Multi-agents and uses thereof

Abstract

The present application relates to the field of medicine biology, specifically relates to a kind of triple agonist polypeptide compound of general formula (I) or its salt or solvate with triple agonist activity to glucagon-like peptide-1 receptor (GLP-1R), glucose-dependent insulinotropic polypeptide receptor (GIP R) and glucagon receptor (GCG R), and to its application in treating metabolic syndrome.

Description

TECHNICAL FIELD

[0001] The present application relates to a class of polypeptide compounds and their use in the field of medicine. More specifically, the present application relates to polypeptide compounds having triple agonistic activity on the glucagon-like peptide-1 receptor (GLP-1 R), the glucose-dependent insulinotropic polypeptide receptor (GIP R) and the glucagon receptor (GCG R), and to their use in the treatment of metabolic syndrome. BACKGROUND

[0002] Type 2 diabetes and obesity are becoming global diseases that affect human health. Obesity is the main cause of many chronic diseases such as diabetes, hypertension, heart disease, dyslipidemia, fatty liver disease, atherosclerosis, arthritis, stroke, neurodegenerative diseases, etc. Diabetes can also cause various complications such as cardiovascular and cerebrovascular diseases. Most of the currently marketed hypoglycemic drugs can only control blood glucose and cannot improve the body weight of obese patients, and even some drugs have the side effect of increasing body weight. Therefore, there is still an urgent need to develop drugs that can lower blood glucose and improve body weight, and contain multiple beneficial effects to meet the needs of most obese and type 2 diabetic populations.

[0003] Incretins are a class of polypeptide hormones secreted from the intestinal tract under normal physiological conditions after food stimulation. Early studies have found that they can stimulate the secretion of insulin from pancreatic beta cells, regulate glucose homeostasis, protect pancreatic beta cells, and reduce body weight by inhibiting appetite and delaying gastric emptying. GLP-1 and GIP are two kinds of incretins discovered so far.

[0004] GLP-1 is expressed by the proglucagon gene in the intestinal mucosa L cell, and is a polypeptide with 31 amino acids. It mainly acts on the GLP-1 receptor (GLP-1 R), stimulates insulin secretion, inhibits glucagon secretion, protects pancreatic beta cells, and has a physiological role in regulating blood glucose homeostasis. It can also inhibit food intake and gastric emptying through central nervous system signaling pathways, increase satiety, and thus reduce body weight. Exendin-4 is a GLP-1 analogue extracted from the salivary glands of African toad gecko, which has stronger GLP-1 receptor agonistic effect and similar GLP-1 effect. Compared with natural GLP-1, Exendin-4 has stronger resistance to DPP-4, and its plasma half-life is also longer.

[0005] GIP is a 42-amino acid single-chain polypeptide produced by the small intestinal mucosa K cells, mainly acting on GIP receptors (GIP R) in islet cells and adipocytes. GIP stimulates insulin secretion in a glucose-dependent manner, enhances islet β-cell mass, stimulates insulin secretion, inhibits gastric acid secretion, and slows gastric motility. In addition, it also stimulates adipose tissue cells to uptake and utilize fatty acids. GIP also has the physiological effects of promoting osteoblast differentiation, inhibiting osteoblast apoptosis, inhibiting bone resorption, and increasing bone mineral density, playing a protective role in bone.

[0006] GCG is a 29-amino acid polypeptide expressed and secreted by the proglucagon gene in islet α-cells, acting on glucagon receptors (GCG R) mainly distributed in the liver and kidney, stimulating glycogenolysis, increasing blood glucose, activating lipase, promoting lipolysis, while inhibiting hepatic lipogenesis, and enhancing fatty acid oxidation. Studies have shown that GCG has certain effects on reducing food intake, increasing energy consumption in adipose tissue, and reducing body fat. The appropriate blood glucose-raising effect of GCG can feedback regulate the effect of insulin, reducing the occurrence of hypoglycemia.

[0007] In view of the effect of enteroincretin, GLP-1 receptor agonists such as exenatide, liraglutide, dulaglutide, semaglutide, etc. have been successfully developed for the treatment of type Ⅱ diabetes. In addition, liraglutide has also been successfully developed for weight loss, and semaglutide is also undergoing clinical research for obesity indications. The advantage of GLP-1 analogs is that they can lower blood glucose while providing cardiovascular benefits and weight management effects, but the weight loss effect of current GLP-1 receptor agonists alone is still less than 10%, and there are obvious dose-related gastrointestinal side effects (mainly nausea, vomiting, and diarrhea). For complex metabolic diseases such as obese type Ⅱ diabetes, non-alcoholic fatty liver disease / non-alcoholic steatohepatitis (NAFLD / NASH), and diabetes and obesity with cardiovascular risk, there is still an urgent need for therapeutic drugs with stronger weight loss effect.

[0008] Based on the physiological functions of GLP-1, GIP, and GCG, multiple studies have confirmed that simultaneously stimulating the activity of two or all three can achieve better therapeutic effects for diabetes and obesity than stimulating GLP-1R alone. Literature reports that hyperglycemia, obesity, and insulin resistance inhibit the effects of GIPR and its signaling pathway; however, as blood glucose levels decrease and insulin resistance improves, the insulin-stimulating effects of GIP and its ability to improve pancreatic function can be enhanced. In addition to promoting glycogenolysis and raising blood glucose, GCG can also promote lipolysis and inhibit hepatic fat synthesis, thus lowering blood lipids and reducing weight, but this requires the synergistic inhibition of its hyperglycemic effect by GLP-1. Therefore, by leveraging the "frontline" effect of GLP-1 to lower blood glucose and improve insulin resistance, it is possible to further enhance the insulin-stimulating function and insulin-sensitizing synergistic effect of GIP, improve pancreatic function, further enhance the lipolytic effect of GCG and improve lipid metabolism, and enhance the weight-reducing effect.

[0009] With the release of clinical data on GLP-1 / GIP and GLP-1 / GCG dual agonists, the impact of the distribution of receptor activity in GLP-1 / GIP or GLP-1 / GCG dual agonists on the clinical therapeutic effect of the drugs is gradually becoming clear.

[0010] For example, the results of a Phase II clinical trial of Eli Lilly's Tirzepatide (LY3298176) showed that a 1 mg dose of Tirzepatide had almost no weight-loss effect, and its blood sugar-lowering effect was significantly lower than that of 1.5 mg dulaglutide. Only when the dose of Tirzepatide was increased to 5 mg did it produce a blood sugar-lowering and weight-loss effect superior to that of 1.5 mg dulaglutide. This is likely because Tirzepatide has a stronger GLP-1 receptor agonist activity, while GLP-1 receptor activity is lower. 50 Wild-type GLP-1 active EC only 50 This is attributed to approximately 15% of the drug's effects. In pursuit of maximum efficacy, the dosage of Tirzepatide has been significantly increased (up to a maximum of 15 mg), which may increase the drug's safety risks.

[0011] On the other hand, because GCG has a strong hyperglycemic effect, sufficient GLP-1 activity is required in GLP-1 / GCG receptor dual agonists to balance and suppress the hyperglycemic effect of GCG, thereby ensuring a hypoglycemic effect. AstraZeneca's GLP-1 / GCG receptor dual agonist MEDI0382 (Cotadutide) has a relative activity (EC) of GLP-1 and GCG receptor. 50respectively. The results of a 26-week clinical trial showed that 100-300ug Cotadutide reduced body weight, blood lipids, and ALT and AST levels in a dose-dependent manner compared with liraglutide, and the effect of the 300ug dose group was significantly better than that of 1.8mg liraglutide. However, in terms of reduction of glycosylated hemoglobin (HbA1c), each dose group had no significant advantage over liraglutide. And with the increase of Cotadutide dose, the effect of glycosylated hemoglobin reduction of the 300ug group was actually worse than that of the 200ug group. This is very likely due to the fact that with the increase of dose, the GLP-1 receptor activity of the Cotadutide molecule is low, which is not enough to suppress the effect of GCG.

[0012] An ideal once-a-week, once-every-two-weeks, or once-every-three-weeks long-acting GLP-1 / GIP / GCG triple receptor agonist molecule should have as high GLP-1R / GIPR activity and relatively controllable GCGR activity as possible to maximize weight loss and blood sugar reduction effects. CN104902919A and CN111040022A disclose a series of GLP-1 / GIP / GCG R triple agonist molecules based on structural modification of exendin-4; CN109071624A discloses a series of molecules composed of ring peptides and long-acting conjugates. In addition, WO2015067716A1, WO2019125929A1 and WO2019125938A1 also disclose some polypeptides with fatty acid linked to the side chain of the 17th amino acid. These polypeptides all show GLP-1 / GIP / GCG R triple agonist effects and have once-a-week long-acting potential. The molecules disclosed in the above patent applications cannot have sufficiently high activity on GLP-1R / GIPR / GCGR at the same time.

[0013] There is still room for improvement in further optimizing triple agonist molecules. SUMMARY

[0014] In view of the above technical status, the present application provides a novel polypeptide molecule with GLP-1 / GIP / GCG R triple agonist activity, which can be used in the treatment of type II diabetes, obesity, dyslipidemia, non-alcoholic fatty liver disease / non-alcoholic steatohepatitis and other related metabolic diseases.

[0015] The present application provides a GLP-1 / GIP / GCG R triple agonist polypeptide compound having the general formula (I) or a salt or solvate thereof:

[0016] Y-Aib-X3-GT-X6-TSDYSI-X13-LDK-X17-AQ-Aib-AFIE-X25-LLE-X29-X30-PSS-X34-X35-PP-X38-S-R 1 (I),

[0017] wherein,

[0018] X3 is Q or H;

[0019] X6 is F, aMeF, or aMeF(2F);

[0020] X13 is aMeL, F, aMeF, or L;

[0021] X17 is ψ;

[0022] X25 is Y or F;

[0023] X29 is T, S, G, or Aib;

[0024] X30 is G, H, R, or Aib;

[0025] X34 is G or Aib;

[0026] X35 is A, Q, Aib, H;

[0027] X38 is Ac3c, P;

[0028] R 1 is NH2 or OH, or pharmaceutically acceptable salts and / or esters thereof;

[0029] wherein, ψ is Lys modified with a side chain having the following general formula (II):

[0030] Y-Z (II), wherein Y is (AEEAc or Glu) a -(AEEAc or Glu) b -(AEEAc or Glu) c wherein a, b, c are each independently 0 or 1, and a, b, c are not simultaneously 0 (as an exemplary illustration, it can be AEEAc-AEEAc-γGlu), the carboxyl end of Y is connected to the ε-amino group of the side chain of Lys, and Z is -CO-(CH2) m -R 2 , m is an integer between 6 and 24, R 2 is selected from -COOH.

[0031] In the present application, as one of the embodiments, the compound of general formula (I) contains at least two specific amino acids at the following positions:

[0032] X13 is F or aMeF;

[0033] X25 is F;

[0034] X29 is T or S;

[0035] X30 is H, R or Aib;

[0036] X35 is Q, Aib or H;

[0037] X38 is Ac3c.

[0038] In the present application, as one of the embodiments, the general formula (II) is AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH.

[0039] In the present application, as one of the embodiments, the compound is selected from the group consisting of:

[0040]

[0041]

[0042]

[0043]

[0044] In the present application, as one of the embodiments, the compound is further selected from the group consisting of:

[0045]

[0046]

[0047] In the present application, as one of the embodiments, the relative activity of the compound in agonizing GLP-1 receptor is at least 30%, preferably at least 60%, more preferably at least 80%, and further more preferably at least 100% of that of native GLP-1 in agonizing GLP-1 receptor in terms of agonizing ability in GLP-1 receptor stable cells.

[0048] In the present application, as one of the embodiments, the relative activity of the compound in agonizing GIP receptor is at least 100%, and more preferably at least 150% of that of native GIP in agonizing GIP receptor in terms of agonizing ability in GIP receptor stable cells.

[0049] In the present application, as one of the embodiments, the relative activity of the compound in agonizing GCG receptor is at least 10%, and more preferably at least 30% of that of native GCG in agonizing GCG receptor in terms of agonizing ability in GCG receptor stable cells.

[0050] In the present application, as one of the embodiments, the relative activity of the compound on RIN-m5F cell agonism is at least 60%, preferably at least 80%, more preferably at least 100% compared with native GLP-1 (7-37) on pancreatic tissue representative cell RIN-m5F.

[0051] In the present application, as one of the embodiments, the relative activity of the compound on 3T3-L1 cell agonism is at least 60%, preferably at least 100% compared with native GIP on adipose tissue representative cell 3T3-L1.

[0052] In the present application, as one of the embodiments, the relative activity of the compound on hepatocyte agonism is at least 60%, preferably at least 100% compared with native GCG on liver tissue representative cell human primary hepatocyte.

[0053] The present application also provides a pharmaceutical composition comprising an effective amount of the compound or salt or solvate thereof according to any one of the preceding aspects, and a pharmaceutically acceptable adjuvant, diluent, carrier or excipient.

[0054] In one aspect, the pharmaceutical composition is in the form of an injection or lyophilized powder, tablet, pill, lozenge, soft capsule, hard capsule, granule, powder, solution, suspension or syrup; or the pharmaceutical composition is in the form of microcapsule, microsphere, nanoparticle or liposome.

[0055] In one aspect, the pharmaceutical composition is for oral administration, inhalation administration or parenteral administration selected from intraperitoneal, intramuscular, intra-arterial, intravenous, subcutaneous or intradermal injection administration.

[0056] In one aspect, the pharmaceutical composition is administered at a frequency of at least once a day, once a week, once every two weeks or once a month.

[0057] In one aspect, the pharmaceutical composition can also be used in combination with at least one of the following therapeutically active substances, including anti-diabetic agents (such as: insulin and analogs thereof, biguanides, sulfonylureas, thiazolidinediones, alpha-glucosidase inhibitors, DPP-4 inhibitors, SGLT2 inhibitors, dual SGLT1 / SGLT2 inhibitors, GLP-1 receptor agonists, amylin and analogs thereof), GIP receptor agonists, GCG receptor agonists or antagonists, GLP-1 / GIP receptor agonists, GLP-1 / GCG receptor agonists, GIP / GCG receptor agonists, FGF-21 and analogs thereof, cholecystokinin B (CCKB) and analogs thereof, PYY (3-36) and analogs thereof, leptin and analogs thereof, calcitonin and analogs thereof, lipid-regulating agents, PPAR-alpha, beta, delta agonists or modulators, anti-platelet aggregation agents, PCSK9 inhibitors, lipase inhibitors, anti-liver fibrosis or cirrhosis agents, anti-inflammatory agents. In one embodiment, the anti-diabetic agents include insulin and analogs thereof, biguanides, sulfonylureas, thiazolidinediones, alpha-glucosidase inhibitors, DPP-4 inhibitors, SGLT2 inhibitors, dual SGLT1 / SGLT2 inhibitors, GLP-1 receptor agonists, or amylin and analogs thereof.

[0058] The use of any of the aforementioned compounds or salts or solvates thereof or any of the aforementioned pharmaceutical compositions in the manufacture of a medicament for promoting insulin secretion and lowering blood glucose.

[0059] The use of any of the aforementioned compounds or salts or solvates thereof or any of the aforementioned pharmaceutical compositions in the manufacture of a medicament for inhibiting food intake, delaying gastric emptying, increasing energy expenditure, and reducing body weight.

[0060] The use of any of the aforementioned compounds or salts or solvates thereof or any of the aforementioned pharmaceutical compositions in the manufacture of a medicament for reducing pancreatic beta-cell apoptosis, increasing pancreatic beta-cell mass, and improving pancreatic beta-cell function.

[0061] The use of any of the aforementioned compounds or salts or solvates thereof or any of the aforementioned pharmaceutical compositions in the manufacture of a medicament for improving lipid profile, reducing liver fat accumulation, inhibiting liver inflammation progression, and preventing and treating non-alcoholic fatty liver disease.

[0062] The use of any of the aforementioned compounds or salts or solvates thereof or any of the aforementioned pharmaceutical compositions in the manufacture of a medicament for promoting brain neuron growth, removing neurotoxic substances, inhibiting inflammation progression, and providing neuroprotection.

[0063] Use of any of the aforementioned compounds or salts or solvates thereof or any of the aforementioned pharmaceutical compositions in the manufacture of a medicament for the prevention and / or treatment of metabolic disorder diseases and their associated complications, preferably for the treatment of diabetes, obesity or non-alcoholic fatty liver disease.

[0064] Use of any of the aforementioned compounds or salts or solvates thereof or any of the aforementioned pharmaceutical compositions in the manufacture of a medicament for the treatment of blood lipid metabolism disorders and their associated diseases, neurodegenerative diseases including Parkinson's disease, Alzheimer's disease.

[0065] Use of any of the aforementioned compounds or salts or solvates thereof or any of the aforementioned pharmaceutical compositions in the manufacture of a medicament for the treatment of endocrine diseases, metabolic disorders, kidney diseases, and other diseases associated with bone diseases including osteoporosis, osteoarthritis.

[0066] Any of the aforementioned compounds of the present application can be synthesized by solid phase synthesis.

[0067] In one aspect, there is provided a compound having the following sequence or a salt or solvate thereof:

[0068] Compound 1 (SEQ ID NO: 1)

[0069] Y-Aib-QGT-aMeF-TSDYSI-aMeL-LDKK(AEEAc-AEEAc-yGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEYLLETGPSSGAPP-Ac3c-S-NH2

[0070] Compound 2 (SEQ ID NO: 2)

[0071] Y-Aib-QGT-aMeF-TSDYSI-aMeL-LDKK(AEEAc-AEEAc-yGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEYLLETHPSSGAPP-Ac3c-S-NH2

[0072] Compound 3 (SEQ ID NO: 3)

[0073] Y-Aib-QGT-aMeF-TSDYSI-aMeL-LDKK(AEEAc-AEEAc-yGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEYLLESHPSSGAPP-Ac3c-S-NH2

[0074] Compound 4 (SEQ ID NO: 4)

[0075] Y-Aib-QGT-αMeF(2F)-TSDYSIFLDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEYLLEGGPSSGAPP-Ac3c-S-NH2

[0076] Compound 5 (SEQ ID NO: 5)

[0077] Y-Aib-QGT-αMeF(2F)-TSDYSIFLDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLEGGPSSGAPP-Ac3c-S-NH2

[0078] Compound 6 (SEQ ID NO: 6)

[0079] Y-Aib-HGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEYLLE-Aib-HPSSGQPPPS-NH2

[0080] Compound 7 (SEQ ID NO: 7)

[0081] Y-Aib-QGT-αMeF-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEYLLETGPSSG-Aib-PPPS-NH2

[0082] Compound 8 (SEQ ID NO: 8)

[0083] Y-Aib-QGT-αMeF-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEYLLETGPSSGQPPPS-NH2

[0084] Compound 9 (SEQ ID NO: 9)

[0085] Y-Aib-QGT-αMeF(2F)-TSDYSIFLDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)2)2-Aib- AQ-AFIEFLLETGPSSGAPPPS-NH2

[0086] Compound 10 (SEQ ID NO: 10)

[0087] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)2)2-Aib- AQ-AFIEFLLETGPSSGAPPPS-NH2 18 Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)2)2-Aib- AQ-AFIEFLLETGPSSGAPPPS-NH2

[0088] Compound 11 (SEQ ID NO: 11)

[0089] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)2)2-Aib- AQ-AFIEFLLETGPSSGAPPPS-NH2 18 Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)2)2-Aib- AQ-AFIEFLLETGPSSGAPPPS-NH2

[0090] Compound 12 (SEQ ID NO: 12)

[0091] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)2)2-Aib- AQ-AFIEFLLETGPSSGAPPPS-NH2 18 Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)2)2-Aib- AQ-AFIEFLLETGPSSGAPPPS-NH2

[0092] Compound 13 (SEQ ID NO: 13)

[0093] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)2)2-Aib- AQ-AFIEFLLETGPSSGAPPPS-NH2 18 Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)2)2-Aib- AQ-AFIEFLLETGPSSGAPPPS-NH2

[0094] Compound 14 (SEQ ID NO: 14)

[0095] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)2)2-Aib- AQ-AFIEFLLETGPSSGAPPPS-NH2 18 Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)2)2-Aib- AQ-AFIEFLLETGPSSGAPPPS-NH2

[0096] Compound 15 (SEQ ID NO: 15)

[0097] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLE-Aib-HPSSGAPPPS-NH2

[0098] Compound 16 (SEQ ID NO: 16)

[0099] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLE-Aib-HPSSGAPPPS-NH2

[0100] Compound 17 (SEQ ID NO: 17)

[0101] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLE-Aib-HPSSGAPPPS-NH2

[0102] Compound 18 (SEQ ID NO: 18)

[0103] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLE-Aib-HPSSGAPPPS-NH2

[0104] Compound 19 (SEQ ID NO: 19)

[0105] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLE-Aib-HPSSGAPPPS-NH2

[0106] Compound 20 (SEQ ID NO: 20)

[0107] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLE-Aib-HPSSGAPPPS-NH2

[0108] Compound 21 (SEQ ID NO: 21)

[0109] Y-Aib-QGT-aMeF(2F)-TSDYSI-aMeL-LDKK(AEEAc-AEEAc-yGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLEGGPSSGQPPPS-NH2

[0110] Compound 22 (SEQ ID NO: 22)

[0111] Y-Aib-QGT-aMeF(2F)-TSDYSI-aMeL-LDKK(AEEAc-AEEAc-yGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLEGGPSSGQPPPS-NH2

[0112] Compound 23 (SEQ ID NO: 23)

[0113] Y-Aib-QGT-aMeF(2F)-TSDYSI-aMeL-LDKK(AEEAc-AEEAc-yGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEYLLETGPSSGQPPPS-NH2

[0114] Compound 24 (SEQ ID NO: 24)

[0115] Y-Aib-QGT-aMeF(2F)-TSDYSI-aMeL-LDKK(AEEAc-AEEAc-yGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLETGPSS-Aib-HPPPS-NH2

[0116] Compound 25 (SEQ ID NO: 25)

[0117] Y-Aib-QGT-aMeF(2F)-TSDYSI-aMeL-LDKK(AEEAc-AEEAc-yGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLEGRPSS-Aib-HPPPS-NH2

[0118] Compound 26 (SEQ ID NO: 26)

[0119] Y-Aib-QGT-αMeF-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLESHPSSGAPPPS-NH2

[0120] Compound 27 (SEQ ID NO: 27)

[0121] Y-Aib-QGT-αMeF-TSDYSI-αMeF-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEYLLESHPSSGAPPPS-NH2

[0122] Compound 28 (SEQ ID NO: 28)

[0123] Y-Aib-QGT-αMeF-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLES-Aib-PSSGAPP-Ac3c-S-NH2

[0124] Compound 29 (SEQ ID NO: 29)

[0125] Y-Aib-QGT-αMeF-TSDYSIFLDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEYLLES-Aib-PSSGAPP-Ac3c-S-NH2

[0126] Compound 30 (SEQ ID NO: 30)

[0127] Y-Aib-QGT-αMeF-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLET-Aib-PSSGAPP-Ac3c-S-NH2

[0128] Compound 31 (SEQ ID NO: 31)

[0129] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18Y-Aib-QGT-F-TSDYSI-F-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)4)AQ-Aib- AFIEFLLE-Aib-HPSSGAPP-Ac3c-S-NH2

[0130] Compound 32 (SEQ ID NO: 32)

[0131] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)4) AQ-Aib-AFIEYLLE-Aib-HPSSGAPP-Ac3c-S-NH2 18 Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)4) AQ-Aib-AFIEYLLE-Aib-HPSSGAPP-Ac3c-S-NH2

[0132] Compound 33 (SEQ ID NO: 33)

[0133] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)4) AQ-Aib-AFIEYLLE-Aib-HPSSGAPP-Ac3c-S-NH2 18 Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)4) AQ-Aib-AFIEYLLE-Aib-HPSSGAPP-Ac3c-S-NH2

[0134] Compound 34 (SEQ ID NO: 34)

[0135] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)4) AQ-Aib-AFIEYLLE-Aib-HPSSGAPP-Ac3c-S-NH2 18 Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)4) AQ-Aib-AFIEYLLE-Aib-HPSSGAPP-Ac3c-S-NH2

[0136] Compound 35 (SEQ ID NO: 35)

[0137] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)4) AQ-Aib-AFIEYLLE-Aib-HPSSGAPP-Ac3c-S-NH2 18 Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)4) AQ-Aib-AFIEYLLE-Aib-HPSSGAPP-Ac3c-S-NH2

[0138] Compound 36 (SEQ ID NO: 36)

[0139] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)4) AQ-Aib-AFIEYLLE-Aib-HPSSGAPP-Ac3c-S-NH2 18 Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2)4) AQ-Aib-AFIEYLLE-Aib-HPSSGAPP-Ac3c-S-NH2

[0140] Compound 37 (SEQ ID NO: 37)

[0141] Y-Aib-QGT-αMeF-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLEGRPSS-Aib-HPPPS-NH2

[0142] Compound 38 (SEQ ID NO: 38)

[0143] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLETGPSS-Aib-HPPPS-NH2

[0144] Compound 39 (SEQ ID NO: 39)

[0145] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLETRPSS-Aib-HPPPS-NH2

[0146] Compound 40 (SEQ ID NO: 40)

[0147] Y-Aib-QGT-αMeF(2F)-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLESHPSS-Aib-HPP-Ac3c-S-NH2

[0148] Compound 41 (SEQ ID NO: 41)

[0149] Y-Aib-QGT-αMeF(2F)-TSDYSILLDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEFLLESHPSS-Aib-HPP-Ac3c-S-NH2

[0150] Compound 42 (SEQ ID NO: 42)

[0151] Y-Aib-QGT-αMeF-TSDYSILLDKK(AEEAc-AEEAc-γGlu-CO(CH2)18 COOH)AQ-Aib-AFIEFLLESHPSS-Aib-HPP-Ac3c-S-NH2

[0152] Compound 43 (SEQ ID NO: 43)

[0153] Y-Aib-QGT-aMeF(2F)-TSDYSI-aMeL-LDKK(AEEAc-AEEAc-yGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEYLLESHPSS-Aib-HPP-Ac3c-S-NH2.

[0154] GLP-1R, GIP R and GCG R are found to be expressed in multiple metabolic related tissue cells. For example, GLP-1R, GIP R and GCG R are expressed in pancreatic islet cells, and the most abundant receptor is GLP-1R; for example, GLP-1R and GIP R are expressed in adipocytes, and GIP R is the most abundant; and GLP-1R and GCG R are expressed in hepatocytes, and GCG R is the most abundant. The inventors have surprisingly found that some compounds can have better EC 50 than wild-type polypeptides in single receptor stable cell lines, but in the above tissue cells, even higher doses are needed to fully stimulate the tissue cells compared to wild-type polypeptides. This is likely related to the distribution tendency of multi-agonist compounds in multiple receptors. Therefore, to achieve the maximum therapeutic effect, it is required that the tri-agonist molecules should be able to fully stimulate multiple receptors in tissue cells, and at least should be able to better stimulate high-abundance receptors in tissue cells. Therefore, the EC 50 of tri-agonist molecules on each tissue cell should be at least better than the corresponding wild-type polypeptide GLP-1 / GIP / GCG.

[0155] The compounds of the present application have strong relative activity EC 50 on the three of GLP-1 / GIP / GCG R, and can fully stimulate the corresponding target organ tissue cells.

[0156] Preferably, the compounds of the present application can promote insulin secretion and reduce blood glucose. Preferably, they can also inhibit food intake, delay gastric emptying, increase energy consumption, and ultimately observe the effect of weight loss.

[0157] Preferably, the compounds of the present application can reduce pancreatic beta-cell apoptosis, increase the number of pancreatic beta-cells, and improve pancreatic islet cell function.

[0158] Preferably, the compounds of the present application can also improve blood lipid, reduce liver fat accumulation, inhibit liver inflammation development, prevent and treat non-alcoholic fatty liver disease.

[0159] Preferably, the compounds of the present application are expected to promote brain neuron growth, remove neurotoxic substances, inhibit inflammation development, and have neuroprotective effects.

[0160] Preferably, the compounds or compositions of the present application can be used for preventing and / or treating metabolic disorder diseases and their related complications. Preferably, for treating diabetes, obesity and non-alcoholic fatty liver disease.

[0161] Preferably, the compounds or compositions of the present application can be used for treating blood lipid metabolism disorders and their related diseases, neurodegenerative diseases (such as Parkinson's disease, Alzheimer's disease).

[0162] Preferably, the compounds or compositions of the present application can be used for treating endocrine diseases, metabolic disorders, kidney diseases, and other diseases related to bone diseases such as osteoporosis and osteoarthritis.

[0163] The compounds of the present application have significant agonistic effects on GLP-1, GIP and GCG receptors.

[0164] The polypeptide compounds of the present application can be synthesized and modified by known techniques by those skilled in the art. For example, the peptide sequence backbone of the polypeptide compounds of the present application can be prepared by synthetic methods.

[0165] The peptide backbone of the compounds of the present application is chemically modified at least at one site by a fatty acid side chain group. Preferably, the compounds have a stable peptide alpha-helix structure and have enhanced albumin binding, i.e. improved peptide compound stability and prolonged peptide action time.

[0166] The compounds of the present application have agonistic activity on GLP-1, GIP and GCG receptors. The "agonistic activity" refers to the ability of the compounds to stimulate the production of cAMP by specific receptor cells. The cells used can be host cells overexpressing GLP-1, GIP or GCG receptors or islet tissue cells, adipocytes, hepatocytes, etc. constructed by those skilled in the art. The agonistic activity of the receptors can be measured by the EC 50 value of the compounds stimulating the production of cAMP by receptor cells. The EC 50 value refers to the drug concentration value required to achieve half of the maximum activity of the compound (50% activity) in a specific assay system.

[0167] In specific embodiments, the agonistic activity of the compounds can be evaluated by the relative activity of specific natural compounds. The relative activity is the EC50 Values of EC 50 Values of EC

[0168] The GLP-1 / GIP / GCG R triagonist polypeptide molecules provided by the present application have better relative activity EC 50 .

[0169] Definitions

[0170] The "relative activity EC 50 " refers to the ratio of the EC 50 values of the corresponding wild-type positive peptides human GLP-1 (7-37), human GIP and human GCG to the EC 50 values of the compounds of the present application.

[0171] The amino acids in the sequences of the compounds of the present application are derived from natural amino acids or related amino acid isomers and / or derivatives. The abbreviations and codes of the natural amino acids are adopted according to the general rules well known to those skilled in the art. The chemical structures of Aib, α-MeF, α-MeF (2F), α-MeL, Ac3c are as follows:

[0172]

[0173] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present application. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0174] The specific meanings of the abbreviations used in the present application are as follows:

[0175] Aib: α-amino isobutyric acid

[0176] α-MeF: α-methyl phenylalanine

[0177] α-MeF (2F): α-methyl-2-fluorophenylalanine

[0178] α-MeL: α-methyl leucine

[0179] Ac3c: 1 -aminocyclopropanecarboxylic acid

[0180] AEEAc: [2-(2-amino-ethoxy)-ethoxy]-acetyl

[0181] cAMP: cyclic adenosine monophosphate

[0182] Fmoc: fluorenylmethyloxycarbonyl

[0183] Boc: tert-butyloxycarbonyl

[0184] DMF: dimethylformamide

[0185] HBTU: benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0186] Trt: trityl

[0187] ivdde: 1 -(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methyl-butyl

[0188] tBu: tert-butyl

[0189] OtBu: oxy-tert-butyl

[0190] TFA: trifluoroacetic acid

[0191] Tis: triisopropylsilane

[0192] HPLC / MS: high performance liquid chromatography / mass spectrometry

[0193] HPLC-UV: high performance liquid chromatography-ultraviolet

[0194] IPTG: isopropyl-β-D-thiogalactopyranoside

[0195] Tris: tris(hydroxymethyl)aminomethane

[0196] DCM: dichloromethane

[0197] THF: tetrahydrofuran

[0198] DIPEA: N,N-diisopropylethylamine

[0199] NMP: N-methylpyrrolidone

[0200] HEK-293: human embryonic kidney cells

[0201] CHO: Chinese hamster ovary cells

[0202] GLP-1 : glucagon-like peptide-1

[0203] GIP: glucose-dependent insulinotropic peptide

[0204] GCG: glucagon

[0205] GLP-1R: glucagon-like peptide-1 receptor

[0206] GIP R: glucose-dependent insulinotropic peptide receptor

[0207] GCG R: glucagon receptor

[0208] NAFLD: Nonalcoholic fatty liver disease

[0209] NASH: Nonalcoholic steatohepatitis

[0210] DMEM: Dulbecco's Modified Eagle Medium

[0211] FBS: fetal bovine serum

[0212] FCS: fetal calf serum

[0213] P / S: penicillin / streptomycin

[0214] PBS: phosphate buffered saline

[0215] HBSS: Hank's Buffered Salt Solution

[0216] EC 50 : half maximal effective concentration

[0217] IBMX: 3-isobutyl-l-methylxanthine. DETAILED DESCRIPTION

[0218] The following examples are provided to further illustrate the present application, but should not be construed to limit the scope of the application in any way.

[0219] Example 1: Synthesis of Peptide Compounds

[0220] The intermediates and compounds of the present application can be synthesized by a variety of methods known in the art. The following specific examples illustrate the preparation of the compounds of the present application using chemical synthesis. Each of the specific synthesis steps described can be combined in different ways using different materials and reagents to synthesize a variety of corresponding compounds of the present application or salts thereof. The reagents and starting materials used are readily available to one of ordinary skill in the art. In particular, the following examples are provided merely to illustrate the present application and should not be construed to limit the scope of the application in any way.

[0221] Materials:

[0222] The materials and reagents used in the present application are purchased from commercial products, and the protecting amino acids used in the whole synthesis process are as follows: Fmoc-Ser(tBu)-OH, Fmoc-Ac3c-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Phe-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(ivdde)-OH, Fmoc-α-MeLeu-OH, Fmoc-Thr(tBu)-OH, Fmoc-His(Trt)-OH, Fmoc-α-MePhe-OH, Fmoc-α-MePhe(2F)-OH, Fmoc-Aib-OH, Boc-Tyr(tBu)-OH.

[0223] The following is an example of compound 10 to illustrate the synthetic preparation method of the compound of the present application (wherein the preparation of the remaining compounds only needs to replace the amino acid raw material synthesis sequence).

[0224] (1) Rink amino resin pretreatment: weigh 1 g of dry Rink Amide MBHA resin (substitution degree S = 0.28 mmol / g) into the reaction column, add 10 ml of DMF, and nitrogen gas for 30 min, and remove the solvent. Add 10 ml of DMF and wash 3 times, each for 1 min, and remove the solvent.

[0225] (2) Removal of protecting group Fmoc: add 20% piperidine / DMF solution (10 ml) to the above treated Rink amino resin, and nitrogen gas for 20 min. During the reaction, ninhydrin colorimetric method is used to monitor the reaction degree. If the resin color is blue, it indicates that Fmoc is removed successfully. After the reaction is completed, filter out the solvent, and add DMF to the reaction system to wash the resin for 1 min, and repeat the washing for 6 times.

[0226] (3) Coupling reaction (peptide bond formation): The prepared corresponding Fmoc-protected amino acid solution (3.0 eq) was added to the reactor, then DIEA (6.0 eq) was added, 5 ml of DMF was added to the reaction column, and nitrogen was blown. After the amino acid was dissolved, HBTU (2.85 eq) was added. The nitrogen was adjusted to make the resin swell uniformly, and the reaction was carried out at 25°C for 30 min. The reaction was monitored by ninhydrin colorimetry during the reaction. If the resin is colorless and transparent, it means that the coupling is successful. After the reaction is completed, the solvent is removed by filtration, and DMF is added to the reaction system to wash the resin for 1 min. Repeat the washing 6 times. Repeat the above operation, and sequentially add the corresponding amino acid solution until the synthesis of the peptide chain is completed. The last amino acid is coupled with Boc-Tyr(tBu)-OH, and tetrachloroquinone is used to detect the colorless and transparent resin to complete the coupling. Lys at the side chain modification site is replaced with Fmoc-Lys(ivdde)-OH. The order of adding amino acid coupling for the synthesis of the main peptide sequence of compound 10 is Fmoc-Ser(tBu)-OH, Fmoc-Ac3c-OH, Fmoc-Pro-OH (2x), Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH (2x), Fmoc-Pro-OH, Fmoc-Gly-OH (2x), Fmoc-Glu(OtBu)-OH, Fmoc-Leu-OH (2x), Fmoc-Phe-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Ile-OH, Fmoc-Phe-OH, Fmoc-Ala-OH, Fmoc-Aib-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ala-OH, Fmoc-Lys(ivdde)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Phe-OH, Fmoc-Ile-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-α-MeF(2F)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Gly-OH, Fmoc-Gln(Trt)-OH, Fmoc-Aib-OH, Boc-Tyr(tBu)-OH.

[0227] (4) Removal of the side chain protecting group ivdde of Lys: 3% hydrazine hydrate in DMF (10 ml) was added to the reaction column, and the reaction was carried out under nitrogen for 20 min to remove the side chain protecting group ivdde of the modified Lys. The reaction was complete when the resin turned blue under ninhydrin detection. After the reaction was complete, the solvent was removed, DMF was added, and the reaction was washed for 1 min. The solvent was removed, and the washing was repeated 6 times.

[0228] (5) Modification of the side chain of Lys: AEEAc (2.0 eq) was added to the resin, DIEA (4.00 eq) was added, 5 ml of DMF was added to the reaction column, and the reaction was carried out under nitrogen. After the amino acid was dissolved, HBTU (1.9 eq) was added. The resin was uniformly blown up under nitrogen. The reaction was carried out at 25°C for 1 h. The reaction was complete when the resin was colorless and transparent under ninhydrin detection. The reaction solution was removed, and the resin was washed with DMF (10 ml) for 1 min. 20% piperidine / DMF (10 ml) was added to the reaction column, and the reaction was carried out under nitrogen for 20 min to remove the Fmoc group. DMF (10 ml) was added, and the reaction was washed for 1 min. The solvent was removed, and the washing was repeated 6 times. AEEAc, Fmoc-Glu(OtBu)-OH, C 20 The coupling was carried out with the mono-t-butyl ester, and the side chain modification was complete. Finally, MeOH (10 ml) was used to shrink the resin, 3 min each time, the solvent was removed, the resin was poured out and dried, and was ready for use.

[0229] (6) Post-treatment of the peptide resin: The dried peptide resin was added to the prepared cleavage reagent (95% TFA: 2.5% Tis: 2.5% H2O), and the resin was cleaved by shaking for 2.5 h. The filtrate was added to 10 times the volume of ice isopropyl ether, and was centrifuged. The isopropyl ether was washed 5 times. The crude peptide was obtained by vacuum drying for 2 h.

[0230] (7) Purification of the crude peptide compound:

[0231] The obtained crude peptide powder was dissolved in 50% acetonitrile / H2O solution, and was purified by reverse phase C18 preparative chromatography column (Shimadzu, Inertsil ODS 20x250mm 5um). The elution was carried out with 95% buffer A (0.1% TFA / H2O) and 5% buffer B (0.075% TFA / acetonitrile) as the starting eluent, and the proportion of buffer B was gradually increased to 75% for continuous operation for 30 min. The target peptide component was collected. The purified peptide compound was analyzed and confirmed by analytical HPLC / MS method. The purity of the obtained peptide compound was not less than 95%.

[0232] Table 1. List of synthesized peptide compounds and molecular weights

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239] Example 2: Peptide compound activity test on human GLP-1 / GIP / GCG receptor stable-transfected cells

[0240] First, HEK-293 cells stably overexpressing human GLP-1 or GCG receptor and CHO cells stably overexpressing GIP receptor were constructed respectively. Then the agonistic activity of each compound on the corresponding receptor was determined by measuring the cAMP signal response level of the above-mentioned cells. The intracellular cAMP content was determined using the kit of Cisbio Corp. based on the HTRF (homogeneous time-resolved fluorescence) technology.

[0241] The frozen cells stably overexpressing human GLP-1 or GIP or GCG receptor were quickly thawed and recovered in a 37℃ constant temperature water bath, and the cell solution was transferred to 10 ml of HBSS for resuspension. After centrifugation at 1000 rpm for 5 min at room temperature, the supernatant was discarded, and the cells were resuspended with 1×HBSS (containing 0.1% Casein, 250 μΜ IBMX) to adjust the cell density to 1.0×10 5 / mL.

[0242] 10 μL of cell suspension was added to each well of a 384-well plate. The test compound was dissolved in 1×PBS buffer to prepare a certain concentration stock solution, which was diluted by 3 times in stages to prepare 12 concentration points of compound solution. 100 nL of prepared compound solution was added to the corresponding cell suspension in the 384-well plate using the ECHO liquid transfer system, and the mixture was uniformly mixed by rotating and shaking at 1000 rpm for 1 min, followed by incubation at room temperature for 60 min. After the drug incubation was completed, 10 μL of detection reagent in the kit was added to each well, and then incubated at room temperature for 60 min. The plate was placed in an EnVision multifunctional enzyme labeler (PerkinElmer) to measure the readings at 665 / 615 nm. The compound concentration-effect curve was made using the GraphPad Prism 5 plotting software, and the EC 50 (nM) value was calculated.

[0243] The natural wild-type human GLP-1 (7-37), GIP, GCG were used as positive controls for the receptor agonistic effect of the test compound. For GLP-1 receptor cells, the EC50 Values EC 50 The relative activity (%) of the test compound was evaluated as the percentage of the ratio of the values.

[0244] For GIP receptor cells, the EC 50 Values EC 50 The relative activity (%) of the test compound was evaluated as the percentage of the ratio of the values.

[0245] For GCG receptor cells, the EC 50 Values EC 50 The relative activity (%) of the test compound was evaluated as the percentage of the ratio of the values.

[0246] Table 2. Human GLP-1 / GIP / GCG receptor stable cell activity of peptide compounds

[0247]

[0248]

[0249]

[0250] Rel.A:Relative Activity, NT:Not test, each group has at least 3 independent tests.

[0251] The data in the table show that each compound can exhibit high relative activity in human GLP-1 / GIP / GCG receptor stable cells.

[0252] Example 3: Test of the functional activity of peptide compounds on rat islet tumor RIN-m5F cells

[0253] The rat islet tumor RIN-m5F cell line is derived from rat islet tissue and mainly expresses endogenous GLP-1 / GIP / GCG receptors, among which GLP-1 receptors are the most abundant. This experiment determines the cAMP level produced by the action of the compound on RIN-m5F cells.

[0254] The frozen RIN-m5F cells were quickly thawed and recovered in a 37°C constant temperature water bath, the cell solution was transferred to 10 ml HBSS for resuspension, centrifuged at 1000 rpm for 5 min at room temperature, the supernatant was discarded, the cells were resuspended with 1x HBSS (containing 0.1% Casein, 250 μΜ IBMX), and the cell density was adjusted to 1.0x10 5 / mL.

[0255] 384-well plates were seeded with 10 μL of cell suspension per well. The test compounds were dissolved in 1x PBS buffer to prepare a mother liquor of certain concentration, and then diluted by 3 times step by step to prepare 12 concentration points of compound solutions. 100 nL of prepared compound solution was added into the corresponding cell suspension in the 384-well plates by using ECHO liquid transfer system, and then mixed uniformly by rotating and shaking at 1000 rpm for 1 min, followed by incubation at room temperature for 60 min. After the completion of drug incubation, 10 μL of detection reagent in the kit was added into each well, and then incubated at room temperature for 60 min. The plates were placed in EnVision multifunctional microplate reader (PerkinElmer) to determine the readings at 665 / 615 nm. The compound concentration-effect curve was made by using GraphPad Prism 5 drawing software, and the calculation was performed.

[0256] Table 3. RIN-m5F rat pancreatic tumor cell activity of peptide compounds

[0257]

[0258]

[0259]

[0260] Rel.A: Relative Activity, relative activity; NT: Not test, not tested; each group has at least 3 independent tests.

[0261] The compounds of the present application in the table can exhibit high relative activity in pancreatic tumor cells RIN-m5F.

[0262] Example 4: Test of functional activity of peptide compounds on 3T3-L1 adipocytes

[0263] Mouse 3T3-L1 precursor adipocytes can be induced to differentiate into mature adipocytes. 3T3-L1 cells were seeded in 96-well plates at a cell density of 4x10 4 / ml, and cultured in DMEM medium containing 10% FCS and 1% P / S in a 37°C, 5% CO2 incubator. After the cells were fully contacted, DMEM differentiation medium containing 20% FBS, 0.5 mM IBMX, 0.4 ug / mL dexamethasone, and 5 ug / mL insulin was used to induce 3T3-L1 adipocyte differentiation. After 5 days of induction, DMEM medium containing 20% FBS, 4 ug / mL insulin, and 10 uM rosiglitazone was used for continued induction for 3 days, and then DMEM medium containing 10% FBS was used for continued culture for 2-3 days to induce mature 3T3-L1 adipocytes.

[0264] Induced differentiated mature 3T3-L1 adipocytes can express abundant GIP receptors similar to adipose tissue cells. The cAMP level produced by the effect of the compound on 3T3-L1 adipocytes was determined. The solution of the compound to be tested was diluted in a 3-fold concentration gradient, a total of 10 serial concentration solutions were set, and were added to the induced mature 3T3-L1 adipocytes, and incubated at room temperature for 60 min. After the drug incubation was completed, 10 μL of the detection reagent in the kit was added to each well, and incubated at room temperature for 60 min. The plate was placed in an EnVision multifunctional microplate reader (PerkinElmer) to measure the reading at 665 / 615 nm. The compound concentration-effect curve was made using the GraphPad Prism 5 plotting software and calculated.

[0265] Table 4. Mouse 3T3-L1 adipocyte activity of peptide compounds

[0266]

[0267]

[0268]

[0269] Rel.A: Relative Activity, relative activity; NT: Not test, not tested; each group has at least 3 independent tests.

[0270] The compounds of the present application in the table can all exhibit high relative activity in adipocytes 3T3-L1.

[0271] Example 5: Test of the functional activity of peptide compounds on human primary hepatocytes

[0272] The cAMP level produced by the effect of the compound on human primary hepatocytes was determined. Human primary hepatocytes were purchased from Lonza (cell item number HUCPG).

[0273] The frozen human primary hepatocytes were quickly thawed and recovered in a 37°C constant temperature water bath, the cell solution was transferred to 10 ml HBSS for resuspension, centrifuged at 1000 rpm for 5 min at room temperature, the supernatant was discarded, and the cells were resuspended with 1x HBSS (containing 0.1% Casein, 250 μΜ IBMX), and the cell density was adjusted to 1.0x10 5 / mL.

[0274] 384-well plates were seeded with 10 μL of cell suspension per well. The test compounds were dissolved in 1x PBS buffer to prepare a mother liquor of certain concentration, and then diluted by 3 times step by step to prepare 12 concentration points of compound solutions. 100 nL of prepared compound solution was added to the corresponding cell suspension in the 384-well plate by using ECHO liquid transfer system, and then mixed uniformly by rotating and shaking at 1000 rpm for 1 min, followed by incubation at room temperature for 60 min. After the completion of drug incubation, 10 μL of detection reagent in the kit was added to each well, and then incubated at room temperature for 60 min. The plate was placed in EnVision multifunctional microplate reader (PerkinElmer) to measure the readings at 665 / 615 nm. The compound concentration-effect curve was made by using GraphPad Prism 5 drawing software, and the calculation was performed.

[0275] Table 5. Activity of peptide compounds in human primary hepatocytes

[0276]

[0277]

[0278]

[0279] Rel.A: Relative Activity; NT: Not test; each group has at least 3 independent tests.

[0280] The compounds of the present application in the table can exhibit high relative activity in hepatocytes.

[0281] Example 6: In vivo pharmacodynamics

[0282] The high-fat diet-induced obese (DIO) mice have characteristics of obesity, elevated blood glucose, insulin resistance and lipid abnormalities, which are very significant metabolic syndromes similar to human body. The effects of the compounds of the present application on the body weight, food intake, blood glucose and lipid of DIO mice were studied in C57 BL / 6J DIO mice.

[0283] 5-week-old male C57 BL / 6J mice (purchased from Shanghai Slac Laboratory Animal Co. Ltd.) were housed in a pathogen-free clean environment (controlled temperature 20-24°C, relative humidity 30-70%), with a 12-hour light / 12-hour dark cycle, and were fed with normal chow, 4 animals per cage, for 2 weeks of acclimation. Mice were induced to be obese by feeding a high-fat diet (60 kcal% of calories from fat), and after 16 weeks of high-fat diet feeding, DIO mice weighed 41-55 g, with blood glucose ranging from 8-12 mmol / L. The DIO mice were randomly divided into groups (n=6) according to body weight and fasting blood glucose, so that the average body weight and blood glucose of the animals in each group were close. After grouping, the animals were housed one per cage for one week, during which each animal was administered with a subcutaneous injection (S.C.) of vehicle (1xPBS, 5 ml / kg) to make the animals pre-adapt to the operation process.

[0284] After the end of the pre-adaptation of the animals, the animals were administered with a subcutaneous injection according to the experimental grouping, vehicle control, compound, the compound was dissolved in 1xPBS, the administration dose was 5 ml / kg, the administration operation was started at 9:00 in the morning, and the administration was performed once every three days (Q3D) for 15 days. During the entire experimental study, the body weight and food intake of the animals were measured every day before administration, and by comparing with the initial body weight and food intake of the same animals before administration, the percentage change (%) of the body weight and the cumulative food intake of the animals were calculated to evaluate the effect of the compound on the changes of body weight and food intake.

[0285] At the end of the experiment (Day 15), the body weight of the mice was measured, and then the fasting blood glucose of the animals was measured by non-anesthetized tail tip tail blood collection. After blood collection, the animals were anesthetized with CO2 and sacrificed, and then blood was collected by heart puncture, plasma was separated by centrifugation, and plasma was used to measure plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and blood insulin content. The liver was separated for homogenization, the supernatant of the homogenate was separated by centrifugation, and was used to measure the liver triglyceride content.

[0286] All result values are expressed as Mean ± SEM, and the results were analyzed using one-way ANOVA of GraphPad Prism 5 software and Dunnett’s post-test for comparison with the vehicle control group. Differences were considered statistically significant at the level of p<0.05.

[0287] Table 6-1. Effect of compounds on body weight change of DIO mice

[0288]

[0289]

[0290] Table 6-2. Effect of compounds on body weight change of DIO mice

[0291]

[0292] As can be seen from the results in Table 6-1 and Table 6-2, the compounds of the present application have obvious weight loss effects.

[0293] Table 7-1. Effects of compounds on blood lipids of DIO mice

[0294]

[0295]

[0296] Table 7-2. Effects of compounds on blood lipids of DIO mice

[0297]

[0298] As can be seen from the results in Table 7-1 and Table 7-2, the compounds of the present application have obvious blood lipid-lowering effects.

[0299] Table 8-1. Effects of 3nM compounds on blood glucose and blood insulin of DIO mice

[0300]

[0301]

[0302] Table 8-2. Effects of 3nM compounds on blood glucose and blood insulin of DIO mice

[0303]

[0304] As can be seen from the results in Table 8-1 and Table 8-2, the compounds of the present application have obvious blood glucose and blood insulin-lowering effects.

[0305] Table 9-1. Effects of 3nM compounds on liver of DIO mice

[0306] Compound Dose (nmol / kg) Liver TG (mg) Vehicle - 181.5±33.45 3 3 32.2±2.99 10 3 81.6±8.50 20 3 26.7±2.81 24 3 30.7±1.31

[0307] Table 9-2. Effects of 3nM compounds on liver of DIO mice

[0308] Compound Dose (nmol / kg) Liver TG (mg) Vehicle - 129.8±20.21 19 3 38.0±3.37 21 3 41.4±6.33 40 3 42.1±5.22

[0309] As can be seen from the results in Table 9-1 and Table 9-2, the compounds of the present application have obvious liver triglyceride-lowering effects.

[0310] Example 7: Rat pharmacokinetic (PK) study of compounds

[0311] 7-9 week old male SD rats (220-250 g, 3 rats / group) received 30 nmol / kg compound by subcutaneous injection, blood was collected at 0.25, 2, 4, 8, 12, 16, 24, 48, 96, 120, 144 h time points by jugular vein, blood was treated to get plasma samples, then the samples were analyzed by LC-MS / MS, the blood concentration-time curve was analyzed by Phoenix WinNonlin 6.3 version software (non-compartment model), the PK parameters and half-life were calculated.

[0312] The PK parameters calculated by the above method are shown in Table 10.

[0313] Table 10 Rat pharmacokinetic (PK) parameters of compounds

[0314]

[0315] The results in Table 10 show that each compound exhibits an extended pharmacokinetic distribution. SEQUENCE LISTING <110> Federal Biotech (Hengqin) Co., Ltd. <120> Multi-agonists and uses thereof <130> LAPCT210314CN <160> 45 <170> SIPOSequenceListing 1.0 <210> 1 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino group at position 17 chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 1 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Leu Glu Thr Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Xaa Ser 35 <210> 2 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino group at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 2 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Leu Glu Thr His Pro Ser 20 25 30 Ser Gly Ala Pro Pro Xaa Ser 35 <210> 3 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-yGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 3 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Leu Glu Ser His Pro Ser 20 25 30 Ser Gly Ala Pro Pro Xaa Ser 35 <210> 4 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is a-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is a-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (17)..(17) <223> Position 17 Lys side chain amino group chemically modified by a fatty acid side chain group AEEAc-AEEAc-yGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is a-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 4 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Phe Leu Asp Lys 1 5 10 15 Lys Ala Gin Xaa Ala Phe He Glu Tyr Leu Leu Glu Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Xaa Ser 35 <210> 5 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 5 Tyr Xaa Gin Gly Thr Xaa Thr Ser Asp Tyr Ser lie Phe Leu Asp Lys 1 5 10 15 Lys Ala Gin Xaa Ala Phe lie Gin Phe Leu Leu Gin Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Xaa Ser 35 <210> 6 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Position 17 is chemically modified Lys side chain amino group by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (29)..(29) <223> Xaa at position 29 is α-aminoisobutyric acid. <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated. <400> 6 Tyr Xaa His Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Leu Glu Xaa His Pro Ser 20 25 30 Ser Gly Gln Pro Pro Pro Ser 35 <210> 7 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is α-aminoisobutyric acid. <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is α-methylphenylalanine. <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is α-methylleucine. <220> <221> MOD_RES <222> (17)..(17) <223> Position 17 is chemically modified with the Lys side chain amino group AEEAc-AEEAc-γGlu-CO(CH2)18COOH. <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (35)..(35) <223> Xaa at position 35 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 7 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Leu Glu Thr Gly Pro Ser 20 25 30 Ser Gly Xaa Pro Pro Pro Ser 35 <210> 8 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino group at position 17 chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 8 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Leu Glu Thr Gly Pro Ser 20 25 30 Ser Gly Gln Pro Pro Pro Ser 35 <210> 9 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (17)..(17) <223> Position 17 Lys side chain amino group chemically modified by a fatty acid side chain group AEEAc-AEEAc-gamma GIu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 9 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Phe Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Thr Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Xaa Ser 35 <210> 10 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino chemically modified at position 17 by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 10 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Phe Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Ser His Pro Ser 20 25 30 Ser Gly Ala Pro Pro Xaa Ser 35 <210> 11 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-yGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 28 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 11 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Phe Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Thr Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Xaa Ser 35 <210> 12 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino group at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 12 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Phe Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Thr Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 13 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino group at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 13 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Phe Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Leu Glu Thr Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 14 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Position 17 Lys side chain amino group is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 14 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Thr Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 15 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino group at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 15 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Phe Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Ser His Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 16 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino group at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (29)..(29) <223> Xaa at position 29 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 16 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Phe Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Xaa His Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 17 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino group at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 17 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Phe Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Leu Glu Thr Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 18 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino group at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-yGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (29)..(29) <223> Xaa at position 29 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 18 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Phe Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Leu Glu Xaa His Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 19 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Position 17 Lys side chain amino group is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 19 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Thr Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 20 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Position 17 Lys side chain amino group is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (29)..(29) <223> Xaa at position 29 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 20 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Xaa His Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 21 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino group at position 17 chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 21 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Phe Leu Asp Lys 1 5 10 15 Lys Ala Gin Xaa Ala Phe lie Glu Phe Leu Leu Glu Gly Gly Pro Ser 20 25 30 Ser Gly Gin Pro Pro Pro Ser 35 <210> 22 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino group at position 17 is chemically modified by a fatty acid side chain group, AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 22 Tyr Xaa Gin Gly Thr Xaa Thr Ser Asp Tyr Ser lie Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gin Xaa Ala Phe lie Gin Phe Leu Leu Gin Gly Gly Pro Ser 20 25 30 Ser Gly Gin Pro Pro Pro Ser 35 <210> 23 <211> 39 <212> PRT <213> Artificial Sequence (Artificial Sequence) <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino group at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 23 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Leu Glu Thr Gly Pro Ser 20 25 30 Ser Gly Gln Pro Pro Pro Ser 35 <210> 24 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Position 17 Lys side chain amino group is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (34)..(34) <223> Xaa at position 34 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 24 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Thr Gly Pro Ser 20 25 30 Ser Xaa His Pro Pro Pro Ser 35 <210> 25 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Position 17 Lys side chain amino group chemically modified by a fatty acid side chain group AEEAc-AEEAc-gamma GIu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (34)..(34) <223> Xaa at position 34 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 25 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Gly Arg Pro Ser 20 25 30 Ser Xaa His Pro Pro Pro Ser 35 <210> 26 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino group at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 26 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Ser His Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 27 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa in position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa in position 13 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (17)..(17) <223> Position 17 is chemically modified Lys side chain amino group by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa in position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser in position 39 is optionally amidated <400> 27 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Leu Glu Ser His Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 28 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (17)..(17) <223> Position 17 Lys side chain amino group is chemically modified by a fatty acid side chain group AEEAc-AEEAc-yGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (30)..(30) <223> Xaa at position 30 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 28 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala GIn Xaa Ala Phe lie Glu Phe Leu Leu Glu Ser Xaa Pro Ser 20 25 30 Ser Gly Ala Pro Pro Xaa Ser 35 <210> 29 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino group at position 17 chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (30)..(30) <223> Xaa at position 30 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 29 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Phe Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Leu Glu Ser Xaa Pro Ser 20 25 30 Ser Gly Ala Pro Pro Xaa Ser 35 <210> 30 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Position 17 Lys side chain amino group is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (30)..(30) <223> Xaa at position 30 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 30 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Thr Xaa Pro Ser 20 25 30 Ser Gly Ala Pro Pro Xaa Ser 35 <210> 31 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methyl leucine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino chemically modified at position 17 by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (29)..(29) <223> Xaa at position 29 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 31 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Xaa His Pro Ser 20 25 30 Ser Gly Ala Pro Pro Xaa Ser 35 <210> 32 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (29)..(29) <223> Xaa at position 29 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 32 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Phe Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Leu Glu Xaa His Pro Ser 20 25 30 Ser Gly Ala Pro Pro Xaa Ser 35 <210> 33 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (34)..(34) <223> Xaa at position 34 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 33 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Ser His Pro Ser 20 25 30 Ser Xaa His Pro Pro Xaa Ser 35 <210> 34 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 34 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Leu Glu Thr Gly Pro Ser 20 25 30 Ser Gly Gln Pro Pro Xaa Ser 35 <210> 35 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Position 17 Lys side chain amino group chemically modified by a fatty acid side chain group AEEAc-AEEAc-gamma GIu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 35 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Leu Glu Thr Gly Pro Ser 20 25 30 Ser Gly Gln Pro Pro Xaa Ser 35 <210> 36 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (34)..(34) <223> Xaa at position 34 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 36 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Gly Gly Pro Ser 20 25 30 Ser Xaa His Pro Pro Pro Ser 35 <210> 37 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Position 17 Lys side chain amino group is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (34)..(34) <223> Xaa at position 34 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 37 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Gly Arg Pro Ser 20 25 30 Ser Xaa His Pro Pro Pro Ser 35 <210> 38 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Position 17 Lys side chain amino group is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (34)..(34) <223> Xaa at position 34 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 38 Tyr Xaa Gin Gly Thr Xaa Thr Ser Asp Tyr Ser lie Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gin Xaa Ala Phe lie Gin Phe Leu Leu Gin Thr Gly Pro Ser 20 25 30 Ser Xaa His Pro Pro Pro Ser 35 <210> 39 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Position 17 Lys side chain amino group chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (34)..(34) <223> Xaa at position 34 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 39 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Thr Arg Pro Ser 20 25 30 Ser Xaa His Pro Pro Pro Ser 35 <210> 40 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Lys at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (34)..(34) <223> Xaa at position 34 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 40 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Ser His Pro Ser 20 25 30 Ser Xaa His Pro Pro Xaa Ser 35 <210> 41 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino chemically modified at position 17 by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (34)..(34) <223> Xaa at position 34 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 41 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Ser His Pro Ser 20 25 30 Ser Xaa His Pro Pro Xaa Ser 35 <210> 42 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methylphenylalanine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (34)..(34) <223> Xaa at position 34 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 42 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Phe Leu Leu Glu Ser His Pro Ser 20 25 30 Ser Xaa His Pro Pro Xaa Ser 35 <210> 43 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (6)..(6) <223> Xaa at position 6 is alpha-methyl-2-fluorophenylalanine <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Position 17 Lys side chain amino group chemically modified by fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (34)..(34) <223> Xaa at position 34 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (38)..(38) <223> Xaa at position 38 is Ac3c <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 43 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Leu Glu Ser His Pro Ser 20 25 30 Ser Xaa His Pro Pro Xaa Ser 35 <210> 44 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Lys side chain amino at position 17 is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 44 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Leu Glu Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 45 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> MOD_RES <222> (2)..(2) <223> Xaa at position 2 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (13)..(13) <223> Xaa at position 13 is alpha-methylleucine <220> <221> MOD_RES <222> (17)..(17) <223> Position 17 Lys side chain amino group is chemically modified by a fatty acid side chain group AEEAc-AEEAc-gammaGlu-CO(CH2)18COOH <220> <221> MOD_RES <222> (20)..(20) <223> Xaa at position 20 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (29)..(29) <223> Xaa at position 29 is alpha-aminoisobutyric acid <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is optionally amidated <400> 45 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Lys Ala Gln Xaa Ala Phe Ile Glu Tyr Leu Leu Glu Xaa Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35

Claims

1. A GLP-1 / GIP / GCG R tri-agonist polypeptide compound or a salt or solvate thereof, wherein the compound is: Compound 2: Y-Aib-QGT-αMeF-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEYLLETHPSSGAPP-Ac3c-S-NH2; or Compound 3: Y-Aib-QGT-αMeF-TSDYSI-αMeL-LDKK(AEEAc-AEEAc-γGlu-CO(CH2) 18 COOH)AQ-Aib-AFIEYLLESHPSSGAPP-Ac3c-S-NH2.

2. The polypeptide compound or its salt or solvate according to claim 1, characterized in that, Regarding the agonistic activity of the compound in GLP-1 receptor-stabilized cells, compared to natural GLP-1, the relative activity of the compound in agonizing GLP-1 receptor is at least 30%.

3. The polypeptide compound or its salt or solvate according to claim 2, characterized in that, Regarding the agonistic activity of the compound in GLP-1 receptor-stabilized cells, compared to natural GLP-1, the relative activity of the compound in agonizing GLP-1 receptor is at least 60%.

4. The polypeptide compound or its salt or solvate according to claim 3, characterized in that, Regarding the agonistic activity of the compound in GLP-1 receptor-stabilized cells, compared to natural GLP-1, the relative activity of the compound in agonizing GLP-1 receptor is at least 80%.

5. The polypeptide compound or its salt or solvate according to claim 4, characterized in that, Regarding the agonistic activity of the compound in GLP-1 receptor-stabilized cells, compared to natural GLP-1, the relative activity of the compound in agonizing GLP-1 receptor is at least 100%.

6. The polypeptide compound or its salt or solvate according to claim 1, characterized in that, Regarding the agonistic activity of the compound in GIP receptor-stabilized cells, compared to natural GIP, the relative activity of the compound in agonizing the GIP receptor is at least 100%.

7. The polypeptide compound or its salt or solvate according to claim 6, characterized in that, Regarding the agonistic activity of the compound in GIP receptor-stabilized cells, compared to natural GIP, the relative activity of the compound in agonizing the GIP receptor is at least 150%.

8. The polypeptide compound or its salt or solvate according to claim 1, characterized in that, Regarding the agonistic activity of the compound in GCG receptor-stabilized cells, compared to natural GCG, the relative activity of the compound in agonizing the GCG receptor is at least 10%.

9. The polypeptide compound or its salt or solvate according to claim 8, characterized in that, Regarding the agonistic activity of the compound in GCG receptor-stabilized cells, compared to natural GCG, the relative activity of the compound in agonizing the GCG receptor is at least 30%.

10. The polypeptide compound or its salt or solvate according to claim 1, characterized in that, On RIN-m5F cells, representative cells of pancreatic islet tissue, the compound exhibits at least 60% relative agonistic activity against RIN-m5F cells compared to natural GLP-1 (7-37).

11. The polypeptide compound or its salt or solvate according to claim 10, characterized in that, On RIN-m5F cells, representative cells of pancreatic islet tissue, the compound exhibits at least 80% relative agonistic activity against RIN-m5F cells compared to natural GLP-1 (7-37).

12. The polypeptide compound or its salt or solvate according to claim 11, characterized in that, On RIN-m5F cells, representative cells of pancreatic islet tissue, the compound exhibits at least 100% relative agonistic activity against RIN-m5F cells compared to natural GLP-1 (7-37).

13. The polypeptide compound or its salt or solvate according to claim 1, characterized in that, On adipose tissue representative cells 3T3-L1, the compound exhibits at least 60% relative agonistic activity against 3T3-L1 cells compared to natural GIP.

14. The polypeptide compound or its salt or solvate according to claim 13, characterized in that, On adipose tissue representative cells 3T3-L1, the compound exhibits at least 100% relative agonistic activity against 3T3-L1 cells compared to natural GIP.

15. The polypeptide compound or its salt or solvate according to claim 1, characterized in that, In human primary hepatocytes, representative cells of liver tissue, the compound exhibits at least 60% relative activity in stimulating hepatocytes compared to natural GCG.

16. The polypeptide compound or its salt or solvate according to claim 15, characterized in that, In human primary hepatocytes, representative cells of liver tissue, the compound exhibits at least 100% relative activity in stimulating hepatocytes compared to natural GCG.

17. A pharmaceutical composition comprising an effective amount of any one of the compounds of claims 1 to 16 or their salts or solvates, and pharmaceutically acceptable excipients, diluents, carriers or excipients.

18. The pharmaceutical composition according to claim 17, characterized in that, The pharmaceutical composition is an injection or lyophilized powder, tablet, pill, lozenge, soft capsule, hard capsule, granule, powder, solution, suspension or syrup; or the pharmaceutical composition is in the form of microcapsules, microspheres, nanoparticles or liposomes.

19. The pharmaceutical composition according to claim 17, characterized in that, The pharmaceutical composition is for oral, inhalation, or parenteral administration, wherein the parenteral administration is selected from intraperitoneal, intramuscular, intra-arterial, intravenous, subcutaneous, or intradermal injection.

20. The pharmaceutical composition according to claim 17, characterized in that, The pharmaceutical composition is administered at a frequency of at least once a day, once a week, once every two weeks, or once a month.

21. The pharmaceutical composition according to claim 17, characterized in that, The pharmaceutical composition is used in combination with at least one therapeutically active substance, which includes an antidiabetic active agent, a GIP receptor agonist, a GCG receptor agonist or antagonist, a GLP-1 / GIP receptor agonist, a GLP-1 / GCG receptor agonist, a GIP / GCG receptor agonist, FGF-21, cholecystokinin B (CCKB), PYY (3-36), leptin, calcitonin, a lipid-regulating active agent, a PPAR-α, β, δ agonist or modulator, an antiplatelet aggregation active agent, a PCSK9 inhibitor, a lipase inhibitor, an anti-hepatic fibrosis or cirrhosis active agent, or an anti-inflammatory active agent.

22. The pharmaceutical composition according to claim 21, characterized in that, The antidiabetic active agents include insulin, biguanides, sulfonylureas, thiazolidinediones, α-glucosidase inhibitors, DPP-4 inhibitors, SGLT2 inhibitors, dual SGLT1 / SGLT2 inhibitors, GLP-1 receptor agonists, or amylin.

23. The use of any compound of claims 1 to 16 or its salt or solvate, or any pharmaceutical composition of claims 17 to 22, in the preparation of a medicament for promoting insulin secretion and lowering blood glucose.

24. Use of any compound of claims 1 to 16 or its salt or solvate, or any pharmaceutical composition of claims 17 to 22, in the preparation of a medicament for reducing body weight.

25. The use of any compound of claims 1 to 16 or its salt or solvate, or any pharmaceutical composition of claims 17 to 22, in the preparation of a medicament for the prevention and / or treatment of metabolic disorders and their related complications, wherein the medicament for the prevention and / or treatment of metabolic disorders and their related complications is a medicament for the treatment of diabetes, obesity, or non-alcoholic fatty liver disease.

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