each group, and fed in individual cages for adaptive feeding for 1 week. During this period, they maintained a normal diet and free drinking water. After the pre-adaptation of the animals, the basal body weight of each rat was tested before administration (Day 0), and then the vehicle control (Vehicle), Cagrilintide (1nmol / kg, 3nmol / kg, 10nmol / kg, Q2D), and AMY-015 (1nmol / kg, 3nmol / kg, 10nmol / kg, Q2D) were respectively given by subcutaneous injection (sc). After the end of the administration, normal high-fat diet and drinking water were given. The body weight of each rat and the total daily food intake of each group of rats were measured on Day 1, 2, 3, 4, 5, 6, and 7 after administration, and the body weight of each rat (% of the initial value) and the change in the total daily food intake of each group of rats were calculated. The curve was drawn. The results showed that the compound of the present invention can reduce the body weight and food intake of rats. The results of AMY-015 are exemplified in this test example, see Figure 7 .

[0501] Test Example 5: Changes in body weight and adipose tissue in DIO rat model after continuous administration of either single or combined administration of semaglutide

[0502] Adult male Sprague Dawley rats weighing 200-250g were selected for the experiment and fed a high-fat diet for 20 weeks, reaching a weight of about 600-700g. The rats were randomly divided into groups, 7 rats in each group, and fed in individual cages for adaptive feeding for 1 week, during which they maintained a normal diet and free access to water. After the pre-adaptation of the animals, the basal blood glucose and body weight of each mouse were tested before administration (Day 0), and then the vehicle control (Vehicle), Semaglutide (10nmol / kg, QD), Cagrilintide (10nmol / kg, Q2D), AMY-015 (10nmol / kg, Q2D), and Semaglutide (10nmol / kg, QD) combined with AMY-015 (10nmol / kg, Q2D) were given by subcutaneous injection (sc) for 21 consecutive days. The body weight of each rat and the total daily food intake of each group of rats were tested every day after administration, and the body weight (% of the initial value) and the change value of the total daily food intake of each rat group were calculated, and the curve was drawn. After the administration, blood and adipose tissue were dissected, the adipose tissue was weighed, and the biochemical indicators in the blood were detected. The results show that the compound of the present invention has a better weight loss effect than Cagrilintide, and combined with semaglutide, it can more effectively reduce the body weight and food intake of rats, and protect muscle from loss to a certain extent. The results of AMY-015 are exemplified in this test example, see Figure 8 Test Example 6: Changes in body weight, blood sugar and food intake after continuous administration in ZDF rat model

[0503] The experiment used adult male ZDF rats, weighing 350-400g, and fed with diabetic modeling feed. The rats were randomly divided into groups, with 8 rats in each group, and were fed in individual cages for adaptive feeding for 1 week. During this period, they maintained a normal diet and had free access to water. After the pre-adaptation of the animals, the basal blood sugar and body weight of each rat were tested before administration (Day 0), and then the vehicle control (Vehicle), Cagrilintide (30nmol / kg, Q2D), and AMY-015 (30nmol / kg, Q2D) were given subcutaneously (sc) for 28 consecutive days. The blood sugar level of each rat was tested once every two days after administration, the change in blood sugar (% initial value) of each rat was calculated, and the blood sugar-time curve was drawn. The results show that the compound of the present invention can lower blood sugar in rats, which is better than Cagrilintide. The results of AMY-015 are exemplified in this test example, see Figure 9 .

[0504] Test Example 7: Thioflavin T (ThT) Fibrosis Assay

[0505] Amylin analogs are prone to cause fibrosis aggregation in vitro and in vivo due to their structural characteristics, resulting in harsh storage conditions and potential immunogenic risks. The present invention stabilizes the secondary structure of the peptide chain by adopting spiral fixation technology, reduces the stacking effect of hydrophobic groups between chains, and effectively reduces the tendency to fibrosis. The PBS solution (1mg / mL) of the polypeptide to be tested and the PBS working solution (5mM) of ThT are configured, and 400μL of the polypeptide sample to be tested (the polypeptide derivatives prepared in Examples 1 and 2 (i.e., AMY-001~AMY-041)) solution is taken in a 1.5mL EP tube at room temperature, 8μL of ThT storage solution is added, vortexed to mix, and centrifuged at low speed to ensure that there is no liquid hanging, and the liquid is transferred to a 96-well plate, 200μL per well, and multiple groups can be set in parallel, 200μL PBS is added to the peripheral wells of the sample to seal the edges, and a transparent film is attached. The kinetic test was performed using a Biotek microplate reader, with a monitoring point interval of 15 min, an excitation wave of 440 nm, an emission wave of 485 nm, ΔFold change = (detection value / average of the first ten detection points), the horizontal axis is time (h), the vertical axis is ΔFold change, and the graph was drawn using Graphpad nonlinear fitting. The results showed that the polypeptide derivatives of the present invention can significantly reduce fibrosis aggregation and have higher stability. This example exemplifies the results of some polypeptide derivatives, see Figure 10 .

[0506] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means 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 may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0507] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary 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 or pharmaceutically acceptable salt thereof has a structure shown in formula (I): U-X1SHX4SX6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 DX 22 PX 24 TDVGAGSX 32 -NH2(I); wherein each U is independently hydrogen, acetyl, or benzoyl; X1 is A or K; X4 is L or αMeL; X6 is Z1, Z2 or T; X7 is Z1, Z2 or A; X8 is Z1, Z2 or V; X9 is Z1, Z2 or L; X 10 is Z1, Z2 or G; X 11 is Z1, Z2, homoR, Orn, or R; X 12 is Z1, Z2 or L; X 13 is Z1, Z2 or S; X 14 is Z1, Z2 or A; X 15 is Z1, Z2 or E; X 16 is Z1, Z2 or L; X 17 is Z1, Z2 or H; X 18 is Z1, Z2, K, αMeK or Orn; X 19 is Z1, Z2 or L; X 20 is Z1, Z2 or Aib; X 22 is Y or αMeF; X 24 is R, N-Me-R, homoR, norR, Q or r; X 32 is P, Hyp, cis-P(4-NH2), trans-P(4-NH2) or p; The structure shown in formula (I) contains two amino acids Z1 or two amino acids Z2, and the positions of the two amino acids Z1 or the two amino acids Z2 are respectively i and X i+7 , i is any integer between 6 and 13; Each amino acid Z1 is independently selected from C, C, αMeC, HoC, Hoc, Pen or N-Me-C; Each amino acid Z2 is independently selected from K, k, Dap, Dab, Orn, HomoK, N-Me-K, N-Me-k, αMeK, αMek.

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 or the two amino acids Z2 are one of the following groups: X6 and X 13 , X7 and X 14 , X8 and X 15 , X9 and X 16 , X 10 and X 17 , X 11 and X 18 , X 12 and X 19 , X 13 and X 20 ; Optionally, the positions of the two amino acids Z1 or the two amino acids Z2 are X8 and X 15 ; Optionally, the two amino acids Z1 or the two amino acids Z2 are each independently selected from K, C or C; Optionally, X1 is A or K; Optionally, X1 is A; Optionally, X4 is L; Optionally, X6 is K, C, C or T; Optionally, X6 is C or T; Optionally, X6 is T; Optionally, X7 is K, C, C or A; Optionally, X7 is C or A; Optionally, X7 is A; Optionally, X8 is C, V, C, HoC, Pen, αMeC, N-Me-C, K, Orn, k or Dab; Optionally, X8 is K, C, C or V; Optionally, X8 is C, V or K; Optionally, X8 is C or V; Optionally, X8 is V; Optionally, X9 is K, C, C or L; Optionally, X9 is C or L; Optionally, X9 is L; Optionally, X 10 is K, c, C or G; Optionally, X 10 is C or G; Optionally, X 10 is G; Optionally, X 11 is K, c, C, homoR, Orn or R; Optionally, X 11 is K, C, homoR, Orn, or R; Optionally, X 11 is K, C, homoR or R; Optionally, X 11 is C, homoR or R; Optionally, X 11 is homoR or R; Optionally, X 12 is K, c, C or L; Optionally, X 12 is C or L; Optionally, X 12 is L; Optionally, X 13 is K, c, C or S; Optionally, X 13 is C or S; Optionally, X 13 is S; Optionally, X 14 is K, C, C or A; Optionally, X 14 is C or A; Optionally, X 14 is A; Optionally, X 15 is C, E, c, HoC, Pen, αMeC, αMeK, N-Me-C, K, Orn, k or Dab; Optionally, X 15 is K, c, C or E; Optionally, X 15 is K, C or E; Optionally, X 15 is C or E; Optionally, X 15 is C; Optionally, X 16 is K, c, C or L; Optionally, X 16 is C or L; Optionally, X 16 is L; Optionally, X 17 is K, c, C or H; Optionally, X 17 is C or H; Optionally, X 17 is H; Optionally, X 18 is c, K, C, k, αMeK or Orn; Optionally, X 18 is C, K, αMeK or Orn; Optionally, X 18 is C, K or αMeK; Optionally, X 18 is K or αMeK; Optionally, X 19 is K, c, C or L; Optionally, X 19 is C or L; Optionally, X 19 is L; Optionally, X 20 is K, c, C or Aib; Optionally, X 20 C or Aib; Optionally, X 20 for Aib; Optionally, X 22 is Y; Optionally, X 23 is P; Optionally, X 24 is R, N-Me-R, homoR, norR, r or Q; Optionally, X 24 is R, N-Me-R, homoR, norR or Q; Optionally, X 24 is R, N-Me-R or Q; Optionally, X 29 is A; Optionally, X 32 It is P or Hyp.

3. The polypeptide or its derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, characterized in that: The structure shown in the formula (I) has the following structure: U-X1SHX4STX7X8LGX 11 LX 13 X 14 X 15 LHX 18 LX 20 DX 22 X 23 X 24 TDVGAGSX 32 -NH2(Ia); Optionally, the structure represented by formula (I) has the following structure: U-X1SHX4STA X8LGX 11 LSAX 15 LHX 18 L-Aib-DX 22 PX 24 TDVGAGSX 32 -NH2(Ib); Optionally, the structure represented by formula (I) has the following structure: U-ASHX4STX7X8LGX 11 X 12 X 13 X 14 X 15 LX 17 X 18 X 19 X 20 DX 22 PX 24 TDVGAGSX 32 -NH2(II); Optionally, the structure represented by formula (I) has the following structure: U-ASHX4STAX8LGX 11 LX 13 AX 15 LHX 18 LX 20 DX 22 PX 24 TDVGAGSX 32 -NH2(IIa); Optionally, the structure represented by formula (I) has the following structure: ASHLSTAX8LGX 11 LSAX 15 LHX 18 L-Aib-DYPX 24 TDVGAGSX 32 -NH2(IIb)? Optionally, the structure represented by formula (I) has the following structure: <h2 style=";text-align:left;direction:ltr">U-ASHLSTACLGX<h2 style=";text-align:left;direction:ltr"> 11 <h2 style=";text-align:left;direction:ltr"> LSACLHX<h2 style=";text-align:left;direction:ltr"> 18 <h2 style=";text-align:left;direction:ltr"> L-Aib-DYPX<h2 style=";text-align:left;direction:ltr"> 24 <h2 style=";text-align:left;direction:ltr"> TDVGAGSX<h2 style=";text-align:left;direction:ltr"> 32 <h2 style=";text-align:left;direction:ltr"> -NH2(III) 4. The polypeptide or its derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, characterized in that: The structure represented by the formula (I) has at least one of the following structures: U-ASHLSCAVLGRLCAELHKL-Aib-DYPRTDVGAGSP-NH2; U-ASHLSTCVLGRLSCELHKL-Aib-DYPRTDVGAGSP-NH2; U-ASHLSTACLGRLSACLHKL-Aib-DYPRTDVGAGSP-NH2; U-ASHLSTAVCGRLSAECHKL-Aib-DYPRTDVGAGSP-NH2; U-ASHLSTAVLCRLSAELCKL-Aib-DYPRTDVGAGSP-NH2; U-ASHLSTAVLGCLSAELHCL-Aib-DYPRTDVGAGSP-NH2; U-ASHLSTAVLGRCSAELHKC-Aib-DYPRTDVGAGSP-NH2; <h2 style=";text-align:left;direction:ltr">U-ASHLSTAVLGRLCAELHKLCDYPRTDVGAGSP-NH2; <h2 style=";text-align:left;direction:ltr"> U-ASHLSTACLGRLSACLH-Orn-L-Aib-D-(αMeF)-PRTDVGAGS-Hyp-NH2; <h2 style=";text-align:left;direction:ltr"> U-ASH-(αMeL)-STACLGRLSACLHKL-Aib-D-(αMeF)-P-(N-Me-R)-TDVGAGSP-NH2; <h2 style=";text-align:left;direction:ltr"> U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYP-(N-Me-R)-TDVGAGS-Hyp-NH2; <h2 style=";text-align:left;direction:ltr"> U-ASHLSTACLG-homoR-LSACLH-(αMeK)-L-Aib-DYP-(N-Me-R)-TDVGAGSP-NH2; <h2 style=";text-align:left;direction:ltr"> U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYP-homoR-TDVGAGS-Hyp-NH2; <h2 style=";text-align:left;direction:ltr"> U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYP-norR-TDVGAGS-Hyp-NH2; <h2 style=";text-align:left;direction:ltr"> U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2; <h2 style=";text-align:left;direction:ltr"> U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYP-r-TDVGAGS-Hyp-NH2; <h2 style=";text-align:left;direction:ltr"> U-ASHLSTAVLGCLSAELHCL-Aib-DYPQTDVGAGS-Hyp-NH2; <h2 style=";text-align:left;direction:ltr"> U-KSHLSTACLGRLSACLH-(αMeK)-L-Aib-DYP-(N-Me-R)-TDVGAGS-Hyp-NH2; <h2 style=";text-align:left;direction:ltr"> U-KSHLSTAVLGCLSAELHCL-Aib-DYPQTDVGAGS-Hyp-NH2; <h2 style=";text-align:left;direction:ltr"> U-KSHLSTA-c-LGRLSA-c-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2; <h2 style=";text-align:left;direction:ltr"> U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYPQTDVGAGS-(cis-P(4-NH2))-NH2; <h2 style=";text-align:left;direction:ltr"> U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYPQTDVGAGS-(trans-P(4-NH2))-NH2; <h2 style=";text-align:left;direction:ltr"> U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYPQTDVGAGS-p-NH2; <h2 style=";text-align:left;direction:ltr"> U-ASHLSTACLG-homoR-LSACLH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2; U-ASHLSTACLG-Orn-LSACLH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2; U-ASHLSTA-HoC-LGRLSA-HoC-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2; U-ASHLSTA-Pen-LGRLSA-Pen-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2; U-ASHLSTA-(αMeC)-LGRLSA-(αMeC)-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2; U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2; U-ASHLSTA-(N-Me-C)-LGRLSA-(N-Me-C)-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2; U-ASHLSTAKLGRLSAKLH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2; U-ASHLSTAVLGKLSAELHKL-Aib-DYPQTDVGAGS-Hyp-NH2; U-ASHLSTA-Orn-LGRLSA-Orn-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2; U-ASHLSTA-Dab-LGRLSA-Dab-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2; Each U is independently selected from H, acetyl, benzoyl; Optionally, U is H; Optionally, U is acetyl; Optionally, U is benzoyl.

5. The polypeptide or its derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: further comprising a modifying group; Optionally, the modifying group is connected to the two amino acids Z1 or two amino acids Z2 in the polypeptide represented by formula (I) or its derivative; Optionally, the modifying group is connected to the -SH of the amino acid Z1 side chain via a sulfur-carbon bond; Optionally, the modifying group is linked to the -NH2 of the side chain of the amino acid Z2 via an amide bond.

6. The polypeptide or its derivative or pharmaceutically acceptable salt thereof according to claim 5, characterized in that: The modifying group has a structure shown in formula (IV): Where R1 is C, N, -C 3～10 Heteroalkylene, -C 3～10 Arylene or -C 3～10 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 3～10 Arylene-R9, or optionally one or more R 5a Replaced-C 5～10 Alkylene-OC 3～10 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.

7. The polypeptide or its derivative or pharmaceutically acceptable salt thereof according to claim 6, 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 3～10 Arylene-R9, or -C 5～10 Alkylene-OC 3～10 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 (IV) has a structure represented by formula (IVa): 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 (IVa) has the structure shown below: Optionally, the modifying group represented by formula (IV) has a structure represented by formula (IVb): 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 formula (IVb) has the structure shown below: Optionally, the modifying group represented by formula (IV) has a structure represented by formula (IVc): 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 (IVc) has the structure shown below: Optionally, the polypeptide represented by formula (I) or its derivative contains two amino acids Z1, and the modification group has the structure represented by formula (IV).

8. The polypeptide or its derivative or pharmaceutically acceptable salt thereof according to claim 5, characterized in that: The modifying group has a structure shown in formula (V): Among them, R 20 C, N, -C 3～10 Arylene or -C 3～10 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 3～10 Arylene-R 28 , or optionally one or more R 5b Replaced-C 5～10 Alkylene-OC 3～10 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.

9. The polypeptide or its derivative or pharmaceutically acceptable salt thereof according to claim 8, 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 3～10 Arylene-R 28 , or -C 5～10 Alkylene-OC 3～10 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 (V) has a structure represented by formula (Va): 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 (Va) has the structure shown below: Optionally, the modifying group represented by formula (V) has a structure represented by formula (Vb): 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 (Vb) has the structure shown below: Optionally, the modifying group represented by formula (V) has a structure represented by formula (Vc): Among them, R 30 " for -C 1～6 Alkylene-; R 31 "-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 (Vc) has the structure shown below: Optionally, the polypeptide represented by formula (I) or its derivative contains two amino acids Z2, and the modification group has the structure represented by formula (V).

10. The polypeptide or its derivative or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The polypeptide derivative has a structure shown in any one of Table A or Table B: Table A Table B 11. A pharmaceutical composition, characterized in that A polypeptide or a derivative thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10; Optionally, it further includes a pharmaceutically acceptable excipient or carrier.

12. A combined drug or drug kit, characterized in that: include: The polypeptide or derivative thereof or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, or the pharmaceutical composition according to claim 11 as a first active ingredient; and a second active ingredient; Wherein, the second active ingredient includes a drug for preventing and / or treating a disease; Optionally, the disease comprises an amylin receptor and / or a calcitonin receptor related disease; Optionally, the amylin receptor and / or calcitonin receptor related diseases include lipodystrophy, dysglycemia, cardiovascular disease, brain system disease, mental system disease or nervous system disease; Optionally, the amylin receptor and / or calcitonin receptor-related diseases include at least one of metabolic disorder-related diseases, bone-related diseases, cardiovascular diseases not related to metabolic diseases, symptoms or diseases related to alcohol or drug addiction, and neurodegenerative diseases; Optionally, the amylin receptor and / or calcitonin receptor-related diseases include at least one of diabetes, hypertension, arteriosclerosis, liver cirrhosis, coronary heart disease, angina pectoris, myocardial infarction, inflammatory bowel disease, dyspepsia, gastrointestinal ulcer, hyperglycemia, impaired glucose tolerance, syndrome X, cognitive impairment, stroke, dyslipidemia-related diseases (hyperlipidemia, dyslipidemia), metabolic syndrome, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, abnormal body weight, obesity, fatty liver disease, diabetic nephrotic syndrome, diabetes-related renal fibrosis, liver fibrosis, Alzheimer's disease and Parkinson's disease; Optionally, the amylin receptor and / or calcitonin receptor related diseases include at least one of cardiovascular, diabetes and / or obesity; Optionally, the drug is selected from at least one of adrenergic receptor blockers, HMG-CoA reductase inhibitors, angiotensin receptor antagonists, angiotensin converting enzyme inhibitors, calcium channel blockers, endothelin antagonists, renin inhibitors, diuretics, aldosterone receptor blockers, endothelin receptor blockers, aldosterone synthase inhibitors, CETP inhibitors, relaxin, PCSK9 inhibitors, BNP and NEP inhibitors, GLP-1 analogs, insulin, sulfonylureas, biguanides, meglitazones, glucosidase inhibitors, DPP IV inhibitors, and SGLT2 inhibitors; Optionally, the drug is selected from one of a GLP-1 analog drug, a gliflozin-type hypoglycemic drug, a biguanide drug, and acarbose; Optionally, the GLP-1 analog drug includes at least one of semaglutide, exenatide, liraglutide, dulaglutide, telpotide, and retaglutide; Optionally, the glucose-lowering drug of the gliflozin class includes at least one of dapagliflozin and empagliflozin; Optionally, the biguanide comprises metformin.

13. Use of the polypeptide or derivative thereof or pharmaceutically acceptable salts thereof according to any one of claims 1 to 10, the pharmaceutical composition according to claim 11, or the combined drug or drug kit according to claim 12 in the preparation of a drug for treating or preventing amylin receptor and / or calcitonin receptor related diseases; Optionally, the amylin receptor and / or calcitonin receptor related diseases include lipodystrophy, dysglycemia, cardiovascular disease, brain system disease, mental system disease or nervous system disease; Optionally, the amylin receptor and / or calcitonin receptor-related diseases include at least one of metabolic disorder-related diseases, bone-related diseases, cardiovascular diseases not related to metabolic diseases, symptoms or diseases related to alcohol or drug addiction, and neurodegenerative diseases; Optionally, the amylin receptor and / or calcitonin receptor-related diseases include at least one of diabetes, hypertension, arteriosclerosis, liver cirrhosis, coronary heart disease, angina pectoris, myocardial infarction, inflammatory bowel disease, dyspepsia, gastrointestinal ulcer, hyperglycemia, impaired glucose tolerance, syndrome X, cognitive impairment, stroke, dyslipidemia-related diseases (hyperlipidemia, dyslipidemia), metabolic syndrome, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, abnormal body weight, obesity, fatty liver disease, diabetic nephrotic syndrome, diabetes-related renal fibrosis, liver fibrosis, Alzheimer's disease and Parkinson's disease.

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