Triple agonist of GLP-1, GCG and GIP receptors

Abstract

The present invention relates to a triple agonist of GLP-1, GCG and GIP receptors. The compound provided by the present invention has strong agonist activity on glucagon-like peptide-1 (GLP-1) receptor, glucagon (GCG) receptor and glucose-dependent incretin (GIP) receptor; it can be used to treat and / or prevent metabolic disorders including diabetes, obesity, fatty liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, dyslipidemia and metabolic syndrome and related diseases.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a triple agonist of GLP-1, GCG and GIP receptors. Background Art

[0002] At present, there are 537 million diabetes patients in the world, and nearly 140 million in China, ranking first in the world. It is one of the major disease burdens in China. And obese type 2 diabetes patients are the largest group of diabetes patients. Obesity can disrupt the levels of insulin, sugar and blood lipids in the blood. In addition to type 2 diabetes, it is also easy to cause a variety of metabolic diseases such as hypertension, non-alcoholic fatty liver disease and atherosclerosis. This series of health problems are risk factors for cardiovascular disease. At present, the drugs for the treatment of type 2 diabetes on the market mainly focus on hypoglycemic treatment, and the effect of reducing weight is very limited. While paying attention to the effectiveness of hypoglycemic treatment, it is also necessary to take into account weight control. Only such hypoglycemic drugs can truly bring more levels and longer-term benefits.

[0003] Glucagon-like peptide-1 (GLP-1) is a polypeptide hormone secreted by intestinal L-cells after eating. It can stimulate pancreatic beta cells to secrete insulin, thereby stabilizing postprandial blood sugar fluctuations. Its effect of lowering blood sugar is dependent on glucose concentration. While regulating blood sugar, it greatly reduces the risk of hypoglycemia. In recent years, GLP-1-based drugs, such as liraglutide, dulaglutide and semaglutide, have gradually occupied a very important position in diabetes drugs. GLP-1 drugs also have the effect of weight loss when lowering blood sugar. Its mechanism is that GLP-1 acts on the gastrointestinal tract to delay gastric emptying and intestinal motility, and acts on the central nervous system to suppress appetite, thereby reducing food intake to achieve the purpose of weight loss. However, when GLP-1 receptor agonist drugs are used for weight loss, the dosage required is generally large, gastrointestinal side effects are prone to occur, tolerance is poor, the therapeutic window is narrow, and the weight loss effect still does not fully meet clinical needs.

[0004] Glucagon (GCG) is a polypeptide hormone secreted by pancreatic α cells, which can promote glycogenolysis and gluconeogenesis, significantly increasing blood sugar; it can also activate lipase, promote fat decomposition, increase fatty acid oxidation, and increase energy consumption, thus reducing fat and body weight. Due to its physiological effect of increasing blood sugar, although it can be used to treat hypoglycemia, single-target therapy limits its application in obesity indications, especially in obese people with type 2 diabetes.

[0005] Glucose-dependent incretin (GIP) is a polypeptide hormone secreted by intestinal K cells. GIP and GLP-1 are both incretins, and both can promote insulin secretion and lower blood sugar in a blood sugar concentration-dependent manner. The blood sugar lowering effect mediated by GIP is even stronger than that of GLP-1. However, perhaps due to receptor tolerance caused by high blood sugar, diabetic patients show insensitivity to GIP, so the use of GIP receptor agonists alone in diabetic patients does not achieve the purpose of improving blood sugar.

[0006] At present, there are many diabetes drugs on the market, but the low diabetes treatment compliance rate is still a problem. There is still a long way to go to cure diabetes, and the research and development of new diabetes drugs is still a long way to go. By targeting multiple targets, the disease symptoms can be controlled in all directions in order to bring good clinical benefits. Therefore, those skilled in the art hope to develop new single-molecule GLP-1 / GCG / GIP triple receptor agonists to overcome the shortcomings of existing single-target drugs. Summary of the invention

[0007] The object of the present invention is to provide a triple agonist of GLP-1, GCG and GIP receptors, which has strong agonist activity on glucagon-like peptide-1 (GLP-1) receptor, glucagon (GCG) receptor and glucose-dependent incretin (GIP) receptor.

[0008] To this end, in the first aspect, the present invention provides a compound, which is a peptide having the general formula I or a pharmaceutically acceptable salt or solvate thereof:

[0009] Xaa1-Xaa2-Xaa3-Gly-Thr-Xaa6-Thr-Ser-Asp-Tyr-Ser-Ile-Xaa13-Leu-Asp-Xaa 16-Xaa17-Ala-Xaa19-Xaa20-Xaa21-Phe-Xaa23-Glu-Xaa25-Leu-Xaa27-Xaa28-Xaa 29-R1 (general formula I, SEQ ID NO: 1);

[0010] Wherein, Xaa1 is tyrosine (Tyr, Y) or histidine (His, H);

[0011] Xaa2 is serine (Ser, S) or 2-aminoisobutyric acid (Aib);

[0012] Xaa3 is glutamine (Gln, Q) or histidine (His, H);

[0013] Xaa6 is phenylalanine (Phe, F) or α-methyl-2-fluorophenylalanine (α-Me-(2-F)-Phe);

[0014] Xaa13 is leucine (Leu, L), tyrosine (Tyr, Y), or alanine (Ala, A);

[0015] Xaa16 is lysine (Lys, K), glutamic acid (Glu, E), or arginine (Arg, R);

[0016] Xaa17 is lysine (Lys, K) or isoleucine (Ile, I);

[0017] Xaa19 is glutamine (Gln, Q) or alanine (Ala, A);

[0018] Xaa20 is arginine (Arg, R), glutamine (Gln, Q), lysine (Lys, K), or histidine (His, H);

[0019] Xaa21 is aspartic acid (Asp, D), alanine (Ala, A), or glutamic acid (Glu, E);

[0020] Xaa23 is isoleucine (Ile, I) or valine (Val, V);

[0021] Xaa25 is tryptophan (Trp, W) or tyrosine (Tyr, Y);

[0022] Xaa27 is leucine (Leu, L) or glutamic acid (Glu, E);

[0023] Xaa28 is alanine (Ala, A), serine (Ser, S), or glutamic acid (Glu, E);

[0024] Xaa29 is glycine (Gly, G), glutamine (Gln, Q), or alanine (Ala, A);

[0025] R1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (GPSSGAPPPS, SEQ ID NO: 2), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (PSSGAPPPS, SEQ ID NO: 3), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (PSSGAPPS, SEQ ID NO: 4) or absent;

[0026] At least one of Xaa17 and Xaa20 is unmodified or lysine modified as follows: ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γGlu) b-CO-(CH2) c -CO2H is conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18.

[0027] In some embodiments, in Formula I,

[0028] Xaa17 is lysine, Xaa20 is lysine; or,

[0029] Xaa17 is lysine modified as follows: ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γGlu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, c is 16 or 18; Xaa20 is arginine, glutamine or histidine; or,

[0030] Xaa17 is isoleucine and Xaa20 is lysine modified as follows: ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γGlu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18; or

[0031] Xaa17 is lysine modified as follows: ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γGlu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, c is 16 or 18; and Xaa20 is lysine.

[0032] In some embodiments, in Formula I,

[0033] Xaa1 is tyrosine (Tyr, Y) or histidine (His, H);

[0034] Xaa2 is serine (Ser, S) or 2-aminoisobutyric acid (Aib);

[0035] Xaa3 is glutamine (Gln, Q) or histidine (His, H);

[0036] Xaa6 is phenylalanine (Phe, F) or α-methyl-2-fluorophenylalanine (α-Me-(2-F)-Phe);

[0037] Xaa13 is leucine (Leu, L) or alanine (Ala, A);

[0038] Xaa16 is lysine (Lys, K), glutamic acid (Glu, E), or arginine (Arg, R);

[0039] Xaa17 is lysine (Lys, K) or isoleucine (Ile, I);

[0040] Xaa19 is glutamine (Gln, Q) or alanine (Ala, A);

[0041] Xaa20 is arginine (Arg, R), glutamine (Gln, Q), lysine (Lys, K), or histidine (His, H);

[0042] Xaa21 is aspartic acid (Asp, D), alanine (Ala, A), or glutamic acid (Glu, E);

[0043] Xaa23 is isoleucine (Ile, I) or valine (Val, V);

[0044] Xaa25 is tryptophan (Trp, W) or tyrosine (Tyr, Y);

[0045] Xaa27 is leucine (Leu, L);

[0046] Xaa28 is alanine (Ala, A), serine (Ser, S), or glutamic acid (Glu, E);

[0047] Xaa29 is glycine (Gly, G) or alanine (Ala, A);

[0048] R1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (GPSSGAPPPS, SEQ ID NO: 2), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (PSSGAPPPS, SEQ ID NO: 3), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (PSSGAPPS, SEQ ID NO: 4) or absent;

[0049] At least one of Xaa17 and Xaa20 is unmodified or lysine modified as follows: ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γGlu) b -CO-(CH2) c-CO2H is conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18.

[0050] In some embodiments, in Formula I,

[0051] Xaa1 is tyrosine (Tyr, Y) or histidine (His, H);

[0052] Xaa2 is serine (Ser, S) or 2-aminoisobutyric acid (Aib);

[0053] Xaa3 is glutamine (Gln, Q) or histidine (His, H);

[0054] Xaa6 is phenylalanine (Phe, F) or α-methyl-2-fluorophenylalanine (α-Me-(2-F)-Phe);

[0055] Xaa13 is leucine (Leu, L);

[0056] Xaa16 is lysine (Lys, K);

[0057] Xaa17 is lysine (Lys, K) or isoleucine (Ile, I);

[0058] Xaa19 is glutamine (Gln, Q) or alanine (Ala, A);

[0059] Xaa20 is arginine (Arg, R), glutamine (Gln, Q), lysine (Lys, K), or histidine (His, H);

[0060] Xaa21 is aspartic acid (Asp, D);

[0061] Xaa23 is isoleucine (Ile, I);

[0062] Xaa25 is tryptophan (Trp, W);

[0063] Xaa27 is leucine (Leu, L);

[0064] Xaa28 is alanine (Ala, A) or glutamic acid (Glu, E);

[0065] Xaa29 is glycine (Gly, G);

[0066] R1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (GPSSGAPPPS, SEQ ID NO: 2), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (PSSGAPPPS, SEQ ID NO: 3), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (PSSGAPPS, SEQ ID NO: 4) or absent;

[0067] At least one of Xaa17 and Xaa20 is unmodified or lysine modified as follows: ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γGlu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18.

[0068] In some embodiments, in Formula I,

[0069] Xaa1 is tyrosine (Tyr, Y) or histidine (His, H);

[0070] Xaa2 is 2-aminoisobutyric acid (Aib);

[0071] Xaa3 is glutamine (Gln, Q) or histidine (His, H);

[0072] Xaa6 is α-methyl-2-fluorophenylalanine (α-Me-(2-F)-Phe);

[0073] Xaa13 is leucine (Leu, L);

[0074] Xaa16 is lysine (Lys, K);

[0075] Xaa17 is lysine modified as follows: ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γGlu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18;

[0076] Xaa19 is glutamine (Gln, Q);

[0077] Xaa20 is arginine (Arg, R), glutamine (Gln, Q), or histidine (His, H);

[0078] Xaa21 is aspartic acid (Asp, D);

[0079] Xaa23 is isoleucine (Ile, I);

[0080] Xaa25 is tryptophan (Trp, W);

[0081] Xaa27 is leucine (Leu, L);

[0082] Xaa28 is alanine (Ala, A) or glutamic acid (Glu, E);

[0083] Xaa29 is glycine (Gly, G);

[0084] R1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (GPSSGAPPPS, SEQ ID NO: 2), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (PSSGAPPPS, SEQ ID NO: 3), or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (PSSGAPPS, SEQ ID NO: 4).

[0085] In some embodiments, the peptide having the general formula I further has one or more modifications selected from the following: N-terminal acetylation, C-terminal amidation, glycosylation, phosphorylation.

[0086] In some embodiments, the C-terminal amino acid is amidated as a primary amide.

[0087] In some embodiments, positions 1 to 29 of Formula I are the following sequences:

[0088] YSQGTFTSDYSILLDKKAQRDFIEWLLAG (SEQ ID NO: 32, i.e., positions 1 to 29 of SEQ ID NO: 5);

[0089] Y(dS)QGTFTSDYSILLDKKAQRDFIEWLLAG (SEQ ID NO: 33, i.e., positions 1 to 29 of SEQ ID NO: 6);

[0090] Y-Aib-QGTFTSDYSILLDKKAQRDFIEWLLAG (SEQ ID NO: 34, i.e., positions 1 to 29 of SEQ ID NO: 7);

[0091] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLAG (SEQ ID NO: 35, i.e., positions 1 to 29 of SEQ ID NO: 8);

[0092] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQQDFIEWLLAG (SEQ ID NO: 36, i.e., positions 1 to 29 of SEQ ID NO: 9);

[0093] Y-Aib-QGTFTSDYSIYLDKKAQRAFVEWLLAQ (SEQ ID NO: 37, i.e., positions 1 to 29 of SEQ ID NO: 10);

[0094] Y-Aib-QGTFTSDYSIYLDEKAAKEFIEWLESA (SEQ ID NO: 11);

[0095] Y-Aib-QGTFTSDYSIALDKKAQREFVEWLLSA (SEQ ID NO: 38, i.e., positions 1 to 29 of SEQ ID NO: 12);

[0096] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQRDFIEWLLAG (SEQ ID NO: 39, i.e., positions 1 to 29 of SEQ ID NO: 13);

[0097] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQRDFIEWLLEG (SEQ ID NO: 40, i.e., positions 1 to 29 of SEQ ID NO: 14);

[0098] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLEG (SEQ ID NO: 41, i.e., positions 1 to 29 of SEQ ID NO: 15);

[0099] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAAHEFIEWLLAG (SEQ ID NO: 42, i.e., positions 1 to 29 of SEQ ID NO: 16);

[0100] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEKAAQEFIEWLLAG (SEQ ID NO: 43, i.e., positions 1 to 29 of SEQ ID NO: 17);

[0101] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSIYLDKKAQQDFIEWLLEG (SEQ ID NO: 44, i.e., positions 1 to 29 of SEQ ID NO: 18);

[0102] Y-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLAG (SEQ ID NO: 45, i.e., positions 1 to 29 of SEQ ID NO: 19);

[0103] H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKIAAKDFIEWLLEG (SEQ ID NO: 46, i.e., positions 1 to 29 of SEQ ID NO: 20);

[0104] H-Aib-QGTFTSDYSILLDKIAAKDFIEWLLEG (SEQ ID NO: 47, i.e., positions 1 to 29 of SEQ ID NO: 21);

[0105] H-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQQDFIEWLLEG (SEQ ID NO: 48, i.e., positions 1 to 29 of SEQ ID NO: 22);

[0106] H-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQHDFIEWLLEG (SEQ ID NO: 49, i.e., positions 1 to 29 of SEQ ID NO: 23);

[0107] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAAKDFIEWLLEG (SEQ ID NO: 50, i.e., positions 1 to 29 of SEQ ID NO: 24);

[0108] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAQKAFIEYLLEG (SEQ ID NO: 51, i.e., positions 1 to 29 of SEQ ID NO: 25);

[0109] H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAAKAFIEYLLEG (SEQ ID NO: 52, i.e., positions 1 to 29 of SEQ ID NO: 26);

[0110] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQQDFIEWLLEG (SEQ ID NO: 53, i.e., positions 1 to 29 of SEQ ID NO: 27);

[0111] H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRIAAKDFIEWLLEG (SEQ ID NO: 54, i.e., positions 1 to 29 of SEQ ID NO: 28);

[0112] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRAFIEYLLAG (SEQ ID NO: 55, i.e., positions 1 to 29 of SEQ ID NO: 29);

[0113] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRAFIEWLLAG (SEQ ID NO: 56, i.e., positions 1 to 29 of SEQ ID NO: 30); or

[0114] Y-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRAFIEWLLAG (SEQ ID NO: 57, i.e., positions 1 to 29 of SEQ ID NO: 31);

[0115] The lysine at position 17 and / or position 20 is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γGlu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18;

[0116] Furthermore, R1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (GPSSGAPPPS, SEQ ID NO: 2), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (PSSGAPPPS, SEQ ID NO: 3), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (PSSGAPPS, SEQ ID NO: 4) or absent.

[0117] In some embodiments, Formula I is the following sequence:

[0118] YSQGTFTSDYSILLDKKAQRDFIEWLLAGGGPSSGAPPPS(SEQ ID NO: 5);

[0119] Y(dS)QGTFTSDYSILLDKKAQRDFIEWLLAGPPSGAPPPS(SEQ ID NO: 6);

[0120] Y-Aib-QGTFTSDYSILLDKKAQRDFIEWLLAGPGPSSGAPPPS (SEQ ID NO: 7);

[0121] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLAGPSSGAP PPS (SEQ IDNO: 8);

[0122] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQQDFIEWLLAGPPSGAP PPS (SEQ IDNO: 9);

[0123] Y-Aib-QGTFTSDYSIYLDKKAQRAFVEWLLAQGPSSGAPPPS (SEQ ID NO: 10);

[0124] Y-Aib-QGTFTSDYSIYLDEKAAKEFIEWLESA (SEQ ID NO: 11);

[0125] Y-Aib-QGTFTSDYSIALDKKAQREFVEWLLSAGPSSGAPPPS (SEQ ID NO: 12);

[0126] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQRDFIEWLLAGGPSSGAP PPS(SEQ IDNO:13);

[0127] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQRDFIEWLLEGGPSSGAPP PS(SEQ IDNO:14);

[0128] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLEGGPSSGAP PPS(SEQ IDNO:15);

[0129] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAAHEFIEWLLAGGPSSGAP PPS(SEQ IDNO:16);

[0130] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEKAAQEFIEWLLAGGPSSGAPP PS(SEQ IDNO:17);

[0131] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSIYLDKKAQDFFIEWLLEGGPSSGAP PPS(SEQ IDNO:18);

[0132] Y-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLAGGPSSGAP PPS(SEQ IDNO:19);

[0133] H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKIAAKDFIEWLLEGGPSSGAPP PS(SEQ IDNO:20);

[0134] H-Aib-QGTFTSDYSILLDKIAAKDFIEWLLEGGPSSGAPPPS(SEQ ID NO: 21);

[0135] H-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQDFIEWLLEGGPSSGAP PPS(SEQ IDNO:22);

[0136] H-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQHDFIEWLLEGPSSGAP PPS (SEQ IDNO: 23);

[0137] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAAKDFIEWLLEGPSSGAPP PS (SEQ IDNO: 24);

[0138] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAQKAFIEYLLEGPGPSSGAPPP S (SEQ IDNO: 25);

[0139] H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAAKAFIEYLLEGGPSSGAPP PS (SEQ IDNO: 26);

[0140] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQQDFIEWLLEGPSSGAP PPS (SEQ IDNO: 27);

[0141] H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRIAAKDFIEWLLEGPSSGAPP PS (SEQ IDNO: 28);

[0142] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRAFIEYLLAGGPSSGAPP PS (SEQ IDNO: 29);

[0143] or

[0144] Y-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRAFIEWLLAGPSSGAP PPS (SEQ IDNO: 31);

[0145] The lysine at position 17 and / or position 20 is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γGlu) b-CO-(CH2) c -CO2H is conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18.

[0146] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0147] YSQGTFTSDYSILLDKKAQRDFIEWLLAGPGPSSGAPPPS (SEQ ID NO: 5).

[0148] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0149] YSQGTFTSDYSILLDKKAQRDFIEWLLAGPGPSSGAPPPS(SEQ ID NO: 5),

[0150] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0151] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0152] Y(dS)QGTFTSDYSILLDKKAQRDFIEWLLAGPPSGAPPPS(SEQ ID NO: 6),

[0153] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0154] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0155] Y-Aib-QGTFTSDYSILLDKKAQRDFIEWLLAGPGPSSGAPPPS (SEQ ID NO: 7),

[0156] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0157] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0158] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLAGPSSGAP PPS (SEQ IDNO: 8),

[0159] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0160] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0161] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLAGPSSGAP PPS (SEQ IDNO: 8),

[0162] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0163] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0164] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQQDFIEWLLAGPSSGAP PPS (SEQ IDNO: 9),

[0165] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0166] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0167] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQQDFIEWLLAGPSSGAP PPS (SEQ IDNO: 9),

[0168] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0169] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0170] Y-Aib-QGTFTSDYSIYLDKKAQRAFVEWLLAQGPSSGAPPPS (SEQ ID NO: 10),

[0171] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0172] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0173] Y-Aib-QGTFTSDYSIYLDEKAAKEFIEWLESA (SEQ ID NO: 11),

[0174] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0175] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0176] Y-Aib-QGTFTSDYSIALDKKAQREFVEWLLSAGPSSGAPPPS (SEQ ID NO: 12),

[0177] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0178] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0179] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQRDFIEWLLAGPPSGAP PPS (SEQ IDNO: 13),

[0180] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0181] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0182] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQRDFIEWLLEGPSSGAPP PS (SEQ IDNO: 14),

[0183] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0184] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0185] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLEGPSSGAP PPS (SEQ IDNO: 15),

[0186] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0187] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0188] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLEGPSSGAP PPS (SEQ IDNO: 15),

[0189] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0190] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0191] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLEGPSSGAP PPS (SEQ IDNO: 15),

[0192] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 18 -CO2H is conjugated to the ε-amino group of the K side chain.

[0193] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0194] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAAHEFIEWLLAGPPSGAP PPS (SEQ IDNO: 16),

[0195] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0196] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0197] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEKAAQEFIEWLLAGPGPSSGAPP PS (SEQ IDNO: 17),

[0198] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0199] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0200] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSIYLDKKAQQDFIEWLLEGPSSGAP PPS (SEQ IDNO: 18),

[0201] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 16-CO2H is conjugated to the ε-amino group of the K side chain.

[0202] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0203] Y-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLAGPSSGAP PPS (SEQ IDNO: 19),

[0204] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0205] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0206] Y-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLAGPSSGAP PPS (SEQ IDNO: 19),

[0207] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0208] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0209] Y-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLAGPSSGAP PPS (SEQ IDNO: 19),

[0210] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 18 -CO2H is conjugated to the ε-amino group of the K side chain.

[0211] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0212] H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKIAAKDFIEWLLEGPSSGAPP PS (SEQ IDNO: 20),

[0213] The K at position 20 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0214] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0215] H-Aib-QGTFTSDYSILLDKIAAKDFIEWLLEGPSSGAPPPS (SEQ ID NO: 21),

[0216] The K at position 20 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0217] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0218] H-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQQDFIEWLLEGPSSGAP PPS (SEQ IDNO: 22),

[0219] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0220] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0221] H-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQQDFIEWLLEGPSSGAP PPS (SEQ IDNO: 22),

[0222] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 18 -CO2H is conjugated to the ε-amino group of the K side chain.

[0223] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0224] H-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQHDFIEWLLEGPSSGAP PPS (SEQ IDNO: 23),

[0225] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain.

[0226] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0227] H-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQHDFIEWLLEGPSSGAP PPS (SEQ IDNO: 23),

[0228] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 18 -CO2H is conjugated to the ε-amino group of the K side chain.

[0229] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0230] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAAKDFIEWLLEGPSSGAPP PS (SEQ IDNO: 24),

[0231] The K at position 20 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 18 -CO2H is conjugated to the ε-amino group of the K side chain.

[0232] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0233] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAQKAFIEYLLEGPGPSSGAPPP S (SEQ IDNO: 25),

[0234] The K at position 20 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 18 -CO2H is conjugated to the ε-amino group of the K side chain.

[0235] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0236] H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAAKAFIEYLLEGPGPSSGAPP PS (SEQ IDNO: 26),

[0237] The K at position 20 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 18 -CO2H is conjugated to the ε-amino group of the K side chain.

[0238] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0239] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQQDFIEWLLEGPSSGAP PPS (SEQ IDNO: 27),

[0240] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 18 -CO2H is conjugated to the ε-amino group of the K side chain.

[0241] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0242] H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRIAAKDFIEWLLEGPSSGAPP PS (SEQ IDNO: 28),

[0243] The K at position 20 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 18 -CO2H is conjugated to the ε-amino group of the K side chain.

[0244] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0245] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRAFIEYLLAGGPSSGAPP PS (SEQ IDNO: 29),

[0246] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 18 -CO2H is conjugated to the ε-amino group of the K side chain;

[0247] Optionally, the C-terminal amino acid of SEQ ID NO: 29 is amidated.

[0248] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0249] Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRAFIEWLLAGPSSGAP PPS (SEQ IDNO: 30),

[0250] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 18 -CO2H is conjugated to the ε-amino group of the K side chain;

[0251] Optionally, the C-terminal amino acid of SEQ ID NO: 30 is amidated.

[0252] In one embodiment, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0253] Y-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRAFIEWLLAGPSSGAP PPS (SEQ IDNO: 31),

[0254] The K at position 17 has the following chemical modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 18 -CO2H is conjugated to the ε-amino group of the K side chain;

[0255] Optionally, the C-terminal amino acid of SEQ ID NO: 31 is amidated.

[0256] The compounds of the present invention can be formed by reacting the peptide with any one of a variety of inorganic acids and organic acids to form a pharmaceutically acceptable acid addition salt. Pharmaceutically acceptable salts and common methods for preparing them are well known in the art. See, for example, P. Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, Second Revised Edition (Wiley VCH, 2011); SM Berge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977. Pharmaceutically acceptable salts of the present invention include hydrochlorides, bromates, sulfates, nitrates, perchlorates, fumarates, maleates, phosphates, glycolates, lactates, salicylates, succinates, toluene-p-sulfonates, tartrates, acetates, citrates, methanesulfonates, formates, benzoates, malonates, benzenesulfonates, trifluoroacetates, etc.

[0257] In another aspect, the present invention provides a method for preparing the compound.

[0258] The compounds of the present invention can be synthesized according to their sequences and fatty acid side chain structures by methods known in the art, such as by using an automatic peptide synthesizer in a solid phase or liquid phase method step by step or by fragment assembly, and then the target compound can be obtained by separation and purification.

[0259] In another aspect, the present invention provides the compounds as agonists of GLP-1, GCG and GIP receptors.

[0260] The compound according to the present invention has triple activity of GLP-1, GCG and GIP receptors.

[0261] In another aspect, the present invention also provides a composition comprising the compound of the present invention.

[0262] In some embodiments, the composition is a pharmaceutical composition.

[0263] In some embodiments, the composition further comprises a pharmaceutically acceptable carrier, diluent or excipient. A pharmaceutically acceptable carrier, diluent or excipient is not a necessary active ingredient in itself and is not excessively toxic after administration; suitable carriers, diluents or excipients are well known to those of ordinary skill in the art. Pharmaceutically acceptable carriers may include adhesives, lubricants, disintegrants, solubilizers, dispersants, stabilizers, suspending agents, colorants, flavoring agents, buffers, solubilizers, isotonic agents, and the like.

[0264] In another aspect, the present invention also provides a therapeutic kit comprising a compound of the present invention and a device comprising a compound of the present invention.

[0265] On the other hand, the present invention also provides use of the compound and / or composition of the present invention in the preparation of a medicament for treating and / or preventing metabolic disorders.

[0266] In another aspect, the present invention also provides a method for preventing and / or treating metabolic disorders in a subject, comprising administering the compound and / or composition of the present invention to the subject.

[0267] In some embodiments, the metabolic disorder comprises diabetes, diabetes-related disorders, obesity, fatty liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, dyslipidemia, and metabolic syndrome-related disorders.

[0268] In some embodiments, diabetes includes type I diabetes, type II diabetes.

[0269] In some embodiments, diabetes-related disorders include insulin resistance, glucose intolerance, elevated fasting blood glucose, prediabetes, gestational diabetes, hypertension, dyslipidemia, bone-related disorders, and the like.

[0270] In some embodiments, diabetes-related diseases also include arteriosclerosis, coronary heart disease, peripheral arterial disease, stroke, dyslipidemia, increased blood pressure, thrombosis, etc.

[0271] In some embodiments, dyslipidemia includes high triglycerides, low HDL cholesterol, high LDL cholesterol, and plaque buildup in the arterial walls.

[0272] Compared with the prior art, the beneficial effects of the present invention include:

[0273] The compounds provided by the present invention, or their pharmaceutically acceptable salts or solvates have strong agonist activity on the glucagon-like peptide-1 (GLP-1) receptor, glucagon (GCG) receptor and glucose-dependent incretin (GIP) receptor and can therefore be used to treat related metabolic syndromes. BRIEF DESCRIPTION OF THE DRAWINGS

[0274] Various other advantages and benefits will become apparent to those of ordinary skill in the art by reading the detailed description of the preferred embodiments below. The accompanying drawings are only used for the purpose of illustrating the preferred embodiments and are not to be considered as limiting the present invention. In the accompanying drawings:

[0275] Figure 1: Blood glucose concentration-time curves of C57BL / 6 mice 24 hours after a single administration of Semaglutide, HEC-PT26, HEC-PT49, and HEC-PT50;

[0276] Figure 2 : Blood glucose concentration-time curves of C57BL / 6 mice 72 hours after administration of Semaglutide, HEC-PT26, HEC-PT49, and HEC-PT50;

[0277] Figure 3 : Blood glucose concentration-time curve of C57BL / 6 mice 24 hours after single administration of HEC-PT47 and HEC-PT48;

[0278] Figure 4 :Effects of long-term administration of HEC-PT26 on blood glucose in db / db mice;

[0279] Figure 5 : Effects of single administration of HEC-PT26, HEC-PT49, and HEC-PT50 on blood glucose in db / db mice;

[0280] Figure 6 : Effects of single administration of HEC-PT26, HEC-PT49, and HEC-PT50 on the body weight of db / db mice;

[0281] Figure 7 : Effects of single administration of HEC-PT26, HEC-PT49, and HEC-PT50 on food intake in db / db mice;

[0282] Figure 8 :Effects of long-term administration of HEC-PT47, HEC-PT50, and HEC-PT61 on the body weight growth rate of DIO mice;

[0283] Fig. 9 : Effects of long-term administration of HEC-PT47, HEC-PT50, and HEC-PT61 on the cumulative food intake of DIO mice;

[0284] Fig.10 : Effects of long-term administration of HEC-PT47, HEC-PT50, and HEC-PT61 on liver weight in DIO mice;

[0285] Fig.11 : Effects of long-term administration of HEC-PT47, HEC-PT50, and HEC-PT61 on liver indexes in DIO mice. DETAILED DESCRIPTION

[0286] The exemplary embodiments of the present disclosure will be described in more detail below with reference to the accompanying drawings. Although the exemplary embodiments of the present disclosure are shown in the accompanying drawings, it should be understood that the present disclosure can be implemented in various forms and should not be limited by the embodiments described herein. On the contrary, these embodiments are provided in order to enable a more thorough understanding of the present disclosure and to fully convey the scope of the present disclosure to those skilled in the art.

[0287] In the present invention, the conventional single-letter and three-letter codes of natural amino acids are used, as well as the generally accepted three-letter codes of other (unnatural) amino acids, for example, Aib (2-aminoisobutyric acid). Unless explicitly stated, all amino acid residues of the present invention are preferably in the L-configuration, for example, dS represents D-type Ser.

[0288]

[0289] Example 1

[0290] This embodiment provides a method for synthesizing the compound of the present invention.

[0291] 1. Solid phase peptide synthesis on a peptide synthesizer: Place the resin in a 150 ml reactor and add 50 ml of dichloromethane (DCM) to soak for 2 hours. Wash the resin with N, N-dimethylformamide (DMF) and then drain it. Repeat this four times and drain the resin. Weigh the first amino acid (protected) at the Fmoc-C terminal + DCM + N, N-diisopropylethylamine (DIEA) and add it to the reactor, then place the reactor in a shaker at 30°C for 2 hours. Block with methanol solution (methanol: DIEA: DCM = 1:1:2) for half an hour, then wash four times with DMF and drain. Add 20% piperidine solution to the reactor to remove the Fmoc protecting group. After deprotection, wash four times with DMF and then drain.

[0292] 2. Weigh the second amino acid (protected) at the C-terminus of Fmoc + 1-hydroxybenzotriazole (HOBT) + N,N'-diisopropylcarbodiimide (DIC) and add them to the reactor, then place the reactor in a shaker at 30°C for 1 hour. Take a small amount of resin for testing, and use the ninhydrin method to test. If the resin has color, it means that the condensation is incomplete, and continue the reaction; after the reaction is complete, wash the resin four times with DMF, and then drain it. Add a certain amount of 20% piperidine (piperidine / DMF = 1:4) to the reactor, and shake it on a decolorizing shaker for 20 minutes to remove the Fmoc protecting group on the resin. After deprotection, wash it four times with DMF, then drain it to check whether the protection is removed.

[0293] 3. Connect the amino acids in sequence according to step 2. For Lys that needs to be connected to the fatty acid side chain, use specially protected raw materials, add Boc anhydride to protect the N-terminal amino group, remove the special protecting group of the Lys side chain, and connect the side chain structure according to step 2. Use a cleavage reagent to remove all the polypeptide protecting groups, cut it off from the resin, and send it for purification.

[0294] 4. After the target peptide is synthesized, the target peptide is separated from the impurities by reverse phase liquid chromatography purification, the collected target peptide is lyophilized into powder, and sent to QC for quality inspection and purity and mass spectrometry identification. After HPLC detection, the purity is greater than 95%. The molecular weight of the polypeptide identified by mass spectrometry is consistent with the theoretical molecular weight. Table 1 shows the synthesized compounds.

[0295] Table 1

[0296]

[0297]

[0298] Wherein, B is 2-aminoisobutyric acid (Aib), dS represents D-type Ser; and X is (L)-α-Me-(2-F)-Phe.

[0299] The general structure of a fatty acid chain is as follows:

[0300] ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γGlu) b -CO-(CH2) c -CO2H, conjugated to the ε-amino group of the corresponding K side chain in the polypeptide backbone; wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18; the partial side chain structure is shown below, wherein ---- shows the connection point between the fatty acid chain and the lysine side chain:

[0301] When a is 1, b is 1, and c is 16, the fatty acid chain structure is -OEG-γGlu-CO-(CH2) 16 -CO2H, the specific structure is as follows:

[0302]

[0303] When a is 1, b is 1, and c is 18, the fatty acid chain structure is -OEG-γGlu-CO-(CH2) 18 -CO2H, the specific structure is as follows:

[0304]

[0305] When a is 2, b is 1, and c is 16, the fatty acid chain structure is -OEG-OEG-γGlu-CO-(CH2) 16-CO2H, the specific structure is as follows:

[0306]

[0307] When a is 2, b is 1, and c is 18, the fatty acid chain structure is -OEG-OEG-γGlu-CO-(CH2) 18 -CO2H, the specific structure is as follows:

[0308]

[0309] Example 2

[0310] This example provides a method for determining the in vitro cell activity of a compound

[0311] The specific steps are as follows:

[0312] 1. Prepare Assay buffer: Take complete culture medium (DMEM medium + 10% FBS), add 4 / 1000 of 500mM IBMX mother solution, cAMP-d2 working solution and anti-cAMP-crytate working solution according to the instructions of the kit;

[0313] 2. Dilute the test samples and human control peptides GLP-1 (SEQ ID NO: 58), GCG (SEQ ID NO: 59) and GIP (SEQ ID NO: 60) to a stock solution with an initial concentration of 500 nM, and then dilute them in a gradient by adding 20 μL to 80 μL Assay buffer (diluted 5 times), including the stock solution for a total of 8 compound gradients;

[0314] 3. Preparation of cell suspension: After taking out the frozen HEK293-GLP-1R, HEK293-GCGR and HEK293-GIPR cells from the liquid nitrogen tank, immediately place them in a 37°C water bath. After they are completely thawed within 1.5 min, add the cells dropwise into a 15 mL centrifuge tube containing 8 mL of warm culture medium on a clean bench. Centrifuge at 900 rpm for 5 min, discard the supernatant, resuspend the cells in 1 mL of complete culture medium (pump 15 times), immediately take 20 μL of the suspension and mix it with an equal volume of trypan blue. Take 20 μL to calculate the number of viable cells and dilute the cells to 4 × 10 5 cells / mL;

[0315] 4. Divide the 384-well plate into GLP-1R cell, GCGR cell and GIPR cell areas, use a 12-channel adjustable dispenser to add the cell suspension to the wells in the corresponding area at 5 μL per well, and then use a 12-channel adjustable dispenser to add the test sample and positive control sample gradient dilutions to the 384-well plate of the corresponding cells, 5 μL per well (the same concentration sample is parallel to 2 replicate wells); negative control: 10 μL assay buffer / each well, set 3 wells on each 384-well plate, cover with a white sealing film, put into a 37°C constant temperature incubator, and take out after half an hour;

[0316] 5. Before use, dilute the cAMP-d2 working solution and anti-cAMP-crytate working solution 20 times with the lysis buffer in the kit, and mix them evenly in a ratio of 1:1 to prepare a mixed solution of cAMP detection reagent. Add 10 μL of the mixed solution of cAMP detection reagent to each well of the sample group, and add 5 μL of lysis buffer and 5 μL of the diluted anti-cAMP-crytate working solution to each well of the negative control. Cover with a white lid and place at room temperature away from light for 1 hour.

[0317] 6. The fluorescence values ​​at 665 nm and 620 nm were detected in a multifunctional microplate reader. In GraphPad Prism 6, the signal ratio and sample concentration were nonlinearly fitted using a four-parameter equation to obtain the EC50 value. The specific results are shown in Table 2.

[0318] Table 2 Results of in vitro cell activity assay of polypeptide compounds

[0319]

[0320]

[0321] Example 3

[0322] This example evaluates the effects of HEC-PT26, HEC-PT49, and HEC-PT50 on glucose tolerance in normal C57BL / 6 mice.

[0323] Experimental methods: Normal C57BL / 6 mice were randomly divided into 5 groups (control group, Semaglutide group, HEC-PT26 group, HEC-PT49 group, HEC-PT50 group) according to blood sugar and body weight, with 8 mice in each group. For the Semaglutide group, HEC-PT26 group, HEC-PT49 group and HEC-PT50 group, each group of animals was subcutaneously injected with the corresponding drug, and the dosage was 3nmol / kg; for the control group, the corresponding solvent was subcutaneously injected.

[0324] After a single dose of 12 hours, the animals were fasted for 12 hours and allowed to drink water freely. Blood was collected from the tail vein to determine the basal blood glucose values ​​of each group of animals. Then 2g / kg glucose solution was intraperitoneally injected, and blood glucose was tested at 15, 30, and 60 minutes after glucose administration. The blood glucose concentration-time curve was drawn based on the blood glucose values ​​measured at different time points, and the AUC of each dose group was calculated. 0～60min , as shown in Table 3 and Figure 1 shown.

[0325] After a single administration for 60 hours, the animals were fasted for 12 hours and allowed to drink water freely. Blood was collected from the tail vein to determine the basal blood glucose value of each group of animals, followed by intraperitoneal injection of 2g / kg glucose solution, and blood glucose was tested at 15, 30, 60, and 90 minutes after glucose administration. The blood glucose concentration-time curve was drawn based on the blood glucose values ​​measured at different time points, and the AUC of each dose group was calculated. 0～90min As shown in Table 4 and Figure 2 shown.

[0326] Experimental results:

[0327] Table 3: Effects of single administration of HEC-PT26, HEC-PT49, and HEC-PT50 on glucose tolerance in normal C57 mice 24 hours after administration

[0328]

[0329] Table 4: Effects of single administration of HEC-PT26, HEC-PT49, and HEC-PT50 on glucose tolerance in normal C57 mice 72 hours after administration

[0330]

[0331] Experimental conclusion: 24 hours after a single administration, HEC-PT26, HEC-PT49, and HEC-PT50 can significantly reduce the blood glucose level of normal C57 mice, and the effect is equivalent to Semaglutide; 72 hours after a single administration, HEC-PT26, HEC-PT49, and HEC-PT50 can significantly reduce the blood glucose level of normal C57 mice.

[0332] Example 4

[0333] This example evaluates the effects of HEC-PT47 and HEC-PT48 on glucose tolerance in normal C57BL / 6 mice.

[0334] Experimental method: Normal C57BL / 6 mice were divided into 4 groups (control group, HEC-PT47 group, HEC-PT48 group) according to blood sugar and body weight, with 8 mice in each group. For HEC-PT47 group and HEC-PT48 group, each group was subcutaneously injected with corresponding drugs, and the dosage was 3nmol / kg; for the control group, the corresponding solvent was subcutaneously injected.

[0335] After a single dose of 12 hours, the animals were fasted for 12 hours and allowed to drink water freely. Blood was collected from the tail vein to determine the basal blood glucose value of each group of animals, followed by intraperitoneal injection of 2g / kg glucose solution, and blood glucose was tested 15, 30, and 60 minutes after glucose administration. The blood glucose concentration-time curve was drawn according to the blood glucose values ​​measured at different time points, and the AUC of each dose group was calculated. 0～60min ,like Figure 3 And as shown in Table 5.

[0336] Experimental results:

[0337] Table 5: Effects of single administration of HEC-PT47 and HEC-PT48 on glucose tolerance in normal C57 mice 24 hours after administration

[0338]

[0339] Experimental conclusion: HEC-PT47 and HEC-PT48 can significantly reduce the blood glucose level of normal C57 mice.

[0340] Example 5

[0341] This example evaluates the effect of HEC-PT26 on blood glucose in db / db mice.

[0342] Experimental methods: 7-8 week old db / db mice were randomly divided into 4 groups (Model group, LY3298176 group, Semaglutide group, HEC-PT26 group) according to blood glucose and body weight values, with 8 mice in each group. For the LY3298176 group, Semaglutide group and HEC-PT26 group, each group of animals was subcutaneously injected with the corresponding drug, and the dose of each administration was 10nmol / kg; for the Model group, the corresponding solvent was subcutaneously injected. The Semaglutide group was administered once a day, and the LY3298176 group and the HEC-PT26 group were administered once every 3 days for a total of 4 weeks; the blood glucose of the animals was tested before each administration.

[0343] Experimental results: HEC-PT26 group was able to significantly reduce blood sugar after administration, and the blood sugar level reached the lowest level at 24 hours, which was better than the positive control Semaglutide and LY3298176 at the same dose. Compared with the Model, the blood sugar level of mice in the HEC-PT26 group was significantly reduced after long-term repeated administration and remained stable for a long time. Its hypoglycemic effect was similar to that of the Semaglutide group and better than that of the LY3298176 group. The specific data are shown in Table 6 and Figure 4 .

[0344] Table 6: Effects of long-term administration of HEC-PT26 on blood glucose in db / db mice

[0345]

[0346] Experimental conclusion: Long-term administration of HEC-PT26 can significantly improve the blood glucose level of type 2 diabetes model db / db mice.

[0347] Example 6

[0348] This example evaluates the effects of a single administration of HEC-PT47, HEC-PT48, and HEC-PT50 on blood glucose and body weight in db / db mice.

[0349] Experimental methods: After 1 week of adaptive feeding, 6-7 week old db / db mice were randomly divided into 4 groups (Semaglutide group, HEC-PT47 group, HEC-PT48 group, HEC-PT50 group) according to body weight and blood glucose level, with 5 mice in each group; starting from the second week, a single subcutaneous injection was given to each group, with a dose of 10nmol / kg. Blood glucose, body weight and food intake of each group of animals were tested before and after administration. The test results are shown in Tables 7-9 and Figure 5-7 .

[0350] Table 7: Effects of single administration of HEC-PT47, HEC-PT48, and HEC-PT50 on blood glucose in db / db mice

[0351]

[0352] Table 8: Effects of single administration of HEC-PT47, HEC-PT48, and HEC-PT50 on body weight of db / db mice

[0353]

[0354] Table 9: Effects of single administration of HEC-PT47, HEC-PT48, and HEC-PT50 on food intake in db / db mice

[0355]

[0356]

[0357] Experimental results: Blood glucose test results showed that after a single administration of HEC-PT47, HEC-PT48, and HEC-PT50, the blood glucose of db / db mice decreased significantly within 48 hours, and the blood glucose peaked at about 96 hours and remained relatively constant. HEC-PT47, HEC-PT48, and HEC-PT50 also had a significant effect on the body weight of db / db mice within 3 days after administration, and the body weight growth rate was reduced; moreover, the effect of a single administration on the food intake of db / db mice was better than that of the positive drug Semaglutide at the same dose.

[0358] Example 7

[0359] This example evaluates the effects of long-term repeated administration of HEC-PT47, HEC-PT50 and HEC-PT61 on body weight and food intake in DIO obese mice.

[0360] Experimental methods: C57 / BL6 mice were randomly divided into normal group NFD and model group HFD at the fifth week of age. The normal group was fed with ordinary maintenance feed, while the other groups were fed with high-fat feed D12492. The changes in body weight and food intake of mice were monitored every 3 weeks. After 16 weeks of feeding, the body weights of mice in the model group and normal group were (47.7±3.1) g and (30.9±2.3) g, respectively, and the difference between the two groups was statistically significant. The normal group was divided into the Control group (subcutaneous injection of PBS); the model group mice with successful modeling were divided into the Vehicle group, Semaglutide group, HEC-PT47 group, HEC-PT50 group, and HEC-PT61 group, with 10 mice in each group. For the Semaglutide group, HEC-PT47 group, HEC-PT50 group, and HEC-PT61 group, each group of animals was given subcutaneous injection of the corresponding drugs; for the Vehicle group, PBS was subcutaneously injected. After the first administration, the animals were observed for 7 days, and then each group was administered once every 3 days, with the dose of each group being 10 nmol / kg. Body weight and food intake were tested before each administration. After 3 weeks of administration, an intraperitoneal glucose tolerance test was performed, and samples were collected and slaughtered 72 hours after the last administration. The liver weight was recorded, and the liver pathological conditions and blood biochemical indicators of each group were tested. The test results are shown in Tables 10-13 and Figure 8-11 .

[0361] Table 10: Effects of long-term administration of HEC-PT47, HEC-PT50, and HEC-PT61 on body weight of DIO mice

[0362]

[0363]

[0364] Note: The lowercase letter a in the same column indicates significant difference (P<0.05).

[0365] Table 11: Effects of long-term administration of HEC-PT47, HEC-PT50, and HEC-PT61 on food intake in DIO mice

[0366]

[0367] Note: Lowercase letters in the same column indicate significant differences (P<0.05).

[0368] Table 12: Effects of long-term administration of HEC-PT47, HEC-PT50, and HEC-PT61 on body weight and liver index of DIO mice

[0369] Group Body mass / g Liver / g Liver index / % Control <![CDATA[29.1±2.2 a ]]> <![CDATA[1.0±0.1 a ]]> <![CDATA[3.5±0.0 a ]]> Vehicle 48.0±1.9 2.0±0.4 4.1±0.0 Semaglutide <![CDATA[41.0±4.3 a ]]> <![CDATA[1.1±0.2 a ]]> <![CDATA[2.6±0.0 a ]]> HEC-PT47 <![CDATA[30.5±2.2 a ]]> <![CDATA[1.5±0.1 a ]]> <![CDATA[5.0±0.0 a ]]> HEC-PT50 <![CDATA[34.0±2.0 a ]]> <![CDATA[1.0±0.1 a ]]> <![CDATA[2.8±0.0 a ]]> HEC-PT61 <![CDATA[31.8±3.3 a ]]> <![CDATA[0.9±0.1 a ]]> <![CDATA[2.8±0.0 a ]]>

[0370] Note: Lowercase letters in the same column indicate significant differences (P<0.05).

[0371] Table 13: Effects of long-term administration of HEC-PT47, HEC-PT50, and HEC-PT61 on liver function and blood lipids in DIO mice

[0372]

[0373]

[0374] Note: Lowercase letters in the same column indicate significant differences (P<0.05).

[0375] Experimental results: After 4 weeks of administration, the weight loss effect of HEC-PT47, HEC-PT50, and HEC-PT61 was significantly better than that of the positive drug Semaglutide at the same dose and frequency. The control effect of HEC-PT47, HEC-PT50, and HEC-PT61 on the food intake of DIO mice was basically similar, and was significantly better than Semaglutide.

[0376] The above is only a preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention shall be based on the protection scope of the claims. Sequence Listing <110> Guangdong East Sunshine Pharmaceutical Co., Ltd. <120> Triple agonist of GLP-1, GCG and GIP receptors <150> 202110685293.1 <151> 2021-06-21 <160> 60 <170> PatentIn version 3.5 <210> 1 <211> 30 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (1) <223> Xaa is Tyr or His <220> <221> VARIANT <222> (2)..(2) <223> Xaa is Ser or Aib <220> <221> VARIANT <222> (3) <223> Xaa is Gln or His <220> <221> VARIANT <222> (6) <223> Xaa is Phe or α-Me-(2-F)-Phe <220> <221> VARIANT <222> (13) <223> Xaa is Leu, Tyr or Ala <220> <221> VARIANT <222> (16) <223> Xaa is Lys, Glu or Arg <220> <221> VARIANT <222> (17) <223> Xaa is Ile or unmodified or modified Lys: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the Lys side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <220> <221> VARIANT <222> (19)..(19) <223> Xaa is Gln or Ala <220> <221> VARIANT <222> (20)..(20) <223> Xaa is Arg, Gln, His or unmodified or modified Lys: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the Lys side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <220> <221> VARIANT <222> (21)..(21) <223> Xaa is Asp, Ala or Glu <220> <221> VARIANT <222> (23)..(23) <223> Xaa is Ile or Val <220> <221> VARIANT <222> (25)..(25) <223> Xaa is Trp or Tyr <220> <221> VARIANT <222> (27)..(27) <223> Xaa is Leu or Glu <220> <221> VARIANT <222> (28)..(28) <223> Xaa is Ala, Ser or Glu <220> <221> VARIANT <222> (29)..(29) <223> Xaa is Gly, Gln or Ala <220> <221> VARIANT <222> (30)..(30) <223> Xaa is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, or does not exist <400> 1 Xaa Xaa Xaa Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Xaa 1 5 10 15 Xaa Ala Xaa Xaa Xaa Phe Xaa Glu Xaa Leu Xaa Xaa Xaa Xaa 20 25 30 <210> 2 <211> 10 <212> PRT <213> Artificial Sequence <400> 2 Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser 1 5 10 <210> 3 <211> 9 <212> PRT <213> Artificial Sequence <400> 3 Pro Ser Ser Gly Ala Pro Pro Pro Ser 1 5 <210> 4 <211> 8 <212> PRT <213> Artificial Sequence <400> 4 Pro Ser Ser Gly Ala Pro Pro Ser 1 5 <210> 5 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 5 Tyr Ser Gln Gly Thr Phe Thr Ser Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Asp Phe Ile Glu Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 6 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> D type Ser <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 6 Tyr Ser Gln Gly Thr Phe Thr Ser Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Asp Phe Ile Glu Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 7 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 7 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Asp Phe Ile Glu Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 8 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 8 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Asp Phe Ile Glu Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 9 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 9 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Gln Asp Phe Ile Glu Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 10 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 10 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Ala Phe Val Glu Trp Leu Leu Ala Gln Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 11 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 11 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Lys Ala Ala Lys Glu Phe Ile Glu Trp Leu Glu Ser Ala 20 25 <210> 12 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 12 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ala Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Glu Phe Val Glu Trp Leu Leu Ser Ala 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> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 13 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Arg 1 5 10 15 Lys Ala Gln Arg Asp Phe Ile Glu Trp Leu Leu Ala Gly 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> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 14 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Arg 1 5 10 15 Lys Ala Gln Arg Asp Phe Ile Glu Trp Leu Leu Glu Gly 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> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 15 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Asp Phe Ile Glu Trp Leu Leu Glu Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 16 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 16 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Ala His Glu Phe Ile Glu Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 17 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 17 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Glu 1 5 10 15 Lys Ala Ala Gln Glu Phe Ile Glu Trp Leu Leu Ala Gly 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> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 18 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Lys Ala Gln Gln Asp Phe Ile Glu Trp Leu Leu Glu Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 19 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 19 Tyr Xaa His Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Asp Phe Ile Glu Trp Leu Leu Ala Gly 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> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (20)..(20) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 20 His Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Ile Ala Ala Lys Asp Phe Ile Glu Trp Leu Leu Glu Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> twenty one <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (20)..(20) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> twenty one His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Ile Ala Ala Lys Asp Phe Ile Glu Trp Leu Leu Glu Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> twenty two <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> twenty two His Xaa His Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Gln Asp Phe Ile Glu Trp Leu Leu Glu Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> twenty three <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> twenty three His Xaa His Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln His Asp Phe Ile Glu Trp Leu Leu Glu Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> twenty four <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (20)..(20) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> twenty four Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Glu 1 5 10 15 Ile Ala Ala Lys Asp Phe Ile Glu Trp Leu Leu Glu Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 25 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (20)..(20) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 25 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Glu 1 5 10 15 Ile Ala Gln Lys Ala Phe Ile Glu Tyr Leu Leu Glu Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 26 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (20)..(20) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 26 His Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Glu 1 5 10 15 Ile Ala Ala Lys Ala Phe Ile Glu Tyr Leu Leu Glu Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 27 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 27 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Arg 1 5 10 15 Lys Ala Gln Gln Asp Phe Ile Glu Trp Leu Leu Glu Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 28 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (20)..(20) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 28 His Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Arg 1 5 10 15 Ile Ala Ala Lys Asp Phe Ile Glu Trp Leu Leu Glu Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 29 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 29 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Ala Phe Ile Glu Tyr Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 30 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 30 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Ala Phe Ile Glu Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 31 <211> 39 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 31 Tyr Xaa His Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Ala Phe Ile Glu Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> 32 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 32 Tyr Ser Gln Gly Thr Phe Thr Ser Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Asp Phe Ile Glu Trp Leu Leu Ala Gly 20 25 <210> 33 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> D type Ser <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 33 Tyr Ser Gln Gly Thr Phe Thr Ser Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Asp Phe Ile Glu Trp Leu Leu Ala Gly 20 25 <210> 34 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 34 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Asp Phe Ile Glu Trp Leu Leu Ala Gly 20 25 <210> 35 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 35 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Asp Phe Ile Glu Trp Leu Leu Ala Gly 20 25 <210> 36 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 36 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Gln Asp Phe Ile Glu Trp Leu Leu Ala Gly 20 25 <210> 37 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 37 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Ala Phe Val Glu Trp Leu Leu Ala Gln 20 25 <210> 38 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 38 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ala Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Glu Phe Val Glu Trp Leu Leu Ser Ala 20 25 <210> 39 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 39 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Arg 1 5 10 15 Lys Ala Gln Arg Asp Phe Ile Glu Trp Leu Leu Ala Gly 20 25 <210> 40 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 40 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Arg 1 5 10 15 Lys Ala Gln Arg Asp Phe Ile Glu Trp Leu Leu Glu Gly 20 25 <210> 41 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <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 Arg Asp Phe Ile Glu Trp Leu Leu Glu Gly 20 25 <210> 42 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 42 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Ala His Glu Phe Ile Glu Trp Leu Leu Ala Gly 20 25 <210> 43 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 43 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Glu 1 5 10 15 Lys Ala Ala Gln Glu Phe Ile Glu Trp Leu Leu Ala Gly 20 25 <210> 44 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 44 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Lys Ala Gln Gln Asp Phe Ile Glu Trp Leu Leu Glu Gly 20 25 <210> 45 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 45 Tyr Xaa His Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Asp Phe Ile Glu Trp Leu Leu Ala Gly 20 25 <210> 46 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (20)..(20) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 46 His Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Ile Ala Ala Lys Asp Phe Ile Glu Trp Leu Leu Glu Gly 20 25 <210> 47 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (20)..(20) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 47 His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Ile Ala Ala Lys Asp Phe Ile Glu Trp Leu Leu Glu Gly 20 25 <210> 48 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 48 His Xaa His Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Gln Asp Phe Ile Glu Trp Leu Leu Glu Gly 20 25 <210> 49 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 49 His Xaa His Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln His Asp Phe Ile Glu Trp Leu Leu Glu Gly 20 25 <210> 50 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (20)..(20) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 50 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Glu 1 5 10 15 Ile Ala Ala Lys Asp Phe Ile Glu Trp Leu Leu Glu Gly 20 25 <210> 51 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (20)..(20) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 51 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Glu 1 5 10 15 Ile Ala Gln Lys Ala Phe Ile Glu Tyr Leu Leu Glu Gly 20 25 <210> 52 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (20)..(20) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 52 His Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Glu 1 5 10 15 Ile Ala Ala Lys Ala Phe Ile Glu Tyr Leu Leu Glu Gly 20 25 <210> 53 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 53 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Arg 1 5 10 15 Lys Ala Gln Gln Asp Phe Ile Glu Trp Leu Leu Glu Gly 20 25 <210> 54 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (20)..(20) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 54 His Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Arg 1 5 10 15 Ile Ala Ala Lys Asp Phe Ile Glu Trp Leu Leu Glu Gly 20 25 <210> 55 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 55 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Ala Phe Ile Glu Tyr Leu Leu Ala Gly 20 25 <210> 56 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 56 Tyr Xaa Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Ala Phe Ile Glu Trp Leu Leu Ala Gly 20 25 <210> 57 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> VARIANT <222> (2)..(2) <223> Xaa is 2-aminoisobutyric acid (Aib) <220> <221> VARIANT <222> (6) <223> Xaa is α-Me-(2-F)-Phe <220> <221> VARIANT <222> (17) <223> Lys is unmodified or has the following modification: ([2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γGlu)b-CO-(CH2)c-CO2H conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18 <400> 57 Tyr Xaa His Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys 1 5 10 15 Lys Ala Gln Arg Ala Phe Ile Glu Trp Leu Leu Ala Gly 20 25 <210> 58 <211> 31 <212> PRT <213> Homo sapiens <400> 58 His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 <210> 59 <211> 29 <212> PRT <213> Homo sapiens <400> 59 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 <210> 60 <211> 42 <212> PRT <213> Homo sapiens <400> 60 Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 1 5 10 15 Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys 20 25 30 Lys Asn Asp Trp Lys His Asn Ile Thr Gln 35 40

Claims

1. A compound, which is a peptide having the general formula I or a pharmaceutically acceptable salt thereof: Xaa1-Xaa2-Xaa3-Gly-Thr-Xaa6-Thr-Ser-Asp-Tyr-Ser-Ile-Xaa13-Leu-Asp-Xaa16-Xaa1 7-Ala-Xaa19-Xaa20-Xaa21-Phe-Xaa23-Glu-Xaa25-Leu-Xaa27-Xaa28-Xaa29-R1 (general formula I, SEQ ID NO: 1); in, Positions 1 to 29 of general formula I are the following sequence: H-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQHDFIEWLLEG (SEQ ID NO: 49); The lysine at position 17 is modified as follows: ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γGlu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18; R1 is GPSSGAPPPS (SEQ ID NO: 2), PSSGAPPPS (SEQ ID NO: 3), PSSGAPPS (SEQ ID NO: 4) or absent.

2. The compound according to claim 1, characterized in that General formula I is the following sequence: H-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQHDFIEWLLEGPSSGAPP PS (SEQ ID NO: 23); The lysine at position 17 is modified as follows: ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γGlu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, and c is 16 or 18.

3. Use of the compound according to any one of claims 1 to 2 for preparing agonists of GLP-1, GCG and GIP receptors.

4. A composition comprising the compound according to any one of claims 1-2.

5. The composition according to claim 4, characterized in that The composition also includes a pharmaceutically acceptable carrier, diluent or excipient.

6. Use of the compound according to any one of claims 1 to 2 and / or the composition according to any one of claims 4 to 5 in the preparation of a medicament for treating and / or preventing metabolic disorders; The metabolic disorder is selected from diabetes and obesity.

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