Polypeptide or analog thereof and use thereof

Abstract

Provided is a polypeptide or a derivative thereof or a pharmaceutically acceptable salt thereof, which has a structure as shown in formula (I) (U-X1SHX4SX6X7X8X9X10X11X12X13X14X15X16X17X18X19X20DX22PX24TDVGAGSX32-NH2) and a modification group. The structure as shown in formula (I) contains two amino acids Z1 or two amino acids Z2, wherein the positions of the two amino acids Z1 or the two amino acids Z2 are Xi and Xi+7, respectively, and i is any integer between 6 to 13. The modification group is linked to the two amino acids Z1 or the two amino acids Z2 via covalent bonds. The polypeptide or the derivative thereof has certain activation activity on both an amylin receptor and a calcitonin receptor, and has a longer in vivo half-life by means of modification with a side chain modification group, so as to support low-dose and low-frequency administration. The polypeptide or the derivative thereof can be used for preventing or treating metabolic-related diseases.

Description

Polypeptide or its analogues and use thereof Technical Field

[0001] The present invention belongs to the field of biopharmaceutical technology, and specifically relates to a polypeptide or its analogs and applications thereof, and more specifically to a polypeptide or its derivatives having simultaneous activation activity on amylin receptor (AMYR) and calcitonin receptor (CTR), or their pharmaceutically acceptable salts, pharmaceutical compositions, and their uses. Background Art

[0002] The continued rise in the prevalence of obesity and type 2 diabetes mellitus (T2DM) has led to a lack of effective means. At the same time, obese and T2D patients are often at high risk of developing cardiovascular disease and other metabolic complications, which complicates the safe use of medications. In addition to changes in diet and lifestyle, current bariatric surgery can effectively alleviate obesity and T2D, but surgery is accompanied by risks and irreversible physical changes. Therefore, there is a need to develop novel and more effective drug treatments to achieve blood sugar control and weight management.

[0003] Amylin is a pancreatic hormone composed of 37 amino acids. It is secreted by pancreatic beta cells along with insulin and plays a role in satiety, gastric emptying, and glucagon secretion. Amylin controls satiety signals by directly acting on amylin receptors (AMYR) in the brain. Currently, there are three known amylin receptor subtypes: Amy1R, Amy2R, and Amy3R. Studies have shown that Amy1R is associated with lipid metabolism, while Amy3R is responsible for blood sugar regulation. Amylin is also a potent inhibitor of gastric emptying, which can further inhibit glucagon secretion through central mechanisms.

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

[0005] Studies have shown that synergistic activation of amylin receptors and calcitonin receptors has a positive metabolic promoting effect and can effectively reduce blood sugar levels and body weight. The development of long-acting dual agonists of amylin receptors and calcitonin receptors is expected to provide an effective drug for the treatment of metabolic diseases, including obesity, type 2 diabetes, non-alcoholic fatty liver disease (NASH), dyslipidemia, etc. At present, there are no long-acting dual agonists of amylin receptors and calcitonin receptors (DACRA) approved. Therefore, there is an urgent need to develop a polypeptide or its analogue that can simultaneously activate 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 a certain extent. To this end, the present invention provides a polypeptide or an analog thereof, which has activation activity on both amylin receptor (AMYR) and calcitonin receptor (CTR).

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

[0008] Some long-acting amylin analogs are in the clinical research stage and have shown certain advantages in the treatment of metabolic diseases. Pramlintide is an amylin analog that is approved for use in combination with insulin therapy to improve insulin sensitivity in diabetic patients and help lower blood sugar. However, the drug has an in vivo half-life of less than 1 hour, so patients need to inject it multiple times a day with meals, which is inconvenient. In addition, due to their structural characteristics, amylin analogs 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 for conditions such as hypercalcemia, osteoporosis, and osteitis deformans. Recent studies have shown that calcitonin has other metabolic benefits, such as affecting insulin sensitivity, reducing gastric emptying rate, and promoting satiety. However, its short half-life in vivo requires multiple subcutaneous injections daily, resulting in poor patient compliance. Furthermore, sCT is unstable and prone to aggregation, which can cause immunogenic reactions and pose safety concerns.

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

[0011] Based on this, the method of the present invention introduces residues containing -SH or -NH2 side chains (including but not limited to cysteine ​​(C or c) or lysine (K or k)) at two-point mutations in the polypeptide chain, and performs dual-site fixed modification of the side chains 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 improve the stability and receptor binding activity of the target polypeptide.

[0012] Therefore, in one aspect of the present invention, the present invention provides a polypeptide or its derivative or its pharmaceutically acceptable salt. According to an embodiment of the present invention, the polypeptide or its derivative or its pharmaceutically acceptable salt has a structure shown in formula (I):

[0013] U-X1SHX4SX6X7X8X9X10 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);

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

[0015] X1 is A or K;

[0016] X4 is L or αMeL;

[0017] X6 is Z1, Z2 or T;

[0018] X7 is Z1, Z2 or A;

[0019] X8 is Z1, Z2 or V;

[0020] X9 is Z1, Z2 or L;

[0021] X 10 is Z1, Z2 or G;

[0022] X 11 is Z1, Z2, homoR, Orn, or R;

[0023] X 12 is Z1, Z2 or L;

[0024] X 13 is Z1, Z2 or S;

[0025] X 14 is Z1, Z2 or A;

[0026] X 15 is Z1, Z2 or E;

[0027] X 16 is Z1, Z2 or L;

[0028] X 17 is Z1, Z2 or H;

[0029] X 18 is Z1, Z2, K, αMeK or Orn;

[0030] X 19 is Z1, Z2 or L;

[0031] X 20 is Z1, Z2 or Aib;

[0032] X 22 is Y or αMeF;

[0033] X 24 is R, N-Me-R, homoR, norR, Q or r;

[0034] X 32 is P, Hyp, cis-P(4-NH2), trans-P(4-NH2) or p;

[0035] 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 X i and X i+7 , i is any integer between 6 and 13;

[0036] Each amino acid Z1 is independently selected from C, C, αMeC, HoC, Hoc, Pen or N-Me-C;

[0037] Each amino acid Z2 is independently selected from K, k, Dap, Dab, Orn, HomoK, N-Me-K, N-Me-k, αMeK, αMek.

[0038] The polypeptides or derivatives thereof, or pharmaceutically acceptable salts thereof (hereinafter referred to as polypeptides or analogs) according to embodiments of the present invention are dual agonist polypeptide analogs that can simultaneously exhibit balanced or unbalanced activation activity on both the amylin receptor (AMYR) and the calcitonin receptor (CTR). These polypeptides can be used to prevent or treat metabolic syndromes such as T2DM, obesity, hyperlipidemia, NAFLD, and NASH; they also have potential therapeutic applications in other diseases, such as Alzheimer's disease (AD) and symptoms or diseases related to alcohol or drug addiction.

[0039] In the second aspect of the present invention, the present invention proposes a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises the polypeptide or its derivative or their pharmaceutically acceptable salts described in the first aspect. As mentioned above, the polypeptide or its derivative or their pharmaceutically acceptable salts (hereinafter referred to as polypeptide or its analogues) 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). Therefore, the use of drugs containing polypeptides or their derivatives or their pharmaceutically acceptable salts can effectively prevent or treat amylin receptor and / or calcitonin receptor related diseases.

[0040] In its third aspect, the present invention provides a combination drug or kit. According to embodiments of the present invention, the combination drug or kit comprises: the polypeptide described in the first aspect, its derivative, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition 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 a disease. The combination drug or kit according to embodiments of the present invention can further enhance the therapeutic efficacy of amylin receptor- and / or calcitonin receptor-related diseases.

[0041] In the fourth aspect of the present invention, the present invention provides the polypeptide or its derivative or pharmaceutically acceptable salts described in the first aspect, the pharmaceutical composition described in the second aspect, or the combination drug or drug kit described in the third aspect, for treating or preventing amylin receptor and / or calcitonin receptor related diseases, or has the following uses: treating or preventing amylin receptor and / or calcitonin receptor related diseases; and / or preparing a drug for treating or preventing amylin receptor and / or calcitonin receptor related diseases.

[0042] In a fifth aspect, the present invention provides 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 comprises administering to a subject a pharmaceutically acceptable amount of the polypeptide or derivative thereof or a pharmaceutically acceptable salt thereof according to the first aspect, the pharmaceutical composition according to the second aspect, or the combination drug or kit according to the second aspect.

[0043] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the following description of the embodiments with reference to the accompanying drawings, in which:

[0045] FIG1 is a schematic diagram of the synthesis process of the Staple linker in Example 1 of the present invention;

[0046] FIG2 is a graph showing the binding activity of different polypeptide derivatives to AMY3R in Test Example 1 of the present invention;

[0047] FIG3 is a graph showing the binding activity of different polypeptide derivatives to CTR in Test Example 1 of the present invention;

[0048] FIG4 is a PK curve diagram of different polypeptide derivatives in rats in Test Example 2 of the present invention;

[0049] FIG5 is a PK curve diagram of different polypeptide derivatives in Test Example 2 of the present invention in cynomolgus monkeys;

[0050] FIG6 shows the changes in body weight and food intake in SD rats after a single administration of the polypeptide derivatives in Test Example 3 of the present invention;

[0051] FIG7 shows the changes in body weight and food intake after a single administration of the polypeptide derivative in Test Example 4 of the present invention in a DIO mouse model, with the positive control drug being Cagrilintide;

[0052] Figure 8 shows the changes in body weight and food intake after a single administration of the polypeptide derivative combined with semaglutide in Test Example 5 of the present invention in a DIO mouse model, with the positive control drugs being the same dose of canaglitinide or the same dose of semaglutide;

[0053] FIG9 shows the results of changes in body weight, blood sugar and food intake after continuous administration of the polypeptide derivatives in Test Example 6 of the present invention in the ZDF rat model;

[0054] FIG10 is a result of the stability test of the polypeptide derivative aggregation precipitation in Test Example 9 of the present invention, wherein the positive control is salmon calcitonin. DETAILED DESCRIPTION

[0055] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0056] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood to indicate or imply relative importance or implicitly specify the number of the technical features indicated. Therefore, features defined as "first" or "second" may explicitly or implicitly include one or more of such features. Furthermore, in the description of the present invention, unless otherwise specified, "plurality" means two or more.

[0057] Detailed description of the invention

[0058] Definitions and General Terms

[0059] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention, but not excluding other contents.

[0060] As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the polypeptide or derivative thereof and / or the mammal to be treated therewith. Preferably, the "pharmaceutically acceptable" herein means approved by federal regulatory agencies or national governments or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in animals, particularly humans.

[0061] As used herein, the term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the polypeptides of the present invention or their derivatives. Pharmaceutically acceptable salts are well known in the art, as described in SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.

[0062] In this document, amino acids are referred to using the conventional single-letter and three-letter codes for natural amino acids, as well as the commonly accepted three-letter codes for other α-amino acids, for example, α-aminoisobutyric acid can be represented by two codes, 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 lowercase letters are in the D-configuration.

[0063] In this document, the term "Aib" is

[0064] In this context, the structural formula of the term "αMeF" is

[0065] In this context, the structural formula of the term "Orn" is

[0066] In this context, the structural formula of the term "αMeL" is

[0067] In this context, the structural formula of the term "αMeK" is

[0068] In this context, the structural formula of the term "N-Me-R" is

[0069] In this context, the structural formula of the term "Hyp" is

[0070] As used herein, the structural formula of the term "homoR" is

[0071] In this context, the structural formula of the term "cis-P(4-NH2)" is

[0072] In this context, the structural formula of the term "trans-P(4-NH2)" is

[0073] In this context, the structural formula of the term "αMeC" is

[0074] In this context, the structural formula of the term "HoC" is

[0075] In this context, the structural formula of the term "Hoc" is

[0076] In this document, the structural formula of the term "Pen" is

[0077] In this context, the structural formula of the term "N-Me-C" is

[0078] In this context, the structural formula of the term "Dab" is

[0079] In this context, the structural formula of the term "Dap" is

[0080] In this article, the structural formula of the term "homoK" is

[0081] In this context, the structural formula of the term "αMek" is

[0082] In this article, the structural formula of the term "N-Me-K" is

[0083] As used herein, the terms "optionally," "optional," or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0084] As used herein, the terms "optionally substituted," "optionally substituted," and "substituted or unsubstituted" are used interchangeably. Generally, the term "optionally," whether or not preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specified group, the substituents may be the same or different at each position. Such substituents may include, but are not limited to, F, Cl, Br, CN, OH, NH2, NO2, and the like.

[0085] As used herein, the term "one or more" (e.g., in the definition of substituents of the compounds of the general formulae of the invention (modifying groups)) means "one, two, three, four or five, in particular one, two, three or four, more in particular one, two or three, even more in particular one or two".

[0086] In addition, it should be noted that, unless otherwise explicitly stated, the description methods used in the present invention, "each... is independently" and "... are each independently" and "... are independently" can be interchanged and should be understood in a broad sense. They can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0087] As used herein, the term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.

[0088] In this document, the minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Refers to a carbon atom containing "a" to "b". For example, "C 1～n ” refers to a linear or branched saturated / unsaturated carbon chain containing 1, 2, 3, 4, 5, ... or n carbon atoms; it is further understood that “C 1～n " shall be interpreted as including any sub-ranges therein, such as C 1～20 Including C 1～20 、C 1～18 、C 10～8 、C 12～18 、C 14～18 、C 1～10 、C 1～6 、C 1～3 、C 1～2 、C 2～10 、C 2～9 、C 2～8 、C 2～7 、C 2～6 、C 2～5 、C 2～4 、C 2～3 、C 3～10 、C 3～9 、C 3～8 、C 3～7 、C 3～6 、C 3～5 、C 3～4 、C 4～10 、C 4～9 、C 4～8 、C 4～7 、C 4～6 、C 4～5 .

[0089] In this context, the term "alkyl" is represented by the general formula Alkylene can be a straight chain alkyl or a branched chain alkyl. 1～20 "Alkyl" refers to an alkyl group having 1 to 20 carbon atoms; the term "C 1～6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms.

[0090] In this context, the term "alkylene" is Alkylene can be a straight chain alkylene or a branched chain alkylene. 1～20 "Alkylene" refers to an alkylene group having 1 to 20 carbon atoms; the term "C 1～6 "Alkylene" refers to an alkylene group having 1 to 6 carbon atoms.

[0091] In this article, the term “C 1～6 "Alkoxy" refers to a C 1～6 Alkyl, wherein the term "alkyl" is as defined above. For example: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, isopentyloxy and n-hexyloxy, or isomers of the above groups. In particular, the "C 1～6 The "alkoxy" group may contain 1, 2, 3, 4 or 5 carbon atoms ("C 1～5 Alkoxy”), preferably, may contain 1, 2, 3 or 4 carbon atoms (“C 1～4 (alkoxy").

[0092] As used herein, the term "oxyalkylene" refers to a group formed by removing a hydrogen atom from an "oxyalkyl" group.

[0093] As used herein, the term "aryl" refers to a carbon ring system containing monocyclic, bicyclic, and tricyclic rings, wherein at least one ring system is aromatic, and wherein each ring system comprises a ring composed of 3-10 atoms. An aryl group is typically, but not necessarily, attached to the parent molecule via the aromatic ring of the aryl group. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring." Aryl groups can include phenyl, indenyl, naphthyl, and anthracenyl. The aryl group is optionally substituted with one or more substituents described herein.

[0094] As used herein, the term "arylene" refers to a group formed by removing a hydrogen atom from an "aryl" group.

[0095] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, and tricyclic carbon ring system containing at least one heteroatom, wherein at least one of the ring systems is aromatic. Here, heteroatoms include nitrogen atoms, oxygen atoms, sulfur atoms, and the like. It generally refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon.

[0096] As used herein, the term "heteroarylene" refers to a group formed by removing a hydrogen atom from a "heteroaryl" group.

[0097] The group description of the present invention It is used to describe the position of group substitution.

[0098] In this context, the structural formula of the term "-NH-CO-" or "-NH-C(=O)-" is

[0099] As used herein, "pharmaceutical composition" may refer to a composition used for the treatment of a disease or for in vitro cell culture experiments. When used for the treatment of a disease, the term "pharmaceutical composition" generally refers to a unit dosage form, which may be any type of formulation and may be prepared by any method well known in the pharmaceutical art. All methods include the step of combining the active ingredient with an excipient that constitutes one or more adjunct ingredients. Typically, the composition is prepared by uniformly and thoroughly combining the active polypeptide or its derivative or revitalizing agent with a liquid excipient, a finely divided solid excipient, or both.

[0100] In the chemical structure of the ligand or compound disclosed herein, the bond Indicates that the configuration is not specified. If chiral isomers exist in the chemical structure, the bond Can be or include both Although all of the above structural formulae are drawn as certain isomers for simplicity, the present disclosure may include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates, and enantiomers.

[0101] As used herein, the term "pharmaceutically acceptable excipient" may 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 specific target dosage form. Except to the extent that any conventional excipient is incompatible with the polypeptide or derivative thereof, pharmaceutical composition, or medicament containing the same, such as any adverse biological effect produced or interaction with any other component of the pharmaceutically acceptable composition in a harmful manner, their use is also contemplated by the present invention.

[0102] In addition to any conventional excipients, to the extent that they are incompatible with the polypeptides of the present invention or their derivatives, pharmaceutical compositions or drugs containing them, such as any adverse biological effects produced or interactions with any other components of the pharmaceutically acceptable composition in a harmful manner, their use is also within the scope of the present invention.

[0103] The pharmaceutical compositions of the present disclosure include formulations suitable for parenteral administration. The formulations can be conveniently presented in unit dosage form and can be prepared by any method known in the pharmaceutical art. The amount of active ingredient that can be combined with excipients to prepare a single dose form is generally the amount of polypeptide or its derivative that produces a therapeutic effect.

[0104] As used herein, the term "agonist" refers to a substance (ligand) that activates the receptor type in question.

[0105] As used herein, the term "treatment" refers to any agent used to obtain a desired pharmacological and / or physiological effect. The effect may be preventive in terms of completely or partially preventing a disease or its symptoms, and / or therapeutic in terms of partially or completely curing a disease and / or the adverse effects caused by the disease. "Treatment" as used herein covers diseases in mammals, particularly humans, and includes: (a) preventing the occurrence of a disease or condition in individuals who are susceptible to the disease but have not yet been diagnosed with the disease; (b) inhibiting the disease, such as arresting the progression of the disease; or (c) alleviating the disease, such as alleviating the symptoms associated with the disease. "Treatment" as used herein covers any medication that administers a polypeptide or a derivative thereof to an individual to treat, cure, alleviate, improve, reduce or inhibit the individual's disease, including but not limited to administering a drug containing a polypeptide or a derivative thereof as described herein to an individual in need.

[0106] In this article, the term "non-alcoholic fatty liver disease (NAFLD)" generally refers to a clinical pathological syndrome characterized by excessive fat deposition in hepatocytes, excluding alcohol and other clear liver-damaging factors. It is an acquired metabolic stress-induced liver injury closely related to insulin resistance and genetic susceptibility, including but not limited to simple fatty liver (SFL), non-alcoholic steatohepatitis (NASH) and its related cirrhosis.

[0107] Detailed description of the polypeptide or its analogs of the present invention and their applications

[0108] The present invention provides a polypeptide or its derivatives or pharmaceutically acceptable salts thereof, a pharmaceutical composition and uses thereof, which are described in detail below.

[0109] Polypeptide or its derivative or pharmaceutically acceptable salt thereof

[0110] In one aspect of the present invention, the present invention provides a polypeptide or its derivative or its pharmaceutically acceptable salt. According to an embodiment of the present invention, the polypeptide or its derivative or its pharmaceutically acceptable salt has a structure shown in formula (I):

[0111] 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);

[0112] wherein each U is independently hydrogen, acetyl, or benzoyl;

[0113] 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 Z1, Z2 or L; X 13 Z1, Z2 or S; X 14 Z1, Z2 or A; X 15 Z1, Z2 or E; X 16 Z1, Z2 or L; X 17 Z1, Z2 or H; X 18 is Z1, Z2, K, αMeK or Orn; X 19 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;

[0114] 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 X i and X i+7 , i is any integer between 6 and 13;

[0115] Each amino acid Z1 is independently selected from C, C, αMeC, HoC, Hoc, Pen or N-Me-C;

[0116] Each amino acid Z2 is independently selected from K, k, Dap, Dab, Orn, HomoK, N-Me-K, N-Me-k, αMeK, αMek.

[0117] The polypeptides or derivatives thereof, or pharmaceutically acceptable salts thereof (hereinafter referred to as polypeptides or analogs) according to embodiments of the present invention are dual agonist polypeptide analogs that can simultaneously exhibit balanced or unbalanced activation activity on both the amylin receptor (AMYR) and the calcitonin receptor (CTR). These polypeptides can be used to prevent or treat metabolic syndromes such as T2DM, obesity, hyperlipidemia, NAFLD, and NASH; they also have potential therapeutic applications in other diseases, such as Alzheimer's disease (AD) and symptoms or diseases related to alcohol or drug addiction.

[0118] Furthermore, the two amino acids Z1 or the two amino acids Z2 of the above-mentioned polypeptide or its analogs can be modified to have a longer in vivo half-life to support low-dose and low-frequency administration.

[0119] It should be noted that, herein, unless otherwise specified, U refers to a hydrogen atom or a substituent thereof in the -NH2 of an amino acid X1. When U is hydrogen, the -NH2 of X1 is -NH2 itself; when U is an acetyl group (i.e., Ac), the -NH2 of X1 is -NHAc; and when U is a benzoyl group (i.e., Bzl), the -NH2 of X1 is -NH(Bzl).

[0120] It should be noted that in this article, no special instructions are required. 32 -NH2 refers to X 32 The -OH in the -COOH is replaced by -NH2, that is, -CONH2.

[0121] According to an embodiment of the present invention, 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 .

[0122] According to an embodiment of the present invention, the positions of the two amino acids Z1 or the two amino acids Z2 are X8 and X 15 .

[0123] According to an embodiment of the present invention, the two amino acids Z1 or the two amino acids Z2 are each independently selected from K, C or C.

[0124] According to an embodiment of the present invention, X1 is A or K.

[0125] According to an embodiment of the present invention, X1 is A.

[0126] According to an embodiment of the present invention, X4 is L.

[0127] According to an embodiment of the present invention, X6 is K, C, C or T.

[0128] According to an embodiment of the present invention, X6 is C or T.

[0129] According to an embodiment of the present invention, X6 is T.

[0130] According to an embodiment of the present invention, X7 is K, C, C or A.

[0131] According to an embodiment of the present invention, X7 is C or A.

[0132] According to an embodiment of the present invention, X7 is A.

[0133] According to an embodiment of the present invention, X8 is C, V, C, HoC, Pen, αMeC, N-Me-C, K, Orn, k or Dab.

[0134] According to an embodiment of the present invention, X8 is K, C, C or V.

[0135] According to an embodiment of the present invention, X8 is C, V or K.

[0136] According to an embodiment of the present invention, X8 is C or V.

[0137] According to an embodiment of the present invention, X8 is V.

[0138] According to an embodiment of the present invention, X9 is K, C, C or L.

[0139] According to an embodiment of the present invention, X9 is C or L.

[0140] According to an embodiment of the present invention, X9 is L.

[0141] According to an embodiment of the present invention, X 10 It is K, c, C or G.

[0142] According to an embodiment of the present invention, X 10C or G.

[0143] According to an embodiment of the present invention, X 10 For G.

[0144] According to an embodiment of the present invention, X 11 is K, c, C, homoR, Orn or R.

[0145] According to an embodiment of the present invention, X 11 It is K, C, homoR, Orn or R.

[0146] According to an embodiment of the present invention, X 11 is K, C, homoR or R.

[0147] According to an embodiment of the present invention, X 11 is C, homoR or R.

[0148] According to an embodiment of the present invention, X 11 is homoR or R.

[0149] According to an embodiment of the present invention, X 12 K, c, C or L.

[0150] According to an embodiment of the present invention, X 12 C or L.

[0151] According to an embodiment of the present invention, X 12 For L.

[0152] According to an embodiment of the present invention, X 13 It is K, c, C or S.

[0153] According to an embodiment of the present invention, X 13 C or S.

[0154] According to an embodiment of the present invention, X 13 For S.

[0155] According to an embodiment of the present invention, X 14 It is K, c, C or A.

[0156] According to an embodiment of the present invention, X 14 C or A.

[0157] According to an embodiment of the present invention, X 14 It is A.

[0158] 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.

[0159] According to an embodiment of the present invention, X 15 It is K, c, C or E.

[0160] According to an embodiment of the present invention, X 15 It is K, C or E.

[0161] According to an embodiment of the present invention, X 15 C or E.

[0162] According to an embodiment of the present invention, X 15 For C.

[0163] According to an embodiment of the present invention, X 16 K, c, C or L.

[0164] According to an embodiment of the present invention, X 16 C or L.

[0165] According to an embodiment of the present invention, X 16 For L.

[0166] According to an embodiment of the present invention, X 17 is K, c, C or H.

[0167] According to an embodiment of the present invention, X 17 is C or H.

[0168] According to an embodiment of the present invention, X 17 For H.

[0169] According to an embodiment of the present invention, X 18 is c, K, C, k, αMeK or Orn.

[0170] According to an embodiment of the present invention, X 18 is K, C, k, αMeK or Orn.

[0171] According to an embodiment of the present invention, X 18 is C, K or αMeK.

[0172] According to an embodiment of the present invention, X 18 is K or αMeK.

[0173] According to an embodiment of the present invention, X 19 K, c, C or L.

[0174] According to an embodiment of the present invention, X 19 C or L.

[0175] According to an embodiment of the present invention, X 21 For L.

[0176] According to an embodiment of the present invention, X 20It is K, c, C or Aib.

[0177] According to an embodiment of the present invention, X 20 C or Aib.

[0178] According to an embodiment of the present invention, X 20 For Aib.

[0179] According to an embodiment of the present invention, X 22 is Y.

[0180] According to an embodiment of the present invention, X 23 For P.

[0181] According to an embodiment of the present invention, X 24 is R, N-Me-R, homoR, norR, r or Q.

[0182] According to an embodiment of the present invention, X 24 It is R, N-Me-R, homoR, norR or Q.

[0183] According to an embodiment of the present invention, X 24 It is R, N-Me-R or Q.

[0184] According to an embodiment of the present invention, X 29 It is A.

[0185] According to an embodiment of the present invention, X 32 is P or Hyp.

[0186] According to an embodiment of the present invention, the structure represented by 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).

[0187] In some optional embodiments of the present invention, in the structure represented by formula (Ia), X1 is A or K.

[0188] In some optional embodiments of the present invention, in the structure represented by formula (Ia), X4 is L or αMeL.

[0189] In some optional embodiments of the present invention, in the structure represented by formula (Ia), X7 is C or A.

[0190] In some optional embodiments of the present invention, in the structure represented by formula (Ia), X8 is C or V.

[0191] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 11 is homoR, C or R.

[0192] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 13 C or S.

[0193] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 14 C or A.

[0194] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 15 C or E.

[0195] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 18 is C, K, k, αMeK or Orn.

[0196] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 20 C or Aib.

[0197] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 22 is Y or αMeF.

[0198] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 23 It is P or K.

[0199] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 24 It is R, N-Me-R, homoR, norR or Q.

[0200] In some optional embodiments of the present invention, in the structure shown in formula (Ia), X 32 is P or Hyp.

[0201] According to an embodiment of the present invention, 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).

[0202] In some optional embodiments of the present invention, in the structure represented by formula (Ib), X1 is A or K.

[0203] In some optional embodiments of the present invention, in the structure represented by formula (Ib), X4 is L or αMeL.

[0204] In some optional embodiments of the present invention, in the structure represented by formula (Ib), X8 is C, V, C, HoC, Pen, αMeC, N-Me-C, K, Orn, k or Dab.

[0205] In some optional embodiments of the present invention, in the structure shown in formula (Ib), X 11 is homoR, C, K, Orn or R.

[0206] In some optional 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.

[0207] In some optional embodiments of the present invention, in the structure shown in formula (Ib), X 18 is C, K, αMeK or Orn.

[0208] In some optional embodiments of the present invention, in the structure shown in formula (Ib), X 22 is Y or αMeF.

[0209] In some optional embodiments of the present invention, in the structure shown in formula (Ib), X 24 is R, N-Me-R, homoR, norR, r or Q.

[0210] In some optional embodiments of the present invention, in the structure shown in formula (Ib), X 32 is P or Hyp.

[0211] According to an embodiment of the present invention, the structure shown in 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).

[0212] In some optional embodiments of the present invention, in the structure represented by formula (II), X4 is L or αMeL.

[0213] In some optional embodiments of the present invention, in the structure shown in formula (II), X7 is C or A.

[0214] In some optional embodiments of the present invention, in the structure shown in formula (II), X8 is C, K or V.

[0215] In some optional embodiments of the present invention, in the structure shown in formula (II), X 11 is homoR, C, K or R.

[0216] In some optional embodiments of the present invention, in the structure shown in formula (II), X 12 It is L or C.

[0217] In some optional embodiments of the present invention, in the structure shown in formula (II), X 13 C or S.

[0218] In some optional embodiments of the present invention, in the structure shown in formula (II), X 14 C or A.

[0219] In some optional embodiments of the present invention, in the structure shown in formula (II), X 15 It is K, C or E.

[0220] In some optional embodiments of the present invention, in the structure shown in formula (II), X 17 is C or H.

[0221] In some optional embodiments of the present invention, in the structure shown in formula (II), X 18 is C, K, αMeK or Orn.

[0222] In some optional embodiments of the present invention, in the structure shown in formula (II), X 19 C or L.

[0223] In some optional embodiments of the present invention, in the structure shown in formula (II), X 20 C or Aib.

[0224] In some optional embodiments of the present invention, in the structure shown in formula (II), X 22 is Y or αMeF.

[0225] In some optional embodiments of the present invention, in the structure shown in formula (II), X 24 It is R, N-Me-R or Q.

[0226] In some optional embodiments of the present invention, in the structure shown in formula (II), X 32 is P or Hyp.

[0227] According to an embodiment of the present invention, 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).

[0228] In some optional embodiments of the present invention, in the structure represented by formula (IIa), X4 is L or αMeL.

[0229] In some optional embodiments of the present invention, in the structure represented by formula (IIa), X8 is C, K or V.

[0230] In some optional embodiments of the present invention, in the structure shown in formula (IIa), X 11 is homoR, C, K or R.

[0231] In some optional embodiments of the present invention, in the structure shown in formula (IIa), X 13 C or S.

[0232] In some optional embodiments of the present invention, in the structure shown in formula (IIa), X 15 It is K, C or E.

[0233] In some optional embodiments of the present invention, in the structure shown in formula (IIa), X 18 is C, K, αMeK or Orn.

[0234] In some optional embodiments of the present invention, in the structure shown in formula (IIa), X 20 C or Aib.

[0235] In some optional embodiments of the present invention, in the structure shown in formula (IIa), X 22 is Y or αMeF.

[0236] In some optional embodiments of the present invention, in the structure shown in formula (IIa), X 24 It is R, N-Me-R or Q.

[0237] In some optional embodiments of the present invention, in the structure shown in formula (IIa), X 32is P or Hyp.

[0238] According to an embodiment of the present invention, the structure represented by formula (I) has the following structure: U-ASHLSTAX8LGX 11 LSAX 15 LHX 18 L-Aib-DYPX 24 TDVGAGSX 32 -NH2(IIb).

[0239] In some optional embodiments of the present invention, in the structure represented by formula (IIb), X8 is C, K or V.

[0240] In some optional embodiments of the present invention, in the structure shown in formula (IIb), X 11 is homoR, C or R.

[0241] In some optional embodiments of the present invention, in the structure shown in formula (IIb), X 15 It is K, C or E.

[0242] In some optional embodiments of the present invention, in the structure shown in formula (IIb), X 18 is C, K or αMeK.

[0243] In some optional embodiments of the present invention, in the structure shown in formula (IIb), X 24 It is R, N-Me-R or Q.

[0244] In some optional embodiments of the present invention, in the structure shown in formula (IIb), X 32 is P or Hyp.

[0245] According to an embodiment of the present invention, the structure shown in formula (I) has the following structure: U-ASHLSTACLGX 11 LSACLHX 18 L-Aib-DYPX 24 TDVGAGSX 32 -NH2(III).

[0246] In some optional embodiments of the present invention, in the structure shown in formula (III), X 11 is homoR or R.

[0247] In some optional embodiments of the present invention, in the structure shown in formula (III), X 18 is K or αMeK.

[0248] In some optional embodiments of the present invention, in the structure shown in formula (III), X 24It is R, N-Me-R or Q.

[0249] In some optional embodiments of the present invention, in the structure shown in formula (III), X 32 is P or Hyp.

[0250] According to an embodiment of the present invention, the structure represented by formula (I) has at least one of the following structures:

[0251] U-ASHLSCAVLGRLCAELHKL-Aib-DYPRTDVGAGSP-NH2;

[0252] U-ASHLSTCVLGRLSCELHKL-Aib-DYPRTDVGAGSP-NH2;

[0253] U-ASHLSTACLGRLSACLHKL-Aib-DYPRTDVGAGSP-NH2;

[0254] U-ASHLSTAVCGRLSAECHKL-Aib-DYPRTDVGAGSP-NH2;

[0255] U-ASHLSTAVLCRLSAELCKL-Aib-DYPRTDVGAGSP-NH2;

[0256] U-ASHLSTAVLGCLSAELHCL-Aib-DYPRTDVGAGSP-NH2;

[0257] U-ASHLSTAVLGRCSAELHKC-Aib-DYPRTDVGAGSP-NH2;

[0258] U-ASHLSTAVLGRLCAELHKLCDYPRTDVGAGSP-NH2;

[0259] U-ASHLSTACLGRLSACLH-Orn-L-Aib-D-(αMeF)-PRTDVGAGS-Hyp-NH2;

[0260] U-ASH-(αMeL)-STACLRLSACLHKL-Aib-D-(αMeF)-P-(N-Me-R)-TDVGAGSP-NH2;

[0261] U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYP-(N-Me-R)-TDVGAGS-Hyp-NH2;

[0262] <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"> <h2 style=";text-align:left;direction:ltr">

[0263] <h2 style=";text-align:left;direction:ltr"> U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYP-homoR-TDVGAGS-Hyp-NH2;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0264] <h2 style=";text-align:left;direction:ltr"> U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYP-norR-TDVGAGS-Hyp-NH2;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0265] <h2 style=";text-align:left;direction:ltr"> U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0266] <h2 style=";text-align:left;direction:ltr"> U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYP-r-TDVGAGS-Hyp-NH2;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0267] <h2 style=";text-align:left;direction:ltr"> U-ASHLSTAVLGCLSAELHCL-Aib-DYPQTDVGAGS-Hyp-NH2;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0268] <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"> <h2 style=";text-align:left;direction:ltr">

[0269] <h2 style=";text-align:left;direction:ltr"> U-KSHLSTAVLGCLSAELHCL-Aib-DYPQTDVGAGS-Hyp-NH2;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0270] <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"> <h2 style=";text-align:left;direction:ltr">

[0271] <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"> <h2 style=";text-align:left;direction:ltr">

[0272] <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"> <h2 style=";text-align:left;direction:ltr">

[0273] <h2 style=";text-align:left;direction:ltr"> U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYPQTDVGAGS-p-NH2;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0274] U-ASHLSTACLG-homoR-LSACLH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2;

[0275] U-ASHLSTACLG-Orn-LSA CLH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2;

[0276] U-ASHLSTA-HoC-LGRLSA-HoC-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2;

[0277] U-ASHLSTA-Pen-LGRLSA-Pen-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2;

[0278] U-ASHLSTA-(αMeC)-LGRLSA-(αMeC)-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2;

[0279] U-ASHLSTACLGRLSACLH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2;

[0280] U-ASHLSTA-(N-Me-C)-LGRLSA-(N-Me-C)-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2;

[0281] U-ASHLSTAKLGRLSAKLH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2;

[0282] U-ASHLSTAVLGKLSAELHKL-Aib-DYPQTDVGAGS-Hyp-NH2;

[0283] U-ASHLSTA-Orn-LGRLSA-Orn-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2;

[0284] U-ASHLSTA-Dab-LGRLSA-Dab-LH-(αMeK)-L-Aib-DYPQTDVGAGS-Hyp-NH2;

[0285] Each U is independently selected from H, acetyl, and benzoyl.

[0286] It should be noted that, in the polypeptide in the structure represented by the above formula (I), the “-” between the amino acids represents an amide bond; for example, the “-” in “L-Aib-D” represents an amide bond.

[0287] According to an embodiment of the present invention, in the structure represented by formula (I), U is hydrogen.

[0288] According to an embodiment of the present invention, in the structure represented by formula (I), U is an acetyl group.

[0289] According to an embodiment of the present invention, in the structure represented by formula (I), U is a benzoyl group.

[0290] According to an embodiment of the present invention, the structure represented by formula (I) has at least one of the following structures:

[0291] It should be noted that in the tables herein, when a polypeptide encodes multiple polypeptides corresponding to Table A or Table B, the polypeptide in the table has the same main peptide chain as the polypeptides in Table A or Table B, differing only in the absence of side chains with modifying groups. For example, "1-21 (AMY-021, AMY-038)" means that the main peptide chain of polypeptide 1-21 in the above table is the same as that of AMY-021 and AMY-038 in Table A, but polypeptide 1-21 does not have side chains with modifying groups; the same applies to "1-15 (AMY-015, AMY-016, AMY-017, AMY-018)".

[0292] According to an embodiment of the present invention, the polypeptide or its derivative or pharmaceutically acceptable salt thereof further comprises a modification group.

[0293] According to an embodiment of the present invention, the modifying group is connected to the two amino acids Z1 or the two amino acids Z2 in the polypeptide represented by formula (I) or its derivative.

[0294] According to an embodiment of the present invention, the modifying group is connected to the -SH group of the side chain of the amino acid Z1 via a sulfur-carbon bond.

[0295] According to an embodiment of the present invention, the modifying group is connected to the -NH2 of the side chain of the amino acid Z2 via an amide bond.

[0296] In an optional embodiment of the present invention, the modifying group is connected to the -SH group of the amino acid C side chain via a sulfur-carbon bond.

[0297] In an optional embodiment of the present invention, the modifying group is connected to the ε-amino group of the side chain of amino acid K via an amide bond.

[0298] According to an embodiment of the present invention, the modifying group has a structure shown in formula (IV):

[0299] Wherein, R1 is C, N, -C 3～10 Heteroalkylene, -C 3～10 Arylene or -C 3～10 heteroarylene;

[0300] R2 and R3 are each independently optionally replaced by one or more R 1a Substituted -C 1～6 Alkylene-, optionally one or more R 1a Substituted-NH-C(O)-C 1～6 Alkylene- or optionally one or more R 1a Substituted -C 1～6 Alkylene-NH-C(O)-C 1～6 Alkylene-, wherein each R 1a are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy;

[0301] R4 is empty or optionally replaced by one or more R 2a Substituted -C 1～6 Alkylene-NH-C(O)-C 1～6 Alkylene-, wherein each R 2a are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy;

[0302] R5 is H, -C 1～6 Alkoxy or -C 1～6 Alkyl, wherein the -C 1～6 Alkyl and -C 1～6 Each alkoxy group is independently optionally substituted with one or more halogen, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN;

[0303] R6 is optionally replaced by one or more R 3a Substituted -C 1～6 Alkylene-, or optionally one or more R 3a Substituted-(C 1～3 Alkylene-O) m1 -C 1～6 Alkylene-, wherein each R 3aare independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy;

[0304] R7 is optionally replaced by one or more R 4a Substituted -C 1～6 Alkylene-, wherein each R 4a are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy;

[0305] R8 is optionally replaced by one or more R 5a Substituted -C 10～20 Alkyl, optionally substituted by one or more R 5a Substituted -C 10～20 Alkylene-R9, optionally replaced by one or more R 5a Substituted -C 5～10 Alkylene-OC 3～10 Arylene-R9, or optionally one or more R 5a Substituted -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;

[0306] R9 is -COOH, -C 3～7 heteroaryl, -S(O)2OH, or -PO(OH)2;

[0307] m1 is any integer from 1 to 6;

[0308] n1 is any integer from 0 to 6;

[0309] n2 is any integer from 1 to 10.

[0310] It should be noted that the “-” in the modifying group in the present invention represents a chemical bond connecting chemical groups, such as a covalent bond between atoms (or atoms in a group) and atoms (or atoms in a group).

[0311] According to an embodiment of the present invention, R1 is C, N, -C 5～7 Heteroalkylene, -C 5～7 Arylene or -C5～7 Heteroarylene.

[0312] According to an embodiment of the present invention, R1 is N, N, N, N-phenylene or pyridylene.

[0313] According to an embodiment of the present invention, R1 is

[0314] According to an embodiment of the present invention, R2 and R3 are each independently -C 1～6 Alkylene-, or -C 1～6 Alkylene-NH-C(O)-C 1～6 Alkylene-.

[0315] According to an embodiment of the present invention, R2 and R3 are each independently -C 1～3 Alkylene-, or -C 1～3 Alkylene-NH-C(O)-C 1～3 Alkylene-.

[0316] According to an embodiment of the present invention, each n1 is independently 0, 1, 2, 3, 4 or 5.

[0317] According to an embodiment of the present invention, n1 is 0.

[0318] According to an embodiment of the present invention, R4 is empty, or -C 1～6 Alkylene-NH-C(O)-C 1～6 Alkylene-.

[0319] According to an embodiment of the present invention, R4 is empty, or -C 1～3 Alkylene-NH-C(O)-C 1～3 Alkylene-.

[0320] According to an embodiment of the present invention, R5 is H, -C 1～3 Alkoxy or -C 1～3 alkyl.

[0321] According to an embodiment of the present invention, R6 is -C 1～6 Alkylene-, -(C 1～3 Alkylene-O) m1 -C 1～6 Alkylene-.

[0322] According to an embodiment of the present invention, R6 is -C 1～3 Alkylene-, -(C 1～3 Alkylene-O) m1 -C 1～3 Alkylene-.

[0323] According to an embodiment of the present invention, m1 is 2, 3, 4 or 5.

[0324] According to an embodiment of the present invention, R7 is -C 1～6 Alkylene-.

[0325] According to an embodiment of the present invention, R7 is -C 2～4 Alkylene-.

[0326] According to an embodiment of the present invention, 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.

[0327] According to an embodiment of the present invention, R8 is -C 10～18 Alkyl, -C 14～18 Alkylene-R9, or -C 7～9 Alkylene-OC 5～7 Arylene-COOH.

[0328] According to an embodiment of the present invention, R9 is -COOH, -C 5～6 heteroaryl, -S(O)2OH, or -PO(OH)2.

[0329] According to an embodiment of the present invention, R9 is -COOH, -S(O)2OH, -PO(OH)2, or

[0330] According to an embodiment of the present invention, n2 is 1, 2 or 3.

[0331] According to an embodiment of the present invention, n2 is 3, 4, 5 or 6.

[0332] According to an embodiment of the present invention, the modifying group represented by formula (IV) has a structure represented by formula (IVa):

[0333] Among them, each R 10 and R 11 Each independently is -C 0～3 Alkylene-;

[0334] R 12 -C 1～6 Alkylene-;

[0335] R8 is -C 10～21 Alkyl, or -C 10～21 Alkylene -COOH, preferably -C 14～19 Alkyl or -C 10～18 Alkylene-COOH;

[0336] q1 is 1, 2, 3, or 4;

[0337] q2 is 1, 2, or 3.

[0338] According to an embodiment of the present invention, the modifying group represented by formula (IVa) has one of the following structures:

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

[0340] Among them, each R 10 ' and R 11 'Each independently -C 0～3 Alkylene-;'

[0341] R 12 ' is -C 1～6 Alkylene-;

[0342] R 13 -C 10～20 Alkylene-, preferably -C 14～18 Alkylene-;

[0343] q1' is 1, 2, 3, or 4;

[0344] q2' is 1, 2 or 3.

[0345] According to an embodiment of the present invention, the modifying group represented by formula (IVb) has one of the following structures:

[0346] According to an embodiment of the present invention, the modifying group represented by formula (IV) has a structure represented by formula (IVc):

[0347] Among them, each R 14 Each independently is -C 1～3 Alkylene- or -NH-C(O)-C 1～3 Alkylene-;

[0348] R 15 -C 0～3 Alkylene- or -C(O)-NH-C 1～3 Alkylene-;

[0349] R 12 " is -C 1～6 Alkylene-;

[0350] R13 ' is -C 10～20 Alkylene-, preferably -C 14～18 Alkylene-;

[0351] q1” is 1, 2, 3, or 4;

[0352] q2” is 1, 2, or 3;

[0353] Y1 is C or N.

[0354] According to an embodiment of the present invention, the modifying group represented by formula (IVc) has one of the following structures:

[0355] According to an embodiment of the present invention, the polypeptide represented by formula (I) or its derivative contains two amino acids Z1, and the modification group has a structure represented by formula (IV).

[0356] According to an embodiment of the present invention, the modifying group has a structure shown in formula (V):

[0357] Among them, R 20 C, N, -C 3～10 Arylene or -C 3～10 heteroarylene;

[0358] R 21 and R 22 Each is independently empty, optionally replaced by one or more R 1b Substituted -C 1～6 Alkylene-, or optionally one or more R 1b Substituted -C 1～6 Oxyalkylene-, wherein each R 1b are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy;

[0359] R 23 Empty, optionally replaced by one or more R 2b Substituted -C 1～6 Alkylene-, optionally substituted by one or more R 2b Substituted-C(O)-C 1～6 Alkylene-, optionally substituted by one or more R 2b Substituted-NH-C(O)-C 1～6 Alkylene-, or optionally one or more R 2b Substituted -C 1～6 Alkylene-C(O)-NH-C 1～6Alkylene-, 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;

[0360] R 24 is optionally replaced by one or more R 3b Substituted -C 1～6 Alkylene-, or optionally one or more R 3b Substituted-(C 1～3 Alkylene-O) m2 -C 1～6 Alkylene-, wherein each R 3b are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy;

[0361] R 25 H, -C 1～6 Alkoxy or -C 1～6 Alkyl, wherein the -C 1～6 Alkyl and -C 1～6 Each alkoxy group is independently optionally substituted with one or more halogen, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN;

[0362] R 26 is optionally replaced by one or more R 4b Substituted -C 1～6 Alkylene-, wherein each R 4b are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy;

[0363] R 27 is optionally replaced by one or more R 5b Substituted -C 10～20 Alkyl, optionally substituted by one or more R 5b Substituted -C 10～20 Alkylene-R 28 , optionally one or more R 5b Substituted -C 5～10 Alkylene-OC 3～10 Arylene-R 28 , or optionally one or more R 5bSubstituted -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;

[0364] R 28 -COOH, -C 3～7 heteroaryl, -S(O)2OH, or -PO(OH)2;

[0365] m2 is any integer from 1 to 6;

[0366] n3 is any integer from 1 to 10;

[0367] n3 is 0, 1, or 2;

[0368] Y2 is empty or NH.

[0369] According to an embodiment of the present invention, R 20 C, N, -C 5～7 Arylene or -C 5～7 Heteroarylene.

[0370] According to an embodiment of the present invention, R 20 is C, N, phenylene or pyridylene.

[0371] According to an embodiment of the present invention, R 20 for Preferably

[0372] According to an embodiment of the present invention, R 21 and R 22 Each is independently empty, -C 1～6 Alkylene-, or -C 1～6 Oxyalkylene-.

[0373] According to an embodiment of the present invention, R 21 and R 22 Each is independently empty or -C 1～3 Alkylene-.

[0374] According to an embodiment of the present invention, R 23 Empty, -C 1～6 Alkylene-, -C 1～6 Alkylene-C(O)-NH-C 1～6 Alkylene-, or -C(O)-C 1～6 Alkylene-.

[0375] According to an embodiment of the present invention, R 23 Empty, -C 1～3 Alkylene-, or -C(O)-C 2～4 Alkylene-.

[0376] According to an embodiment of the present invention, R 24 -C 1～6 Alkylene-, or -(C 1～3 Alkylene-O) m2 -C 1～6 Alkylene-.

[0377] According to an embodiment of the present invention, R 24 -C 1～3 Alkylene-, or -(C 1～3 Alkylene-O) m2 -C 1～3 Alkylene-.

[0378] According to an embodiment of the present invention, m2 is 2, 3, 4 or 5.

[0379] According to an embodiment of the present invention, R 25 H, -C 1～6 Alkoxy or -C 1～6 alkyl.

[0380] According to an embodiment of the present invention, R 25 H or -C 1～3 alkyl.

[0381] According to an embodiment of the present invention, R 26 -C 1～6 Alkylene-.

[0382] According to an embodiment of the present invention, R 26 -C 1～3 Alkylene-.

[0383] According to an embodiment of the present invention, R 27 -C 10～20 Alkyl, -C 10～20 Alkylene-R 28 、-C 5～10 Alkylene-OC 3～10 Arylene-R 28 , or -C 5～10 Alkylene-OC 3～10 Heteroarylene-R 28 .

[0384] According to an embodiment of the present invention, R 27 -C 10～18 Alkyl, -C 14～18Alkylene-R 28 , or -C 7～9 Alkylene-OC 5～7 Arylene-COOH.

[0385] According to an embodiment of the present invention, R 28 -COOH, -C 5～6 heteroaryl, -S(O)2OH, or -PO(OH)2.

[0386] According to an embodiment of the present invention, R 28 -COOH, -S(O)2OH, -PO(OH)2, or

[0387] According to an embodiment of the present invention, p is 1, 2 or 3.

[0388] According to an embodiment of the present invention, p is 3, 4, 5 or 6.

[0389] According to an embodiment of the present invention, the modifying group represented by formula (V) has a structure represented by formula (Va):

[0390] Among them, each R 29 Each independently is -C 1～3 Alkylene-;

[0391] R 30 -C(O)-C 1～6 Alkylene-, or -C 1～3 Alkylene-C(O)-NH-C 1～3 Alkylene-;

[0392] R 31 -C 1～6 Alkylene-;

[0393] q3 is 1, 2, 3, or 4;

[0394] q4 is 1, 2, or 3.

[0395] According to an embodiment of the present invention, in formula (Va), R 27 -C 10～20 Alkylene -COOH or -C 10～20 Alkyl, preferably -C 14～18 Alkylene -COOH or -C 10～19 alkyl.

[0396] According to an embodiment of the present invention, the modifying group represented by formula (Va) has the following structure:

[0397] According to an embodiment of the present invention, the modifying group represented by formula (V) has a structure represented by formula (Vb):

[0398] Among them, each R 29 'Each independently -C 1～3 Alkylene-;

[0399] R 30 ' is -C 1～6 Alkylene-;

[0400] R 31 ' is -C 1～6 Alkylene-;

[0401] q3' is 1, 2, 3 or 4, preferably 2;

[0402] q4' is 1, 2 or 3, preferably 2.

[0403] According to an embodiment of the present invention, in formula (Vb), R 27 -C 10～20 Alkylene -COOH or -C 10～20 Alkyl, preferably -C 14～18 Alkylene-COOH.

[0404] According to an embodiment of the present invention, the modifying group represented by formula (Vb) has the following structure:

[0405] According to an embodiment of the present invention, the modifying group represented by formula (V) has a structure represented by formula (Vc):

[0406] Among them, R 30 " is -C 1～6 Alkylene-;

[0407] R 31 " is -C 1～6 Alkylene-;

[0408] q3 is 1, 2, 3, or 4;

[0409] q4 is 1, 2, or 3.

[0410] 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.

[0411] According to an embodiment of the present invention, the modifying group represented by formula (Vc) has the following structure:

[0412] According to an embodiment of the present invention, the polypeptide represented by formula (I) or its derivative contains two amino acids Z2, and the modification group has a structure represented by formula (V).

[0413] According to an embodiment of the present invention, the polypeptide derivative has any one of the structures shown in the following table:

[0414] According to an embodiment of the present invention, the polypeptide derivative has a structure shown in any one of Table A or Table B:

[0415] Table A

[0416] It should be noted that, based on Table A, the two amino acids connecting the modifying groups in polypeptides AMY-001 to AMY-020, AMY-023 to AMY-036 are replaced with K, and the modifying group is replaced with a modifying group represented by formula (V) (e.g., B1). The resulting polypeptide sequences have similar properties to those of polypeptides AMY-001 to AMY-020, AMY-023 to AMY-036 in Table A. Based on this, the present invention does not present all of them, which are all within the scope of protection of this application. The present invention only exemplifies some polypeptides, see Table B for details, and see the Examples and Test Examples of the present invention for specific activity data.

[0417] Table B

[0418] It should be noted that the "attachment site of the modifying group" in Table A and Table B is specifically X in the structure shown in formula (I) of the present invention. i The position of i in .

[0419] Pharmaceutical composition, combination drug or kit

[0420] In the second aspect of the present invention, the present invention proposes a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises the polypeptide or its derivative or their pharmaceutically acceptable salts described in the first aspect. As mentioned above, the polypeptide or its derivative or their pharmaceutically acceptable salts (hereinafter referred to as polypeptide or its analogues) 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). Therefore, the use of drugs containing polypeptides or their derivatives or their pharmaceutically acceptable salts can effectively prevent or treat amylin receptor and / or calcitonin receptor related diseases.

[0421] According to an embodiment of the present invention, the pharmaceutical composition further includes a pharmaceutically acceptable excipient or carrier.

[0422] In its third aspect, the present invention provides a combination drug or kit. According to embodiments of the present invention, the combination drug or kit comprises: the polypeptide described in the first aspect, its derivative, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition 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 a disease. The combination drug or kit according to embodiments of the present invention can further enhance the therapeutic efficacy of amylin receptor- and / or calcitonin receptor-related diseases.

[0423] According to an embodiment of the present invention, the disease includes preventing and / or treating amylin receptor and / or calcitonin receptor related diseases.

[0424] According to an embodiment of the present invention, the amylin receptor and / or calcitonin receptor related diseases include at least one of fat metabolism disorder, blood sugar metabolism disorder, cardiovascular disease, brain system disease, mental system disease or nervous system disease.

[0425] 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, symptoms or diseases related to alcohol or drug addiction, and neurodegenerative diseases.

[0426] 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, 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 weight, obesity, fatty liver disease, diabetic nephrotic syndrome, diabetes-related renal fibrosis, liver fibrosis, Alzheimer's disease and Parkinson's disease.

[0427] According to an embodiment of the present invention, the amylin receptor and / or calcitonin receptor related diseases include at least one of cardiovascular disease, diabetes and / or obesity.

[0428] According to an embodiment of the present invention, the drug is selected from at least one of drugs for cardiovascular disease, diabetes and / or obesity.

[0429] 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, sulfonylureas, biguanides, meglitazones, glucosidase inhibitors, DPP IV inhibitors, and SGLT2 inhibitors.

[0430] According to an embodiment of the present invention, the GLP-1 analog drug includes at least one of semaglutide, exenatide, liraglutide, dulaglutide, tirzepatide and retaglutide.

[0431] According to an embodiment of the present invention, the gliflozin-type hypoglycemic drug includes at least one of dapagliflozin and empagliflozin.

[0432] According to an embodiment of the present invention, the biguanides include metformin.

[0433] Uses and methods

[0434] In a fourth aspect, the present invention provides the polypeptide or derivative thereof or pharmaceutically acceptable salts thereof according to the first aspect, the pharmaceutical composition according to the second aspect, or the combination drug or drug kit according to the second aspect for use in treating or preventing amylin receptor and / or calcitonin receptor-related diseases, or for the following uses:

[0435] Treating or preventing amylin receptor and / or calcitonin receptor related diseases; and / or preparing a drug for treating or preventing amylin receptor and / or calcitonin receptor related diseases.

[0436] According to an embodiment of the present invention, the amylin receptor and / or calcitonin receptor related diseases include at least one of fat metabolism disorder, blood sugar metabolism disorder, cardiovascular disease, brain system disease, mental system disease or nervous system disease.

[0437] 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, symptoms or diseases related to alcohol or drug addiction, and neurodegenerative diseases.

[0438] 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, 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 weight, obesity, fatty liver disease, diabetic nephrotic syndrome, diabetes-related renal fibrosis, liver fibrosis, Alzheimer's disease and Parkinson's disease.

[0439] In the fifth aspect of the present invention, the present invention proposes 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 comprises: administering to a subject a pharmaceutically acceptable amount of the polypeptide or its derivative or its pharmaceutically acceptable salt described in the first aspect, the pharmaceutical composition described in the second aspect, or the combined drug or kit described in the second aspect. As mentioned above, the polypeptide or its derivative or its pharmaceutically acceptable salt (referred to as polypeptide or its analogue) is a dual agonist polypeptide analogue, which can simultaneously have a certain balanced or unbalanced activation activity on the amylin receptor (AMYR) and the calcitonin receptor (CTR). Therefore, the method of the present invention can effectively prevent and / or treat amylin receptor and / or calcitonin receptor related diseases.

[0440] 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, symptoms or diseases related to alcohol or drug addiction, and neurodegenerative diseases.

[0441] 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.

[0442] According to an embodiment of the present invention, the neurodegenerative disease includes at least one of Alzheimer's disease and Parkinson's disease.

[0443] The effective amount of the polypeptide or its derivative or pharmaceutically acceptable salt, or pharmaceutical composition of the present invention may vary depending on the mode of administration and the severity of the disease to be treated. The preferred effective amount can be determined by a person of ordinary skill in the art based on various factors (e.g., through clinical trials). Such factors include, but are not limited to: pharmacokinetic parameters of the active ingredient, such as bioavailability, metabolism, half-life, etc.; the severity of the disease to be treated, the patient's weight, the patient's immune status, the route of administration, etc. For example, depending on the urgency of the treatment, several divided doses may be administered daily, or the dose may be reduced proportionally.

[0444] The polypeptides or derivatives thereof or pharmaceutically acceptable salts thereof or pharmaceutical compositions of the present invention can be incorporated into drugs suitable for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). These drugs can be prepared in various forms. For example, liquid, semisolid and solid dosage forms, including but not limited to liquid solutions (e.g., injection solutions and infusion solutions) or lyophilized powders. Typical drugs are in the form of injection solutions or infusion solutions. The aforementioned polypeptides or derivatives thereof or pharmaceutically acceptable salts thereof or pharmaceutical compositions can be administered by intravenous infusion or injection or intramuscular or subcutaneous injection.

[0445] Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific technology or conditions are not indicated, the technology or conditions described in the literature in this area or the product instructions are used.The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained by commercial purchase.

[0446] Example 1: Preparation of a polypeptide or its derivatives

[0447] 1. The linear peptides in peptides 1 to 20 (AMY-001 to AMY-020) and peptides 23 to 36 (AMY-023 to AMY-031) in Table A were synthesized using the classic Fmoc-tBu solid phase synthesis method. X peptide synthesizer was prepared, and the reaction conditions were as follows:

[0448] (1) Resin swelling: Add Rink Amide MBHA resin to DCM (dichloromethane), react under N2 bubbling at room temperature for 1 hour, filter, and wash the resin with DMF 2-3 times.

[0449] (2) Removal of Fmoc protecting group: Add DMF (N,N-dimethylformamide) solution containing 20% ​​(volume percentage, v / v) piperidine to the above resin, react under N2 bubbling at room temperature for 10 minutes, filter, and repeat the above operation until complete deprotection, and wash the resin with DMF 2-3 times.

[0450] (3) Amino acid coupling: The materials were added according to the reaction ratio of resin: amino acid: DIC: Oxyma Pure = 1:5:5:5 (equivalent ratio). The reactants, DIC (N,N'-diisopropylcarbodiimide) and Oxyma Pure (condensation reagent) were pre-dissolved in DMF and reacted under N2 bubbling at room temperature for 10 minutes. The mixture was then transferred to a resin reaction tank and reacted under N2 bubbling at room temperature for 1-3 hours. After the reaction was completed, the mixture was filtered and the resin was washed with DMF 2-3 times. After the synthesis was completed, the resin was washed with DCM 2-3 times and vacuum dried to obtain the peptide resin.

[0451] The above method is applicable to amino acids (D or L form) or synthetic reagents including but not limited to: 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-P he-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.

[0452] 2. Linear peptide cleavage and drying: Prepare peptide cleavage solution according to the volume ratio of TFA (trifluoroacetic acid): TIPS (triisopropylsilylethynyl): H2O: EDT (1,2-ethanedithiol) = 95:2:2:1. Add cleavage solution (10 mL / g resin) to the dried peptide resin and shake it on a shaker for 3 hours. Filter the resin residue and add 10 volumes of cold MTBE (methyl tert-butyl ether) to the filtrate. Cool the resulting suspension at -20°C for 1 hour, then centrifuge at 3500 rpm. Wash the precipitate with cold MTBE 3-5 times and vacuum dry to obtain the crude peptide.

[0453] 3. Purification of linear peptides: Prepare a dissolving solution in a volume ratio of mobile phase A (0.1% (volume percentage, v / v) TFA (trifluoroacetic acid)-water): mobile phase B (0.1% (volume percentage, v / v) TFA-acetonitrile) = 1.5:1, dissolve the crude peptide in the dissolving solution to prepare a storage solution, filter using a 0.45 micron filter membrane, and 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 peptide compound (i.e., linear peptide).

[0454] 4. The Staple linker (or modification group A) is prepared using the classic Fmoc-tBu solid-phase synthesis method. This step takes Staple-A1 (or modification group A1) as an example. The reaction conditions are as follows (see Figure 1 for the specific synthesis process):

[0455] (1) Resin swelling: Fmoc-L-Lys(ivDde)-2CTC resin was added to DCM and reacted under N2 bubbling at room temperature for 1 hour. The mixture was filtered and the resin was washed with DMF 2-3 times.

[0456] (2) Removal of Fmoc protecting group: Add DMF solution containing 20% ​​piperidine to the above resin, react under N2 bubbling at room temperature for 10 minutes, filter, and repeat the above operation until complete deprotection, and wash the resin with DMF 2-3 times.

[0457] (3) Fatty acid chain coupling: The materials were added according to the reaction ratio of resin: fatty acid: HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate): DIPEA (N,N-diisopropylethylamine) = 1:5:5:10 (volume ratio). Fatty acid mono-tert-butyl ester, HATU and DIPEA were pre-dissolved in DMF, and reacted with N2 bubbling at room temperature for 10 minutes. Then, they were transferred to the resin reaction tank and reacted with N2 bubbling at room temperature for 1-3 hours. After the reaction was completed, the resin was filtered and washed with DMF 2-3 times.

[0458] (4) Removal of the ivDde protecting group: Add a DMF solution containing 5% hydrazine to the resin and react under N2 bubbling at room temperature for 10 minutes. Repeat this operation 2-3 times until it is completely removed. Wash the resin with DMF 2-3 times.

[0459] (5) Coupling of amino acids, 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 reacted at room temperature with N2 bubbling for 10 minutes. The mixture was then transferred to a resin reaction tank and reacted at room temperature with N2 bubbling for 1-3 hours. After the reaction, the mixture was filtered and the resin was washed with DMF 2-3 times. After the synthesis, the resin was washed with DCM 2-3 times and vacuum dried to obtain the linker resin.

[0460] 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:

[0461] 5. Coupling of linear peptides with Staple linkers:

[0462] 1.0 equivalent of the linear peptide (i.e., the target peptide compound obtained in step 3, in this step, the peptide DAC09 (abbreviated as AMY-008) in Table A is used as an example) and 1.2 equivalents of the Staple linker peptide (i.e., the Staple linker obtained in step 4) are dissolved in a reaction solution of PBS (phosphate buffered saline): acetonitrile = 1:1.5 volume ratio (final concentration is 1.2 mM), and the pH of the reaction solution is adjusted to 8.0 using a 10% (volume percentage, v / v) NaOH aqueous solution. The reaction solution is placed on a shaker at room temperature and shaken for 3-8 hours until the linear peptide is completely consumed by LC-MS detection. The reaction solution is neutralized to pH 8.0 using a 5% (volume percentage, v / v) TFA aqueous solution. 6.5. Filter through a 0.45 μm filter membrane and perform gradient elution using a C18 reverse-phase preparative column (20*250 mm, particle size 5 μm) with mobile phase A and mobile phase B at a flow rate of 10 mL / min. Collect the target peaks and lyophilize to obtain the target coupled compounds (i.e., polypeptide derivatives, AMY-001 to AMY-020, AMY-023 to AMY-031). The specific synthesis process is shown in the figure below:

[0463] The purity and mass spectrometry of each polypeptide derivative were determined. The purity of each polypeptide derivative was greater than 90% by HPLC. The molecular weights of the polypeptides determined by mass spectrometry were basically consistent with the theoretical molecular weight (all within the allowable error range). The molecular weights of some polypeptide molecules are exemplified in this example, see Table 1 for details.

[0464] Table 1

[0465] Example 2: Preparation of polypeptide or its derivatives

[0466] 1. The linear peptides in peptides 21 to 22 (AMY-021 to AMY-022) and peptides 37 to 40 (AMY-037 to AMY-041) in Table A were synthesized using the classic Fmoc-tBu solid phase synthesis method. X peptide synthesizer was prepared, and the reaction conditions were as follows:

[0467] (1) Resin swelling: Add Rink Amide MBHA resin to DCM, react with N2 gas at room temperature for 1 hour, filter, and wash the resin with DMF 2-3 times.

[0468] (2) Removal of Fmoc protecting group: Add DMF solution containing 20% ​​(volume percentage, v / v) piperidine to the above resin, react under N2 bubbling at room temperature for 10 minutes, filter, and repeat the above operation until complete deprotection, and wash the resin with DMF 2-3 times.

[0469] (3) Amino acid coupling: The materials were added according to the reaction ratio of resin: Fmoc-AA-OH: DIC: Oxyma Pure = 1:5:5:5. Fmoc-AA-OH, DIC and Oxyma Pure were pre-dissolved in DMF and reacted at room temperature with N2 for 10 minutes. Then, they were transferred to the resin reaction tank and reacted at room temperature with N2 for 1-3 hours. After the reaction, the resin was filtered and washed with DMF 2-3 times. The amino acids with N-terminal amino acids such as Boc-L-His(Trt)-OH and Boc-L-Tyr(tBu)-OH were also synthesized using the above method. After the synthesis, the resin was washed with DCM 2-3 times and vacuum dried to obtain a peptide resin containing a linear peptide.

[0470] The above method is applicable to amino acids (D or L form) or synthetic reagents including but not limited to: 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-methy l-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.

[0471] 2. Connect the Staple linker (or modifying group B) to the peptide resin containing the linear peptide (AMY-022) obtained in step 1. The specific steps are as follows:

[0472] 2.1 Removal of Mtt protecting group from peptide resin: prepare deprotection solution according to the volume ratio of TFA:TIPS:DCM=1:2:97, add Mtt removing solution (10mL / g resin) to the resin, place on a shaker and shake thoroughly for 15 minutes, filter the resin, repeat this process 3-5 times until the color no longer turns bright yellow after the addition of the removing solution, indicating complete removal, and wash the resin 2-3 times with DMF.

[0473] 2.2 Removal of Alloc and Allyl protecting groups on the peptide resin: Add DCM (10 mL / g resin), PhSiH3 (10 equivalents) and Pd(PPh3)4 (0.1 equivalents) to the resin, react with N2 gas at room temperature for 1 hour, filter the resin, repeat the process 1-2 times, and wash the resin with DMF 2-3 times.

[0474] 2.3 On-resin ring closure reaction: To the resin from which the Alloc and Allyl protecting groups had been removed, DMF (10 mL / g resin), PyBOP (5 eq.), HOBt (5 eq.), and DIPEA (10 eq.) were added. The reaction was allowed to proceed under nitrogen bubbling at room temperature for 4 h. The resin was then filtered and the reaction was repeated 1-2 times. The resin was washed with DMF 2-3 times.

[0475] 2.4 Solid-phase side chain introduction: The standard solid-phase synthesis method is used, wherein the side chain has the following structure:

[0476] In addition, the structure of the Staple linker can be the above-mentioned modification groups B1 to B23.

[0477] 3. Cutting and drying: Prepare a peptide cutting solution at a volume ratio of TFA:TIPS:H2O:EDT=95:2:2:1. Add the cutting solution (10 mL / g resin) to the dried resin and shake it on a shaker for 3 hours. Filter the resin residue and add 10 volumes of cold MTBE to the filtrate. Cool the resulting suspension at -20°C for 1 hour and then centrifuge at 3500 rpm. Wash the precipitate 3-5 times with cold MTBE and vacuum dry to obtain the crude peptide.

[0478] 4. Peptide Purification: A dissolving solution was prepared at a volume ratio of mobile phase A (0.1% TFA-water): mobile phase B (0.1% TFA-acetonitrile) = 1.5:1. The crude peptide was dissolved in the dissolving solution to prepare a stock solution, filtered through a 0.45 μm filter membrane, and eluted using a C18 reverse-phase preparative column (20*250 mm, particle size 5 μm) at a flow rate of 10 mL / min using mobile phases A and B for gradient elution. The target peaks were collected and lyophilized to obtain the target peptide derivatives, namely AMY-021 and AMY-022. The purity of each peptide derivative was determined by HPLC and mass spectrometry. The purity was greater than 90% by HPLC. The molecular weights of the peptides determined by mass spectrometry were generally consistent with the theoretical molecular weight (all within the allowable error range). The molecular weights of some peptide molecules are shown in this example. See Table 2 for details.

[0479] Table 2: Compound molecular weight table

[0480] Test Example 1: In vitro activity assay

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

[0482] Construct a HEK293 / pGM-CREB-L-Luc / AMY3R pool stably transfected cell line. The polypeptide derivatives prepared in Example 1 and Example 2 (i.e., AMY-001 to AMY-041) were diluted 5-fold from a maximum of 1000 nM to prepare a dilution series containing 8-11 concentration gradients. Cagrilintide was selected as the positive control for the test, and a dilution series was prepared for testing in the same manner. The corresponding test cells were digested (1 min) and blown off by centrifugation (1000 rpm, 5 min). After discarding the culture medium, the cells were suspended with freestyle culture medium, centrifuged, collected and counted, and diluted to a cell density of 5*10 5 Cells / mL were added to the test wells of a 384-well plate (40 μL / 20,000 cells / well). The corresponding dilution series of the test substance was added using Echo. The cell plate was incubated at 37°C and 5% carbon dioxide for 6 hours, and ONE-GLO (20 μL / well) was added for detection. The plate was placed in the dark for 3 minutes, and the plate was measured using a chemiluminescence microplate reader. The plate was read within 30 minutes and the results were recorded. The activation curve was drawn using GraphPad Prism software to calculate the EC of the compound. 50 The results showed that the polypeptide derivatives of the present invention have binding activity to AMYR and CTR.

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

[0484] Stably transfected HEK293 / pGM-CREB-L-Luc / AMY3R pool and HEK293 / pGM-CREB-L-Luc / CTR pool cell lines were constructed. The polypeptide derivatives prepared in Examples 1 and 2 (i.e., AMY-001 to AMY-041) were diluted 5-fold starting at a maximum concentration of 1000 nM to prepare a dilution series consisting of 8-11 concentrations. Cagrilintide and sCT were selected as positive controls for testing, and a dilution series was prepared using the same method for testing. The test cell lines were digested with cAMP-specific trypsin, then suspended in 3 mL of serum-free DMEM medium by pipetting, and the cells were counted. 5 μL of IBMX (prepared in serum-free DMEM medium, 0.5 mM) and test cells (5 μL / 7500 cells / well) were added to a 384-well plate in sequence. After incubation at 37°C and 5% carbon dioxide for 30 minutes, cAMP-d2 (5 μL, 1x) and Anti-cAMP-Cryptate (5 μL, 1x) were added. The plates were left at room temperature for 1 hour. The HTRF values ​​were measured using a chemiluminescence microplate reader and the results were recorded. Activation curves were drawn using GraphPad Prism software to calculate the IC values ​​of the peptide derivatives. 50 The results show that the polypeptide derivatives of the present invention have binding activity with AMY3R and CTR. This example exemplifies the IC values ​​of some polypeptides. 50 The specific values ​​are shown in Table 3, Figure 2 and Figure 3.

[0485] Table 3: IC values ​​of various target peptide derivatives 50 value

[0486] Test Example 2: Pharmacokinetic Evaluation

[0487] 1. The pharmacokinetic behavior of the polypeptide derivatives prepared in Example 1 and Example 2 (ie, AMY-001 to AMY-041) in SD rats was tested.

[0488] Each polypeptide derivative (i.e., AMY-001 to AMY-041) was administered as a single injection to male SD rats by subcutaneous injection (SC, 3 mg / kg, drug solvent was PBS, concentration was 1.5 mg / mL, and the administration volume was 2 mL) and intravenous injection (IV, 1 mg / kg, drug solvent was PBS, concentration was 0.5 mg / mL, and the administration volume was 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 and placed in a labeled EDTA-K2 anticoagulant tube. After gently inverting the tube upside down to fully mix the anticoagulant (EDTA-K2) and the blood, it was immediately placed on wet ice and centrifuged as quickly as possible to separate the plasma. The centrifugation conditions were set to 4°C, 6800g, and 6 minutes. The plasma samples were stored in a refrigerator not higher than -20°C until used for analysis.

[0489] Under ice-water bath yellow light conditions, (1) 300 μL of precipitant containing internal standard was added to a 96-well plate containing 20 μL of standard curve sample, quality control sample or unknown sample, except for the blank sample; 300 μL of acetonitrile was added to the blank sample; (2) Vortex mixing was performed; (3) Centrifugation was performed; (4) 150 μL of supernatant was taken to a new 96-well plate and 150 μL of ultrapure water was added to mix. (5) The above samples were quantitatively analyzed by LC-MS analysis, and gradient elution was performed using an XB-C18 (2.1*100 mm, 3 μm) chromatograph. The mobile phase used was: mobile phase A = 0.1% (volume percentage, v / v) formic acid-water; mobile phase B = acetonitrile. Pharmacokinetic parameters were calculated using Phoenix WinNonlin software. The results showed that the polypeptide derivatives of the present invention were well absorbed in rats, with high blood drug concentrations and long half-lives. The pharmacokinetic parameter test results of some polypeptide derivatives are shown in Table 4 and Figure 4.

[0490] Table 4: Rat PK data of some peptide derivatives

[0491] 2. The pharmacokinetic behavior of the polypeptide derivatives prepared in Example 1 and Example 2 (ie, AMY-001 to AMY-041) in cynomolgus monkeys was tested.

[0492] Each polypeptide derivative (i.e., AMY-001 to AMY-041) was administered as a single injection to adult male cynomolgus monkeys by subcutaneous injection (SC, 0.2 mg / kg, the drug solvent was PBS, the concentration was 0.2 mg / mL, and the administration volume was 1 mL) and intravenous injection (IV, 1 mg / kg, the drug solvent was PBS, the concentration was 0.2 mg / mL, and the administration volume was 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 a labeled EDTA-K2 anticoagulant tube. After gently inverting the blood upside down to fully mix the anticoagulant (EDTA-K2), it was immediately placed on wet ice and centrifuged as quickly as possible to separate the plasma. The centrifugation conditions were set to 4°C, 6800g, and 6 minutes. The plasma samples were stored in a refrigerator not higher than -20°C until used for analysis.

[0493] Under ice-water bath yellow light conditions, (1) 300 μL of precipitant containing internal standard was added to a 96-well plate containing 20 μL of standard curve sample, quality control sample or unknown sample, except for the blank sample; 300 μL of acetonitrile was added to the blank sample; (2) Vortex mixing was performed; (3) Centrifugation was performed; (4) 150 μL of supernatant was taken to a new 96-well plate and 150 μL of ultrapure water was added to mix. (5) The above samples were quantitatively analyzed by LC-MS analysis, and gradient elution was performed using an XB-C18 (2.1*100 mm, 3 μm) chromatograph. The mobile phase used was: mobile phase A = 0.1% formic acid-water; mobile phase B = acetonitrile. Pharmacokinetic parameters were calculated using Phoenix WinNonlin software. The results showed that the polypeptide derivatives of the present invention were well absorbed in rats, with high blood drug concentrations and long half-lives. The pharmacokinetic parameter test results of some polypeptide derivatives are shown in Table 5 and Figure 5.

[0494] Table 5: PK data of some peptide derivatives in cynomolgus monkeys

[0495] Test Example 3: Changes in body weight and food intake in wild-type SD rats after a single dose

[0496] Adult male wild-type SD rats weighing 200-250g were used in the experiment. The SD rats were randomly divided into groups of 4 rats per group, 2 rats per cage, and adapted for 1 week. During this period, they maintained a normal diet and free access to water. After the animals were pre-adapted, the basal blood glucose level and body weight of each rat were measured before administration (Day 0). Then, according to the experimental group, 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, and 30nmol / kg) were administered by subcutaneous injection (sc), and the normal diet and water were given after the administration. On Days 1, 2, 3, 4, 5, 6, and 7 after administration, the body weight of each rat and the total daily food intake of each group of rats were measured. The body weight of each rat (% of the starting value) and the cumulative change in food intake of each group of rats were calculated, and the curve was plotted. The results showed that the compounds 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, see FIG6 .

[0497] Test Example 4: Changes in body weight, blood sugar, and food intake after continuous administration in the DIO rat model

[0498] Adult male Sprague Dawley rats weighing 200-250g were used in the experiment and fed a high-fat diet for 16 weeks, reaching a body weight of approximately 600-700g. The rats were randomly divided into groups of 5 rats per group and housed in individual cages for one week of adaptive feeding. During this period, they maintained a normal diet and had free access to water. After the animals were pre-adapted, the basal body weight of each rat was measured before dosing (Day 0). Subsequently, the vehicle control (Vehicle), Cagrilintide (1nmol / kg, 3nmol / kg, 10nmol / kg, Q2D), and AMY-015 (1nmol / kg, 3nmol / kg, 10nmol / kg, Q2D) were respectively administered by subcutaneous injection (sc). After the end of the administration, normal high-fat diet and water were given. On Days 1, 2, 3, 4, 5, 6, and 7 after administration, the body weight and total daily food intake of each rat group were measured. The change in body weight (% of the starting value) and total daily food intake of each rat group was calculated, and a curve was plotted. The results show that the compounds of the present invention can reduce rat body weight and food intake. The results for AMY-015 are exemplified in this test example, see Figure 7.

[0499] Test Example 5: Changes in body weight and adipose tissue in the DIO rat model after continuous administration of semaglutide alone or in combination with semaglutide

[0500] Adult male Sprague Dawley rats weighing 200-250g were used in the study. They were fed a high-fat diet for 20 weeks, reaching a weight of approximately 600-700g. The rats were randomly divided into groups of seven and housed individually in individual cages for one week of acclimatization. During this period, they maintained a normal diet and had free access to water. After the animals were pre-adapted, the basal blood glucose and body weight of each mouse were measured before administration (Day 0). Subsequently, the mice were given 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) by subcutaneous injection (sc) for 21 consecutive days. After administration, the body weight of each rat and the total daily food intake of each group of rats were measured every day. The changes in body weight (% of the starting value) and the total daily food intake of each group of rats were calculated and the curve was drawn. At the end of administration, blood and adipose tissue were dissected, the adipose tissue was weighed, and biochemical indicators in the blood were tested. The results showed that the compound of the present invention has a superior weight loss effect, superior to Cagrilintide, and is more effective in reducing rat body weight and food intake when combined with semaglutide, while also protecting against muscle loss to a certain extent. The results of AMY-015 are exemplified in this test example, see Figure 8.

[0501] Test Example 6: Changes in body weight, blood sugar, and food intake after continuous administration in the ZDF rat model

[0502] The experiment selected adult male ZDF rats weighing 350-400g and fed with diabetic modeling feed. The rats were randomly divided into groups of 8 in each group and fed in single cages for adaptive feeding for 1 week. During this period, they maintained a normal diet and had free access to drinking water. After the animal pre-adaptation was completed, 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 respectively given by subcutaneous injection (sc) for 28 consecutive days. The blood sugar level of each rat was tested once every two days after administration, the change value of the 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 and is better than Cagrilintide. The results of AMY-015 are exemplified in this test example, see Figure 9.

[0503] Test Example 7: Thioflavin T (ThT) Fibrosis Assay

[0504] 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 (1 mg / mL) of the polypeptide to be tested and the PBS working solution (5 mM) of ThT are configured, and 400 μL of the polypeptide sample to be tested (the polypeptide derivatives (i.e., AMY-001 to AMY-041) prepared in Example 1 and Example 2) solution are taken in a 1.5 mL EP tube at room temperature, 8 μL of ThT storage solution is added, vortexed to mix, and centrifuged at low speed to ensure that no liquid is hung. The liquid is pipetted into a 96-well plate, 200 μL per well, and multiple groups can be set in parallel. 200 μL PBS is added to the peripheral holes of the sample to seal the edges, and a transparent film is affixed. Kinetic testing was performed using a Biotek microplate reader, with monitoring intervals of 15 minutes, an excitation wavelength of 440 nm, and an emission wavelength of 485 nm. ΔFold change = (detection value / average of the first ten detection points), with time (h) on the abscissa and ΔFold change on the ordinate. Graphpad nonlinear fitting was used to plot the results, revealing that the polypeptide derivatives of the present invention can significantly reduce fibrosis aggregation and have higher stability. This example illustrates the results of some polypeptide derivatives, as shown in Figure 10.

[0505] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0506] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A polypeptide or its derivative or a pharmaceutically acceptable salt thereof, characterized in that: The polypeptide or its derivative 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 X 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 according to claim 1, characterized in that: The polypeptide or its derivative or pharmaceutically acceptable salt thereof includes one or more of the following conditions: 1) 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 ; 2) the two amino acids Z1 or the two amino acids Z2 are each independently selected from K, C or C; 3) X1 is A or K; Alternatively, X1 is A; 4) X4 is L; 5) X6 is K, C, C or T; Alternatively, X6 is C or T; Alternatively, X6 is T; 6) X7 is K, C, C or A; Alternatively, X7 is C or A; Or, X7 is A; 7) X8 is C, V, C, HoC, Pen, αMeC, N-Me-C, K, Orn, k or Dab; Alternatively, X8 is K, C, C, or V; Alternatively, X8 is C, V, or K; Alternatively, X8 is C or V; Alternatively, X8 is V; 8) X9 is K, C, C or L; Alternatively, X9 is C or L; Alternatively, X9 is L; 10)X 10 is K, c, C or G; Or, X 10 is C or G; Or, X 10 is G; 11)X 11 is K, c, C, homoR, Orn, or R; Or, X 11 is K, C, homoR, Orn, or R; Or, X 11 is K, C, homoR or R; Or, X 11 is C, homoR, or R; Or, X 11 is homoR or R; 12)X 12 is K, c, C or L; Or, X 12 is C or L; Or, X 12 is L; 13)X 13 is K, c, C or S; Or, X 13 is C or S; Or, X 13 For S; 14)X 14 is K, c, C or A; Or, X 14 is C or A; Or, X 14 is A; 15)X 15 is C, E, c, HoC, Pen, αMeC, αMeK, N-Me-C, K, Orn, k or Dab; Or, X 15 is K, c, C or E; Or, X 15 is K, C or E; Or, X 15 is C or E; Or, X 15 is C; 16)X 16 is K, c, C or L; Or, X 16 is C or L; Or, X 16 is L; 17)X 17 is K, c, C or H; Or, X 17 is C or H; Or, X 17 is H; 18)X 18 is c, K, C, k, αMeK or Orn; Or, X 18 is C, K, αMeK or Orn; Or, X 18 is C, K or αMeK; Or, X 18 is K or αMeK; 19)X 19 is K, c, C or L; Or, X 19 is C or L; Or, X 19 is L; 20)X 20 is K, c, C or Aib; Or, X 20 is C or Aib; Or, X 20 for Aib; 21)X 22 is Y; 22)X 23 is P; 23)X 24 is R, N-Me-R, homoR, norR, r, or Q; Or, X 24 is R, N-Me-R, homoR, norR, or Q; Or, X 24 is R, N-Me-R or Q; 24)X 29 is A; 25)X 32 is P or Hyp.

3. The polypeptide or derivative thereof or pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, characterized in that: The polypeptide or its derivative or pharmaceutically acceptable salt thereof includes one or more of the following conditions: 1) The positions of the two amino acids Z1 or the two amino acids Z2 are X8 and X 15 ; 2) The structure represented by formula (I) has one of the following structures: U-X1SHX4STX7X8LGX 11 LX 13 X 14 X 15 LHX 18 LX 20 DX 22 X 23 X 24 TDVGAGSX 32 -NH2(Ia); U-X1SHX4STAX8LGX 11 LSAX 15 LHX 18 L-Aib-DX 22 PX 24 TDVGAGSX 32 -NH2(Ib); 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); U-ASHX4STAX8LGX 11 LX 13 AX 15 LHX 18 LX 20 DX 22 PX 24 TDVGAGSX 32 -NH2(IIa); ASHLSTAX8LGX 11 LSAX 15 LHX 18 L-Aib-DYPX 24 TDVGAGSX 32 -NH2(IIb)? <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); 3) further comprising a modifying group, wherein the modifying group is connected to the two amino acids Z1 or the two amino acids Z2 in the polypeptide represented by formula (I) or its derivative.

4. The polypeptide or its derivative or pharmaceutically acceptable salt according to claim 1, 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, and benzoyl.

5. The polypeptide or its derivative or pharmaceutically acceptable salt according to claim 3, characterized in that: The modifying group is connected to the -SH of the side chain of the amino acid Z1 through a sulfur-carbon bond; or The modifying group is connected 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 according to claim 5, characterized in that: The modifying group has a structure shown in formula (IV): Wherein, 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 Substituted -C 1～6 Alkylene-, optionally one or more R 1a Substituted-NH-C(O)-C 1～6 Alkylene- or optionally one or more R 1a Substituted -C 1～6 Alkylene-NH-C(O)-C 1～6 Alkylene-, wherein each R 1a are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy; R4 is empty or optionally replaced by one or more R 2a Substituted -C 1～6 Alkylene-NH-C(O)-C 1～6 Alkylene-, wherein each R 2a are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -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 Each alkoxy group is 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 Substituted -C 1～6 Alkylene-, or optionally one or more R 3a Substituted-(C 1～3 Alkylene-O) m1 -C 1～6 Alkylene-, wherein each R 3a are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy; R7 is optionally replaced by one or more R 4a Substituted -C 1～6 Alkylene-, wherein each R 4a are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy; R8 is optionally replaced by one or more R 5a Substituted -C 10～20 Alkyl, optionally substituted by one or more R 5a Substituted -C 10～20 Alkylene-R9, optionally replaced by one or more R 5a Substituted -C 5～10 Alkylene-OC 3～10 Arylene-R9, or optionally one or more R 5a Substituted -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 according to claim 6, characterized in that: The polypeptide or its derivative or pharmaceutically acceptable salt thereof includes one or more of the following conditions: 1) R1 is C, N, -C 5～7 Heteroalkylene, -C 5～7 Arylene or -C 5～7 heteroarylene; 2) R2 and R3 are each independently -C 1～6 Alkylene-, or -C 1～6 Alkylene-NH-C(O)-C 1～6 Alkylene-; 3) each n1 is independently 0, 1, 2, 3, 4 or 5; 4) R4 is empty or -C 1～6 Alkylene-NH-C(O)-C 1～6 Alkylene-; 5) R5 is H, -C 1～3 Alkoxy or -C 1～3 alkyl; 6) R6 is -C 1～6 Alkylene-, -(C 1～3 Alkylene-O) m1 -C 1～6 Alkylene-; 7) m1 is 2, 3, 4 or 5; 8) R7 is -C 1～6 Alkylene-; 9) 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; 10) R9 is -COOH, -C 5～6 heteroaryl, -S(O)2OH, or -PO(OH)2; 11) n2 is 1, 2 or 3; or n2 is 3, 4, 5, or 6; 12) 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 according to claim 6, characterized in that: The polypeptide or its derivative or pharmaceutically acceptable salt thereof includes one or more of the following conditions: 1) 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 -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; 2) 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 ' is -C 1～6 Alkylene-; R 13 -C 10～20 Alkylene-, preferably -C 14～18 Alkylene-; q1' is 1, 2, 3, or 4; q2' is 1, 2, or 3; 3) 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 -C 0～3 Alkylene- or -C(O)-NH-C 1～3 Alkylene-; R 12 " is -C 1～6 Alkylene-; R 13 ' is -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.

9. The polypeptide or its derivative or pharmaceutically acceptable salt according to claim 6, characterized in that: The polypeptide or its derivative or pharmaceutically acceptable salt thereof includes one or more of the following conditions: 1) The modifying group represented by formula (IVa) has the following structure: 2) The modifying group represented by formula (IVb) has the following structure: 3) The modifying group represented by formula (IVc) has the following structure:

10. The polypeptide or its derivative or pharmaceutically acceptable salt 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 Substituted -C 1～6 Alkylene-, or optionally one or more R 1b Substituted -C 1～6 Oxyalkylene-, wherein each R 1b are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy; R 23 Empty, optionally replaced by one or more R 2b Substituted -C 1～6 Alkylene-, optionally substituted by one or more R 2b Substituted-C(O)-C 1～6 Alkylene-, optionally substituted by one or more R 2b Substituted-NH-C(O)-C 1～6 Alkylene-, or optionally one or more R 2b Substituted -C 1～6 Alkylene-C(O)-NH-C 1～6 Alkylene-, wherein each R 2b are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy; R 24 is optionally replaced by one or more R 3b Substituted -C 1～6 Alkylene-, or optionally one or more R 3b Substituted-(C 1～3 Alkylene-O) m2 -C 1～6 Alkylene-, wherein each R 3b are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy; R 25 H, -C 1～6 Alkoxy or -C 1～6 Alkyl, wherein the -C 1～6 Alkyl and -C 1～6 Each alkoxy group is independently optionally substituted with one or more halogen, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN; R 26 is optionally replaced by one or more R 4b Substituted -C 1～6 Alkylene-, wherein each R 4b are independently halogen, -OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl or -C 1～6 alkoxy; R 27 is optionally replaced by one or more R 5b Substituted -C 10～20 Alkyl, optionally substituted by one or more R 5b Substituted -C 10～20 Alkylene-R 28 , optionally one or more R 5b Substituted -C 5～10 Alkylene-OC 3～10 Arylene-R 28 , or optionally one or more R 5b Substituted -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.

11. The polypeptide or its derivative or pharmaceutically acceptable salt according to claim 10, characterized in that: The polypeptide or its derivative or pharmaceutically acceptable salt thereof includes one or more of the following conditions: 1) R 20 C, N, -C 5～7 Arylene or -C 5～7 heteroarylene; 2) R 21 and R 22 Each is independently empty, -C 1～6 Alkylene-, or -C 1～6 Oxyalkylene-; 3) 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-; 4) R 24 -C 1～6 Alkylene-, or -(C 1～3 Alkylene-O) m2 -C 1～6 Alkylene-; 5) m2 is 2, 3, 4 or 5; 6)R 25 H, -C 1～6 Alkoxy or -C 1～6 alkyl; 7) R 26 -C 1～6 Alkylene-; 8)R 27 -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 ; 9)R 28 -COOH, -C 5～6 heteroaryl, -S(O)2OH, or -PO(OH)2; 10) p is 1, 2 or 3; or p is 3, 4, 5 or 6.

12. The polypeptide or its derivative or pharmaceutically acceptable salt according to claim 10, characterized in that: The polypeptide or its derivative or pharmaceutically acceptable salt thereof includes one or more of the following conditions: 1) 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 -C 1～6 Alkylene-; q3 is 1, 2, 3, or 4; q4 is 1, 2, or 3; 2) 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 ' is -C 1～6 Alkylene-; R 31 ' is -C 1～6 Alkylene-; q3' is 1, 2, 3 or 4, preferably 2; q4' is 1, 2 or 3, preferably 2; 3) The modifying group represented by formula (V) has a structure represented by formula (Vc): Among them, R 30 " is -C 1～6 Alkylene-; R 31 " is -C 1～6 Alkylene-; q3 is 1, 2, 3, or 4; q4 is 1, 2, or 3; 4) 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).

13. The polypeptide or its derivative or pharmaceutically acceptable salt according to claim 12, characterized in that: The polypeptide or its derivative or pharmaceutically acceptable salt thereof includes one or more of the following conditions: 1) The modifying group represented by formula (Va) has the following structure: 2) The modifying group represented by formula (Vb) has the following structure: 3) The modifying group represented by formula (Vc) has the following structure:

14. The polypeptide or its derivative or pharmaceutically acceptable salt 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 15. A pharmaceutical composition, characterized in that The polypeptide according to any one of claims 1 to 14 or its derivatives or pharmaceutically acceptable salts thereof; Optionally, it further includes a pharmaceutically acceptable excipient or carrier.

16. A combination drug or kit, characterized in that: include: The polypeptide or derivative thereof or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, or the pharmaceutical composition according to claim 15 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; Such diseases include amylin receptor and / or calcitonin receptor related diseases.

17. The combined drug or kit according to claim 16, characterized in that: The combination drug or kit includes one or more of the following conditions: 1) The amylin receptor and / or calcitonin receptor-related diseases include fat metabolism disorders, blood sugar metabolism disorders, cardiovascular diseases, brain system diseases, mental system diseases or nervous system diseases; Preferably, 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; Preferably, the amylin receptor and / or calcitonin receptor-related diseases include at least one of diabetes, hypertension, arteriosclerosis, 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 weight, obesity, fatty liver disease, diabetic nephrotic syndrome, diabetic-related renal fibrosis, liver fibrosis, Alzheimer's disease and Parkinson's disease; Preferably, the amylin receptor and / or calcitonin receptor related diseases include at least one of cardiovascular disease, diabetes and / or obesity; 2) 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; Preferably, the drug is selected from one of GLP-1 analogs, gliflozin-type hypoglycemic drugs, biguanides and acarbose; Preferably, the GLP-1 analog drug includes at least one of semaglutide, exenatide, liraglutide, dulaglutide, tilpotide, and retaglutide; Preferably, the glucose-lowering drug of the gliflozin class includes at least one of dapagliflozin and empagliflozin; Preferably, the biguanide includes metformin.

18. The polypeptide according to any one of claims 1 to 14, or its derivative, or pharmaceutically acceptable salt thereof, the pharmaceutical composition according to claim 15, or the combination drug or drug kit according to claim 16 or 17, for treating or preventing amylin receptor and / or calcitonin receptor-related diseases, or for the following uses: Treating or preventing amylin receptor and / or calcitonin receptor related diseases; and / or Preparation of a medicament for treating or preventing amylin receptor and / or calcitonin receptor related diseases.

19. A method for treating or preventing amylin receptor and / or calcitonin receptor related diseases, characterized in that: include: A pharmaceutically acceptable amount of the polypeptide or derivative thereof or pharmaceutically acceptable salts according to any one of claims 1 to 14, the pharmaceutical composition according to claim 15, or the combined drug or kit according to claim 16 or 17 is administered to a subject.

20. The use according to claim 18 or the method according to claim 19, characterized in that The amylin receptor and / or calcitonin receptor related diseases include fat metabolism disorder, blood sugar metabolism disorder, cardiovascular disease, brain system disease, mental system disease or nervous system disease; Preferably, 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; Preferably, the amylin receptor and / or calcitonin receptor-related diseases include at least one of diabetes, hypertension, arteriosclerosis, 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 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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