CN115572326A

CN115572326A - Triplex agonists of GLP-1, GCG and GIP receptors

Info

Publication number: CN115572326A
Application number: CN202210698013.5A
Authority: CN
Inventors: 蒋鹏; 周林俊; 雷丹; 肖�琳; 毛剑铭; 孙宁远; 蒋燕; 程晓莉; 李静; 曹小莲; 郭林峰; 李文佳
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Sunshine Lake Pharma Co Ltd
Priority date: 2021-06-21
Filing date: 2022-06-20
Publication date: 2023-01-06
Also published as: WO2022268029A1

Abstract

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

Description

Triplex agonists of GLP-1, GCG and GIP receptors

Technical Field

The invention relates to the field of biological medicines, in particular to a triple agonist of GLP-1, GCG and GIP receptors.

Background

At present, the number of diabetes mellitus patients in the world is 5.37 hundred million, the number of diabetes mellitus patients in China is nearly 1.4 hundred million, and the diabetes mellitus patients live at the first place of the world, so that the diabetes mellitus patients are one of the main disease burdens in China. While obese type II diabetics are the largest population of diabetics. Obesity disturbs the levels of insulin, sugar and blood lipids in blood, and is also easy to cause various metabolic diseases such as hypertension, non-alcoholic fatty liver disease and atherosclerosis besides type II diabetes, and a series of health problems are risk factors of cardiovascular diseases. At present, the medicines for treating type II diabetes in the market mainly focus on blood sugar reduction treatment, and the effect of reducing weight is very limited. The blood sugar reducing medicine can really bring more benefits and longer benefits only by paying attention to the blood sugar reducing effectiveness and considering the weight control.

Glucagon-like peptide-1 (GLP-1) is a polypeptide hormone secreted by intestinal L-cells after eating, and can stimulate pancreatic beta cells to secrete insulin, thereby stabilizing the fluctuation of postprandial blood sugar. The function of reducing blood sugar has glucose concentration dependency, and the risk of blood sugar is greatly reduced while blood sugar is regulated. GLP-1 based drugs, such as liraglutide, dolabrlutide and somagluteptide, have gradually taken a very important position in diabetes drugs in recent years. The GLP-1 medicines have the effect of losing weight when reducing blood sugar, and the mechanism is that GLP-1 acts on gastrointestinal tracts to delay gastric emptying and intestinal peristalsis, acts on a central nervous system to suppress appetite and the like, thereby reducing food intake and achieving the purpose of losing weight. However, when the GLP-1 receptor agonist drugs are used for losing weight, the dosage is generally large, gastrointestinal side effects are easy to generate, the tolerance is poor, the treatment window is narrow, and the weight reduction effect still does not completely meet the clinical requirement.

Glucagon (GCG) is a polypeptide hormone secreted by pancreatic islet alpha cells that promotes glycogenolysis and gluconeogenesis, resulting in a significant increase in blood glucose; simultaneously, the lipase can be activated, lipolysis is promoted, fatty acid oxidation is improved, energy consumption is increased, and therefore the effects of reducing fat and reducing weight are achieved. Because of its physiological action of increasing blood sugar, it can be used for treating hypoglycemia, but its application in obesity indication is limited by single-target treatment, and it is not suitable for obesity and type II diabetes obesity patient.

Glucose-dependent incretins (GIP) is a polypeptide hormone secreted by intestinal K cells. GIP and GLP-1 are intestinal hypoglycemic, can promote the secretion of insulin in a blood sugar concentration-dependent mode, and reduce blood sugar, and the blood sugar reducing effect mediated by GIP is even stronger than that of GLP-1. However, diabetic patients show GIP insensitivity, probably due to receptor tolerance by hyperglycemia, and thus the GIP receptor agonist alone does not achieve the goal of improving blood glucose in diabetic patients.

At present, most diabetes drugs on the market exist, but the low standard-reaching rate of diabetes treatment is still a difficult problem, and a great distance is left to cure diabetes, so that the development of new diabetes drugs is still far from the original way. By targeting multiple action targets, the disease symptoms are controlled in multiple directions, so that good clinical benefits are expected. Therefore, those skilled in the art would like to develop new single molecule GLP-1/GCG/GIP triple receptor agonists to overcome the deficiencies of the existing single target drugs.

Disclosure of Invention

The present invention aims to provide a triple agonist of GLP-1, GCG and GIP receptors, which has strong agonistic activity to glucagon-like peptide-1 (GLP-1) receptor, glucagon (GCG) receptor and glucose-dependent incretin (GIP) receptor.

To this end, in a first aspect, the present invention is a compound which is a peptide having the general formula I:

xaa1-Xaa2-Xaa3-Gly-Thr-Xaa6-Thr-Ser-Asp-Tyr-Ser-Ile-Xaa13-Leu-Asp-Xaa16-Xaa17-Ala-Xaa19-Xaa20-Xaa21-Phe-Xaa23-Glu-Xaa25-Leu-Xaa27-Xaa28-Xaa29-R1 (general formula I, SEQ ID NO: 1);

wherein Xaa1 is tyrosine (Tyr, Y) or histidine (His, H);

xaa2 is serine (Ser, S), or 2-aminoisobutyric acid (Aib);

xaa3 is glutamine (Gln, Q), or histidine (His, H);

xaa6 is phenylalanine (Phe, F), or α -methyl-2-fluorophenylalanine (. Alpha. -Me- (2-F) -Phe);

xaa13 is leucine (Leu, L), tyrosine (Tyr, Y), or alanine (Ala, A);

xaa16 is lysine (Lys, K), glutamic acid (Glu, E), or arginine (Arg, R);

xaa17 is lysine (Lys, K), or isoleucine (Ile, I);

xaa19 is glutamine (Gln, Q), or alanine (Ala, A);

xaa20 is arginine (Arg, R), glutamine (Gln, Q), lysine (Lys, K), or histidine (His, H);

xaa21 is aspartic acid (Asp, D), alanine (Ala, A), or glutamic acid (Glu, E);

xaa23 is isoleucine (Ile, I), or valine (Val, V);

xaa25 is tryptophan (Trp, W), or tyrosine (Tyr, Y);

xaa27 is leucine (Leu, L), or glutamic acid (Glu, E);

xaa28 is alanine (Ala, A), serine (Ser, S), or glutamic acid (Glu, E);

xaa29 is glycine (Gly, G), glutamine (Gln, Q), or alanine (Ala, A);

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 deleted;

at least one of Xaa17 and Xaa20 is a lysine that is unmodified or modified as follows: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl group) _a -(γGlu) _b -CO-(CH ₂ ) _c -CO ₂ H is conjugated to the epsilon-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, c is 16 or 18.

In some embodiments, in formula I,

xaa17 is lysine, xaa20 is lysine; or the like, or, alternatively,

xaa17 is lysine modified as follows: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl group) _a -(γGlu) _b -CO-(CH ₂ ) _c -CO ₂ H is conjugated to the epsilon-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 the like, or, alternatively,

xaa17 is isoleucine, xaa20 is lysine modified as follows: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl group) _a -(γGlu) _b -CO-(CH ₂ ) _c -CO ₂ H is conjugated to the epsilon-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, c is 16 or 18; or the like, or, alternatively,

xaa17 is lysine modified as follows: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl group) _a -(γGlu) _b -CO-(CH ₂ ) _c -CO ₂ H is conjugated to the epsilon-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 lysine.

In some embodiments, in formula I,

xaa1 is tyrosine (Tyr, Y) or histidine (His, H);

xaa2 is serine (Ser, S), or 2-aminoisobutyric acid (Aib);

xaa3 is glutamine (Gln, Q), or histidine (His, H);

xaa6 is phenylalanine (Phe, F), or α -methyl-2-fluorophenylalanine (α -Me- (2-F) -Phe);

xaa13 is leucine (Leu, L), or alanine (Ala, A);

xaa16 is lysine (Lys, K), glutamic acid (Glu, E), or arginine (Arg, R);

xaa17 is lysine (Lys, K), or isoleucine (Ile, I);

xaa19 is glutamine (Gln, Q), or alanine (Ala, A);

xaa21 is aspartic acid (Asp, D), alanine (Ala, A), or glutamic acid (Glu, E);

xaa23 is isoleucine (Ile, I), or valine (Val, V);

xaa25 is tryptophan (Trp, W), or tyrosine (Tyr, Y);

xaa27 is leucine (Leu, L);

xaa28 is alanine (Ala, A), serine (Ser, S), or glutamic acid (Glu, E);

xaa29 is glycine (Gly, G), or alanine (Ala, A);

In some embodiments, in formula I,

xaa1 is tyrosine (Tyr, Y) or histidine (His, H);

xaa2 is serine (Ser, S), or 2-aminoisobutyric acid (Aib);

xaa3 is glutamine (Gln, Q), or histidine (His, H);

xaa13 is leucine (Leu, L);

xaa16 is lysine (Lys, K);

xaa17 is lysine (Lys, K), or isoleucine (Ile, I);

xaa19 is glutamine (Gln, Q), or alanine (Ala, A);

xaa21 is aspartic acid (Asp, D);

xaa23 is isoleucine (Ile, I);

xaa25 is tryptophan (Trp, W);

xaa27 is leucine (Leu, L);

xaa28 is alanine (Ala, A), or glutamic acid (Glu, E);

xaa29 is glycine (Gly, G);

In some embodiments, in formula I,

xaa1 is tyrosine (Tyr, Y) or histidine (His, H);

xaa2 is 2-aminoisobutyric acid (Aib);

xaa3 is glutamine (Gln, Q), or histidine (His, H);

xaa6 is α -methyl-2-fluorophenylalanine (α -Me- (2-F) -Phe);

xaa13 is leucine (Leu, L);

xaa16 is lysine (Lys, K);

xaa17 is lysine modified as follows: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl group) _a -(γGlu) _b -CO-(CH ₂ ) _c -CO ₂ H is conjugated to the epsilon-amino group of the K side chain, wherein a is 1 or 2, b is 1 or 2, c is 16 or 18;

xaa19 is glutamine (Gln, Q);

xaa20 is arginine (Arg, R), glutamine (Gln, Q), or histidine (His, H);

xaa21 is aspartic acid (Asp, D);

xaa23 is isoleucine (Ile, I);

xaa25 is tryptophan (Trp, W);

xaa27 is leucine (Leu, L);

xaa28 is alanine (Ala, A), or glutamic acid (Glu, E);

xaa29 is glycine (Gly, G);

r1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (GPSSGAPPPS, SEQ ID NO: 2), pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (PSSGAPPPS, SEQ ID NO: 3), or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (PSSGAPPS, SEQ ID NO: 4).

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

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

In some embodiments, positions 1 to 29 of formula I are the following sequence:

YSQGTFTSDYSILLDKKAQRDFIEWLAG (SEQ ID NO:32, i.e., positions 1 to 29 of SEQ ID NO: 5);

y (dS) QGTFTSDYSILLDKKAQRDFIEWLAG (SEQ ID NO:33, i.e., positions 1 to 29 of SEQ ID NO: 6);

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

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

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

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

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

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

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

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

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

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

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

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

Y-Aib-HGT- (. Alpha. -Me- (2-F) -Phe) -TSDYSILLDKKAQRDFIEWLAG (SEQ ID NO:45, i.e., positions 1 to 29 of SEQ ID NO: 19);

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

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

H-Aib-HGT- (. Alpha. -Me- (2-F) -Phe) -TSDYSLDLKKAQQDFIEWLLEG (SEQ ID NO:48, i.e., positions 1 to 29 of SEQ ID NO: 22);

H-Aib-HGT- (. Alpha. -Me- (2-F) -Phe) -TSDYSILLDKKAQHDFIEWLEG (SEQ ID NO:49, i.e., positions 1 to 29 of SEQ ID NO: 23);

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

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

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

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

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

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

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

Y-Aib-HGT- (. Alpha. -Me- (2-F) -Phe) -TSDYSILLDKKAQRAFIEWLAG (SEQ ID NO:57, i.e., positions 1 to 29 of SEQ ID NO: 31);

wherein the lysine at position 17 and/or 20 is unmodified or there is a modification: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl group) _a -(γGlu) _b -CO-(CH ₂ ) _c -CO ₂ H is conjugated to the epsilon-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, c is 16 or 18;

and R1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (GPSSGAPPPS, SEQ ID NO: 2), pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (PSSGAPPPS, SEQ ID NO: 3), pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (PSSGAPPPS, SEQ ID NO: 4) or deleted.

In some embodiments, formula I is the following sequence:

YSQGTFTSDYSILLDKKAQRDFIEWLLAGGPSSGAPPPS(SEQ ID NO： 5)；

Y(dS)QGTFTSDYSILLDKKAQRDFIEWLLAGGPSSGAPPPS(SEQ ID NO： 6)；

Y-Aib-QGTFTSDYSILLDKKAQRDFIEWLLAGGPSSGAPPPS(SEQ ID NO：7)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLAGGPSSGAP PPS(SEQ ID NO：8)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQQDFIEWLLAGGPSSGAP PPS(SEQ ID NO：9)；

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

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

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

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQRDFIEWLLAGGPSSGAP PPS(SEQ ID NO：13)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQRDFIEWLLEGGPSSGAPP PS(SEQ ID NO：14)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLEGGPSSGAP PPS(SEQ ID NO：15)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAAHEFIEWLLAGGPSSGAP PPS(SEQ ID NO：16)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEKAAQEFIEWLLAGGPSSGAPP PS(SEQ ID NO：17)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSIYLDKKAQQDFIEWLLEGGPSSGAP PPS(SEQ ID NO：18)；

Y-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLAGGPSSGAP PPS(SEQ ID NO：19)；

H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKIAAKDFIEWLLEGGPSSGAPP PS(SEQ ID NO：20)；

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

H-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQQDFIEWLLEGGPSSGAP PPS(SEQ ID NO：22)；

H-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQHDFIEWLLEGGPSSGAP PPS(SEQ ID NO：23)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAAKDFIEWLLEGGPSSGAPP PS(SEQ ID NO：24)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAQKAFIEYLLEGGPSSGAPPP S(SEQ ID NO：25)；

H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAAKAFIEYLLEGGPSSGAPP PS(SEQ ID NO：26)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQQDFIEWLLEGGPSSGAP PPS(SEQ ID NO：27)；

H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRIAAKDFIEWLLEGGPSSGAPP PS(SEQ ID NO：28)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRAFIEYLLAGGPSSGAPP PS(SEQ ID NO：29)；

Y-Aib-QGT- (α -Me- (2-F) -Phe) -TSDYSLDLKKAQRAFIEWLAGLSSGAP PPS (SEQ ID NO: 30); or

Y-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRAFIEWLLAGGPSSGAP PPS(SEQ ID NO：31)；

Wherein the lysine at position 17 and/or 20 is unmodifiedOr the following modifications are present: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl group) _a -(γGlu) _b -CO-(CH ₂ ) _c -CO ₂ H is conjugated to the epsilon-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, c is 16 or 18.

In one embodiment, the present invention provides a compound of the formula:

YSQGTFTSDYSILLDKKAQRDFIEWLLAGGPSSGAPPPS(SEQ ID NO： 5)。

in one embodiment, the present invention provides a compound of the formula:

YSQGTFTSDYSILLDKKAQRDFIEWLLAGGPSSGAPPPS(SEQ ID NO： 5)，

wherein K at position 17 has the following chemical modification: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl group) ₂ -(γGlu)-CO-(CH ₂ ) ₁₆ -CO ₂ H is conjugated to the epsilon-amino group of the K side chain.

In one embodiment, the invention provides a compound of the formula:

Y(dS)QGTFTSDYSILLDKKAQRDFIEWLLAGGPSSGAPPPS(SEQ ID NO： 6)，

In one embodiment, the present invention provides a compound of the formula:

Y-Aib-QGTFTSDYSILLDKKAQRDFIEWLLAGGPSSGAPPPS(SEQ ID NO：7)，

In one embodiment, the present invention provides a compound of the formula:

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLAGGPSSGAP PPS(SEQ ID NO：8)，

In one embodiment, the present invention provides a compound of the formula:

wherein K at position 17 has the following chemical modification: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl) - (gamma Glu) -CO- (CH ₂ ) ₁₆ -CO ₂ H is conjugated to the epsilon-amino group of the K side chain.

In one embodiment, the present invention provides a compound of the formula:

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQQDFIEWLLAGGPSSGAP PPS(SEQ ID NO：9)，

In one embodiment, the present invention provides a compound of the formula:

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

wherein K at position 17 is chemically modified as follows: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl group) ₂ -(γGlu)-CO-(CH ₂ ) ₁₆ -CO ₂ Conjugation of H to the K side chainEpsilon-amino group of (a).

In one embodiment, the present invention provides a compound of the formula:

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

wherein K at position 17 is chemically modified as follows: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl group) ₂ -(γGlu)-CO-(CH ₂ ) ₁₆ -CO ₂ H is conjugated to the epsilon-amino group of the K side chain.

In one embodiment, the invention provides a compound of the formula:

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

In one embodiment, the present invention provides a compound of the formula:

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQRDFIEWLLAGGPSSGAP PPS(SEQ ID NO：13)，

wherein K at position 17 is chemically modified as follows: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl) - (gamma Glu) -CO- (CH ₂ ) ₁₆ -CO ₂ H is conjugated to the epsilon-amino group of the K side chain.

In one embodiment, the invention provides a compound of the formula:

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQRDFIEWLLEGGPSSGAPP PS(SEQ ID NO：14)，

In one embodiment, the present invention provides a compound of the formula:

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLEGGPSSGAP PPS(SEQ ID NO：15)，

In one embodiment, the present invention provides a compound of the formula:

In one embodiment, the invention provides a compound of the formula:

wherein K at position 17 is chemically modified as follows: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl) - (gamma Glu) -CO- (CH ₂ ) ₁₈ -CO ₂ H is conjugated to the epsilon-amino group of the K side chain.

In one embodiment, the present invention provides a compound of the formula:

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAAHEFIEWLLAGGPSSGAP PPS(SEQ ID NO：16)，

In one embodiment, the present invention provides a compound of the formula:

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEKAAQEFIEWLLAGGPSSGAPP PS(SEQ ID NO：17)，

In one embodiment, the present invention provides a compound of the formula:

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSIYLDKKAQQDFIEWLLEGGPSSGAP PPS(SEQ ID NO：18)，

In one embodiment, the invention provides a compound of the formula:

Y-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLAGGPSSGAP PPS(SEQ ID NO：19)，

In one embodiment, the present invention provides a compound of the formula:

In one embodiment, the invention provides a compound of the formula:

wherein K at position 17 has the following chemical modification: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl) - (gamma Glu) -CO- (CH ₂ ) ₁₈ -CO ₂ H is conjugated to the epsilon-amino group of the K side chain.

In one embodiment, the present invention provides a compound of the formula:

H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKIAAKDFIEWLLEGGPSSGAPP PS(SEQ ID NO：20)，

wherein K at position 20 has the following chemical modification: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl group) ₂ -(γGlu)-CO-(CH ₂ ) ₁₆ -CO ₂ H is conjugated to the epsilon-amino group of the K side chain.

In one embodiment, the invention provides a compound of the formula:

H-Aib-QGTFTSDYSILLDKIAAKDFIEWLLEGGPSSGAPPPS(SEQ ID NO： 21)，

wherein K at position 20 is chemically modified as follows: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl group) ₂ -(γGlu)-CO-(CH ₂ ) ₁₆ -CO ₂ H is conjugated to the epsilon-amino group of the K side chain.

In one embodiment, the invention provides a compound of the formula:

H-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQQDFIEWLLEGGPSSGAP PPS(SEQ ID NO：22)，

In one embodiment, the present invention provides a compound of the formula:

H-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQHDFIEWLLEGGPSSGAP PPS(SEQ ID NO：23)，

wherein K at position 17 is chemically modified as follows: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl) - (γGlu)-CO-(CH ₂ ) ₁₆ -CO ₂ H is conjugated to the epsilon-amino group of the K side chain.

In one embodiment, the invention provides a compound of the formula:

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAAKDFIEWLLEGGPSSGAPP PS(SEQ ID NO：24)，

wherein K at position 20 has the following chemical modification: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl group) ₂ -(γGlu)-CO-(CH ₂ ) ₁₈ -CO ₂ H is conjugated to the epsilon-amino group of the K side chain.

In one embodiment, the present invention provides a compound of the formula:

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAQKAFIEYLLEGGPSSGAPPP S(SEQ ID NO：25)，

In one embodiment, the invention provides a compound of the formula:

H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAAKAFIEYLLEGGPSSGAPP PS(SEQ ID NO：26)，

In one embodiment, the present invention provides a compound of the formula:

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQQDFIEWLLEGGPSSGAP PPS(SEQ ID NO：27)，

In one embodiment, the invention provides a compound of the formula:

H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRIAAKDFIEWLLEGGPSSGAPP PS(SEQ ID NO：28)，

In one embodiment, the present invention provides a compound of the formula:

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRAFIEYLLAGGPSSGAPP PS(SEQ ID NO：29)，

wherein K at position 17 is chemically modified as follows: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl) - (gamma Glu) -CO- (CH ₂ ) ₁₈ -CO ₂ H is conjugated to the epsilon-amino group of the K side chain;

alternatively, SEQ ID NO: the C-terminal amino acid of 29 is amidated.

In one embodiment, the invention provides a compound of the formula:

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRAFIEWLLAGGPSSGAP PPS(SEQ ID NO：30)，

wherein K at position 17 has the following chemical modification: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl) - (gamma Glu) -CO- (CH ₂ ) ₁₈ -CO ₂ H is conjugated to the epsilon-amino group of the K side chain;

alternatively, SEQ ID NO: the C-terminal amino acid of 30 was amidated.

In one embodiment, the invention provides a compound of the formula:

Y-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRAFIEWLLAGGPSSGAP PPS(SEQ ID NO：31)，

alternatively, SEQ ID NO: the C-terminal amino acid of 31 is amidated.

The compounds of the present invention may be pharmaceutically acceptable acid addition salts formed by reacting the peptides with any of a variety of inorganic and organic acids. Pharmaceutically acceptable salts and common methods for preparing them are well known in the art. See, e.g., P.Stahl et al, handbook of Pharmaceutical Salts: properties, selection and Use, second revision (Wiley VCH, 2011); berge, et al, "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, vol.66, no.1, month 1 1977. The pharmaceutically acceptable salts include hydrochloride, bromate, sulfate, nitrate, perchlorate, fumarate, maleate, phosphate, glycolate, lactate, salicylate, succinate, toluene-p-sulfonate, tartrate, acetate, citrate, methanesulfonate, formate, benzoate, malonate, benzenesulfonate, trifluoroacetate and the like.

In another aspect, the invention provides methods for the preparation of the compounds.

The compounds of the present invention can be synthesized by methods known in the art, for example, stepwise in a solid phase or liquid phase method by an automatic peptide synthesizer or by fragment assembly, according to their sequences and fatty acid side chain structures, followed by isolation and purification to obtain the target compounds.

In another aspect, the invention provides agonists of the compounds for GLP-1, GCG, GIP receptors.

The compound has triple activities of GLP-1, GCG and GIP receptors.

In another aspect, the invention also provides compositions comprising the compounds of the invention.

In some embodiments, the composition is a pharmaceutical composition.

In some embodiments, the composition further comprises a pharmaceutically acceptable carrier, diluent or excipient. The pharmaceutically acceptable carrier, diluent or excipient is not an essential active ingredient per se and is not unduly toxic after administration; suitable carriers, diluents or excipients are well known to those of ordinary skill in the art. Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, solubilizers, dispersants, stabilizers, suspending agents, colorants, flavoring agents, buffers, solubilizers, isotonic agents, and the like.

In another aspect, the invention also provides therapeutic kits comprising a compound described herein and devices comprising a compound described herein.

In another aspect, the invention also provides the use of a compound and/or composition according to the invention in the manufacture of a medicament for the treatment and/or prevention of a metabolic disorder.

In another aspect, the present invention also provides a method for preventing and/or treating a metabolic disorder in a subject, comprising administering to the subject a compound and/or composition according to the present invention.

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

In some embodiments, diabetes comprises type I diabetes, type II diabetes.

In some embodiments, the diabetes-related disorders include insulin resistance, glucose intolerance, elevated fasting glucose, pre-diabetes, gestational diabetic hypertension, dyslipidemia, bone-related disorders, and the like.

In some embodiments, diabetes-related conditions further include arteriosclerosis, coronary heart disease, peripheral arterial disease, stroke, dyslipidemia, elevated blood pressure, thrombosis, and the like.

In some embodiments, the lipid disorder comprises high triglycerides, low HDL cholesterol, high LDL cholesterol, and plaque accumulation in the arterial wall.

Compared with the prior art, the invention has the beneficial effects that:

the compounds provided by the present invention, or pharmaceutically acceptable salts or solvates thereof, glucagon-like peptide-1 (GLP-1) receptor, glucagon (GCG) receptor and glucose-dependent incretin (GIP) receptor all have strong agonist activity and are therefore useful in the treatment of related metabolic syndrome.

Drawings

Various other advantages and benefits will become apparent to those of ordinary skill in the art upon reading the following detailed description of the preferred embodiments. The drawings are only for purposes of illustrating the preferred embodiments and are not to be construed as limiting the invention. In the drawings:

FIG. 1: blood glucose concentration-time curve of C57BL/6 mice 24h after single administration of Semaglutide, HEC-PT26, HEC-PT49 and HEC-PT 50;

FIG. 2 is a schematic diagram: blood glucose concentration-time profile of C57BL/6 mice after 72h administration of Semaglutide, HEC-PT26, HEC-PT49, HEC-PT 50;

FIG. 3: blood glucose concentration-time curves of C57BL/6 mice 24h after single administration of HEC-PT47, HEC-PT 48;

FIG. 4 is a schematic view of: effects of chronic administration of HEC-PT26 on blood glucose in db/db mice;

FIG. 5: effects of HEC-PT26, HEC-PT49, HEC-PT50 on blood glucose in db/db mice following a single administration;

FIG. 6: effects of HEC-PT26, HEC-PT49, HEC-PT50 on body weight in db/db mice following a single administration;

FIG. 7 is a schematic view of: effect on food intake in db/db mice following a single administration of HEC-PT26, HEC-PT49, HEC-PT 50;

FIG. 8: the effect of long-term administration of HEC-PT47, HEC-PT50, HEC-PT61 on the rate of body weight gain in DIO mice;

FIG. 9: the influence of long-term administration of HEC-PT47, HEC-PT50 and HEC-PT61 on the cumulative food intake of DIO mice;

FIG. 10: the influence of long-term administration of HEC-PT47, HEC-PT50 and HEC-PT61 on the liver weight of DIO mice;

FIG. 11: effect of long-term administration of HEC-PT47, HEC-PT50, HEC-PT61 on liver index in DIO mice.

Detailed Description

Exemplary embodiments of the present disclosure will be described in more detail below with reference to the accompanying drawings. While exemplary embodiments of the present disclosure are shown in the drawings, it should be understood that the present disclosure may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art.

In the present invention, the conventional one-letter and three-letter codes for natural amino acids are used, as well as the commonly accepted three-letter codes for other (non-natural) amino acids, e.g., aib (2-aminoisobutyric acid). Unless explicitly indicated otherwise, all amino acid residues of the present invention are preferably in the L-configuration, e.g., dS denotes Ser in D-form.

Example 1

This example provides a method for synthesizing a compound of the invention.

1. Solid phase peptide synthesis was performed on a peptide synthesizer: the resin was placed in a 150ml reactor and soaked for 2 hours with 50ml Dichloromethane (DCM). The resin was washed with N, N-Dimethylformamide (DMF) and then drained, and this was repeated four times and the resin was drained. The first amino acid (protected) + DCM + N, N-Diisopropylethylamine (DIEA) at the Fmoc-C terminal was weighed into a reactor, and the reactor was placed in a shaker at 30 ℃ for 2 hours. Blocking with methanol solution (methanol: DIEA: DCM = 1) for half an hour, then washing four times with DMF and draining. The Fmoc protecting group was removed by adding a 20% piperidine solution to the reactor. After deprotection, four washes with DMF were performed, followed by suction drying.

2. The Fmoc-C terminal second amino acid (with protection) + 1-Hydroxybenzotriazole (HOBT) + N, N' -Diisopropylcarbodiimide (DIC) was weighed into a reactor, and then the reactor was placed in a shaker at 30 ℃ for 1 hour. Detecting a small amount of resin by an indantrione method, if the resin has a color, indicating that the condensation is incomplete, and continuing to react; after the reaction was complete, the resin was washed four times with DMF and then drained. The Fmoc protecting group on the resin was removed by adding a quantity of 20% piperidine (piperidine/DMF = 1) to the reactor and shaking on a decolourising shaker for 20 min. After the protection is removed, washing the mixture with DMF for four times, and then draining the mixture to detect whether the protection is removed.

3. The amino acids are linked in sequence according to step 2. Here, lys to which a fatty acid side chain should be bonded is prepared by using a specifically protected raw material, protecting the N-terminal amino group with Boc anhydride, removing the specific protecting group of the Lys side chain, and bonding the side chain structure in reference to step 2. The polypeptide protecting groups are cleaved off completely with a cleavage reagent and cleaved from the resin for purification.

4. After the target peptide is synthesized, separating the target peptide segment from impurities through reversed phase liquid chromatography purification, freeze-drying the collected target peptide into powder, and sending the powder to QC quality inspection for purity and mass spectrum identification. The purity is more than 95% by HPLC detection. The molecular weight of the polypeptide identified by mass spectrum is consistent with the theoretical molecular weight. Table 1 shows the synthesized compounds.

TABLE 1

Wherein B is 2-aminoisobutyric acid (Aib), dS represents Ser form D; x is (L) -alpha-Me- (2-F) -Phe.

The structural general formula of the fatty acid chain is as follows:

([ 2- (2-amino-ethoxy) -ethoxy]-acetyl group) _a -(γGlu) _b -CO-(CH ₂ ) _c -CO ₂ H, conjugated to the corresponding K side chain in the polypeptide backboneEpsilon-amino; wherein a is 1 or 2, b is 1 or 2, c is 16 or 18; part of the side chain structure is shown below, where- - -shows the point of attachment of the fatty acid chain to the lysine side chain:

when a is 1, b is 1, c is 16, the fatty acid chain structure is-OEG-gamma Glu-CO- (CH) ₂ ) ₁₆ -CO ₂ H, the specific structure is as follows:

when a is 1, b is 1, c is 18, the fatty acid chain structure is-OEG-gamma Glu-CO- (CH) ₂ ) ₁₈ -CO ₂ H, the specific structure is as follows:

when a is 2, b is 1, c is 16, the fatty acid chain structure is-OEG-OEG-gamma Glu-CO- (CH) ₂ ) ₁₆ -CO ₂ H, the specific structure is as follows:

when a is 2, b is 1, c is 18, the fatty acid chain structure is-OEG-OEG-gamma Glu-CO- (CH) ₂ ) ₁₈ -CO ₂ H, the specific structure is as follows:

example 2

This example provides a method for measuring the in vitro cell activity of a compound

The method comprises the following specific steps:

1. preparing an Assay buffer: taking complete culture solution (DMEM medium +10% FBS), adding 4/1000 of 500mM IBMX mother solution, and preparing cAMP-d2 working solution and anti-cAMP-cryptate working solution according to the kit specification;

2. diluting a sample to be detected and human reference polypeptides GLP-1 (SEQ ID NO: 58), GCG (SEQ ID NO: 59) and GIP (SEQ ID NO: 60) to a mother solution with the initial concentration of 500nM, and then gradually diluting the mother solution according to the gradient of adding 20 mu L of the diluted mother solution to 80 mu L of Assay buffer (diluted by 5 times), wherein the gradient comprises 8 compounds in total;

3. preparing a cell suspension: taking out the frozen cells HEK293-GLP-1R, HEK293-GCGR and HEK293-GIPR from a liquid nitrogen tank, immediately carrying out water bath at 37 ℃, completely melting the cells within 1.5min, dropwise adding the cells into a 15mL centrifuge tube filled with 8mL warm culture medium in an ultraclean bench, centrifuging the centrifuge tube at 900rpm for 5min, discarding the supernatant, resuspending the cells in 1mL complete culture solution (blowing for 15 times), immediately mixing 20 mu L of suspension with trypan equal volume of trypan blue, counting the number of viable cells by taking 20 mu L, diluting the cells to 4X 10 ⁵ cells/mL；

4. Dividing a 384-well plate into GLP-1R cells, GCGR cells and GIPR cell areas, adding 5 mu L of cell suspension into the wells of the corresponding areas by using a 12-channel lane-changing adjustable dispenser according to each well, and adding 5 mu L of gradient diluent of a test sample and a positive control into the 384-well plate of the corresponding cells by using a 12-channel lane-changing adjustable dispenser, wherein each well is 5 mu L (samples with the same concentration are parallelly provided with 2 multiple wells); negative control: setting 3 holes in each 384-hole plate at 10 mu L of assay buffer per hole, covering a white sealing plate film, putting the plate into a constant-temperature incubator at 37 ℃, and taking out the plate after half an hour;

5. diluting a cAMP-d2 working solution and an anti-cAMP-cryptate working solution by 20 times by using a lysine buffer in a kit before use, then uniformly mixing 1;

6. the fluorescence values of 665nm and 620nm are detected in a multifunctional microplate reader. The signal ratio and sample concentration were fitted non-linearly in GraphPad Prism 6 using a four parameter equation to give EC50 values, with the specific results shown in table 2.

TABLE 2 results of in vitro cell Activity assay of polypeptide Compounds

Example 3

This example evaluates the effect of HEC-PT26, HEC-PT49, HEC-PT50 on glucose tolerance in normal C57BL/6 mice.

The experimental method comprises the following steps: normal C57BL/6 mice were randomly divided into 5 groups (control group, semaglutide group, HEC-PT26 group, HEC-PT49 group, HEC-PT50 group) by blood glucose and body weight, and 8 mice were administered to each group. For the Semaglutide group, the HEC-PT26 group, the HEC-PT49 group and the HEC-PT50 group, the corresponding drugs are injected into animals of each group by subcutaneous injection, and the administration dose is 3nmol/kg; for the control group, the corresponding vehicle was injected subcutaneously.

After 12h of single administration, animals are fasted for 12h and are freely drunk, blood is taken from tail veins to determine the blood sugar basic value of each group of animals, then 2g/kg of glucose solution is given by intraperitoneal injection, and blood sugar detection is carried out at the time points of 15 min, 30 min and 60min after the administration of the glucose. Drawing a blood glucose concentration-time curve according to blood glucose values measured at different time points, and calculating AUC of each dosage group _0～60min As shown in table 3 and fig. 1.

Animals fasted for 12h after a single administration of 60h, had free access to water. Blood was taken from the tail vein to determine the blood glucose basal value of each group of animals, followed by intraperitoneal injection of 2g/kg glucose solution, and blood glucose measurements were performed at

time points

15, 30, 60, and 90min after administration of glucose. Drawing a blood glucose concentration-time curve according to blood glucose values measured at different time points, and calculating AUC (oral glucose value) of each dose group _0～90min As shown in table 4 and fig. 2.

The experimental results are as follows:

table 3: effect of single administration of HEC-PT26, HEC-PT49 and HEC-PT50 on glucose tolerance in Normal C57 mice after 24h

Table 4: effect of single administration of HEC-PT26, HEC-PT49 and HEC-PT50 on glucose tolerance of normal C57 mice for 72h

And (4) experimental conclusion: 24h, HEC-PT26, HEC-PT49 and HEC-PT50 can obviously reduce the blood sugar level of a normal C57 mouse after single administration, and the effect is equivalent to that of Semaglutide; the blood sugar level of normal C57 mice can be obviously reduced by HEC-PT26, HEC-PT49 and HEC-PT50 72h after single administration.

Example 4

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

The experimental method comprises the following steps: normal C57BL/6 mice were divided into 4 groups (control group, HEC-PT47 group, HEC-PT48 group) of 8 mice per group according to blood glucose and body weight. For the HEC-PT47 group and the HEC-PT48 group, the corresponding medicines are administered by subcutaneous injection, and the administration dose is 3nmol/kg; for the control group, the corresponding vehicle was injected subcutaneously.

After a single administration for 12 hours, animals are fasted for 12 hours and have free water. Blood was taken from tail vein to determine the blood glucose basal value of each group of animals, followed by intraperitoneal injection of 2g/kg glucose solution, and blood glucose was measured 15, 30, and 60min after administration of glucose. Drawing a blood glucose concentration-time curve according to blood glucose values measured at different time points, and calculating AUC of each dosage group _0～60min As shown in fig. 3 and table 5.

The experimental results are as follows:

table 5: effect of a single administration of HEC-PT47 and HEC-PT48 on glucose tolerance in Normal C57 mice after 24h

And (4) experimental conclusion: HEC-PT47 and HEC-PT48 significantly reduced blood glucose levels in normal C57 mice.

Example 5

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

The experimental method comprises the following steps: the db/db mice 7-8 weeks old were randomly divided into 4 groups (Model group, LY3298176 group, semaglutide group, HEC-PT26 group) according to blood sugar and body weight values, and 8 mice were used in each group. For LY3298176 group, semaglutide group and HEC-PT26 group, the corresponding medicine is administered by subcutaneous injection to animals of each group, and the dosage of each administration is 10nmol/kg; for the Model group, the corresponding vehicle was injected subcutaneously. The Semaglutide group was administered once a day, and the LY3298176 group and the HEC-PT26 group were administered once every 3 days for 4 weeks; blood glucose measurements were performed on the animals prior to each dose.

The experimental results are as follows: the HEC-PT26 group can obviously reduce blood sugar after administration, the blood sugar reaches the lowest level at 24h, and the effect is superior to that of positive controls Semaglutide and LY3298176 of the same dose. Compared with the Model, the blood sugar value of mice in the HEC-PT26 group is obviously reduced after long-term repeated administration, the long-term stability is kept, the blood sugar reducing effect of the mice is similar to that of the Semaglutide group and is superior to that of the LY3298176 group, and the specific data are shown in the table 6 and the figure 4.

Table 6: effect of chronic administration of HEC-PT26 on blood glucose in db/db mice

And (4) experimental conclusion: the blood sugar level of a type II diabetes model db/db mouse can be obviously improved by long-term administration of HEC-PT 26.

Example 6

This example evaluates the effect of a single dose of HEC-PT47, HEC-PT48 and HEC-PT50 on blood glucose and body weight in db/db mice.

The experimental method comprises the following steps: after adaptive feeding of db/db mice of 6-7 weeks for 1 week, randomly dividing the mice into 4 groups (a Semaglutide group, an HEC-PT47 group, an HEC-PT48 group and an HEC-PT50 group) according to body weight and blood sugar value, wherein each group comprises 5 mice; a single subcutaneous injection was administered beginning at week 2, each group was dosed with the corresponding drug at 10nmol/kg, and blood glucose, body weight and food intake of each group of animals were examined before and after administration. The results are shown in tables 7-9 and FIGS. 5-7.

Table 7: effect of a Single administration of HEC-PT47, HEC-PT48, HEC-PT50 on blood glucose in db/db mice

Table 8: effect of a Single administration of HEC-PT47, HEC-PT48, HEC-PT50 on the body weight of db/db mice

Table 9: effect of Single administration of HEC-PT47, HEC-PT48, HEC-PT50 on food intake in db/db mice

The experimental results are as follows: blood sugar test results show that after single administration of HEC-PT47, HEC-PT48 and HEC-PT50, the blood sugar of db/db mice is remarkably reduced within 48 hours, and the blood sugar rises to a peak and is relatively constant at about 96 hours. The HEC-PT47, the HEC-PT48 and the HEC-PT50 also have a remarkable effect on controlling the body weight of db/db mice within 3 days after being administrated, and the body weight growth rate is reduced; moreover, the single administration of the preparation has better effect on controlling the food intake of db/db mice than the positive drug Semaglutide with the same dose.

Example 7

This example evaluates the effect of chronic repeated doses of HEC-PT47, HEC-PT50, and HEC-PT61 on body weight and food intake in DIO obese mice.

The experimental method comprises the following steps: C57/BL6 mice were randomized at the fifth week of age into normal group NFD, model group HFD, normal group given normal maintenance diet, and other groups given high fat diet D12492. Mice were monitored for changes in body mass and food intake every 3 weeks. After being raised for 16 weeks, the body masses of the mice in the model group and the normal group are respectively (47.7 +/-3.1) g and (30.9 +/-2.3) g, and the comparison difference between the two groups has statistical significance. The normal group was divided into Control group(s) (PBS injected subcutaneously); the model group mice successfully molded are divided into a Vehicle group, a Semaglutide group, an HEC-PT47 group, an HEC-PT50 group and an HEC-PT61 group, and each group comprises 10 mice. For the Semaglutide group, the HEC-PT47 group, the HEC-PT50 group and the HEC-PT61 group, animals in each group were administered the corresponding drugs by subcutaneous injection; for the Vehicle group, PBS was injected subcutaneously. The first dose was observed 7 days later, and each group was dosed every 3 days at a dose of 10nmol/kg. Body weight and food intake were measured before each administration. After 3 weeks of administration, an abdominal glucose tolerance test is carried out, the sample is slaughtered and collected 72 hours after the last administration, the weight of the liver is recorded, and the pathological condition of the liver and the blood biochemical index of each group are detected. The results are shown in tables 10-13 and FIGS. 8-11.

Table 10: effect of Long-term administration of HEC-PT47, HEC-PT50, HEC-PT61 on body weight of DIO mice

Note: the lower case letter a in the same column with shoulder marks indicates significant difference (P < 0.05)

Table 11: effect of long-term administration of HEC-PT47, HEC-PT50, HEC-PT61 on food intake of DIO mice

Note: the same column of shoulder marks are marked with lower case letters to indicate significant difference (P < 0.05)

Table 12: effect of HEC-PT47, HEC-PT50, HEC-PT61 Long-term administration on physical quality and liver index of DIO mice

Group of	Mass/g	Liver/g	Liver index%
				Control	29.1±2.2 ^a	1.0±0.1 ^a	3.5±0.0 ^a
Vehicle	48.0±1.9	2.0±0.4	4.1±0.0
				Semaglutide	41.0±4.3 ^a	1.1±0.2 ^a	2.6±0.0 ^a
HEC-PT47	30.5±2.2 ^a	1.5±0.1 ^a	5.0±0.0 ^a
				HEC-PT50	34.0±2.0 ^a	1.0±0.1 ^a	2.8±0.0 ^a
HEC-PT61	31.8±3.3 ^a	0.9±0.1 ^a	2.8±0.0 ^a

Table 13: effect of long-term administration of HEC-PT47, HEC-PT50 and HEC-PT61 on liver function and blood fat of DIO mice

The experimental results are as follows: after administration for 4 weeks, the weight loss effect of HEC-PT47, HEC-PT50 and HEC-PT61 is obviously superior to that of the positive medicament Semaglutide under the same dose and the same administration frequency. The control effect of HEC-PT47, HEC-PT50 and HEC-PT61 on the food intake of DIO mice is basically similar and is obviously superior to that of Semaglutide.

The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Sequence listing

<110> Guangdong Dongyuang pharmaceutical Co., ltd

<120> triple agonists 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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (1)..(1)

<223> Xaa is Tyr or His

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is Ser or Aib

<220>

<221> VARIANT

<222> (3)..(3)

<223> Xaa is Gln or His

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is Phe or α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (13)..(13)

<223> Xaa is Leu, tyr or Ala

<220>

<221> VARIANT

<222> (16)..(16)

<223> Xaa is Lys, glu or Arg

<220>

<221> VARIANT

<222> (17)..(17)

<223> Xaa is Ile or Lys unmodified or modified as follows: ([ 2- (2-amino-ethoxy) -ethoxy ] -acetyl) a- (gammaglu) b-CO- (CH 2) c-CO2H conjugated to the epsilon-amino group of the Lys side chain, wherein a is 1 or 2, b is 1 or 2, 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 Lys either unmodified or modified as follows: ([ 2- (2-amino-ethoxy) -ethoxy ] -acetyl) a- (gammaglu) b-CO- (CH 2) c-CO2H conjugated to the epsilon-amino group of the Lys side chain, wherein a is 1 or 2, b is 1 or 2, c is 16 or 18, c is

<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-Ser, pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or is absent

<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 (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 (Artificial Sequence)

<400> 3

Pro Ser Ser Gly Ala Pro Pro Pro Ser

1 5

<210> 4

<211> 8

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<400> 4

Pro Ser Ser Gly Ala Pro Pro Ser

1 5

<210> 5

<211> 39

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<221> VARIANT

<222> (17)..(17)

<223> Lys is unmodified or the following modifications are present: ([ 2- (2-amino-ethoxy) -ethoxy ] -acetyl) a- (gammaglu) b-CO- (CH 2) c-CO2H conjugated to the epsilon-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, c is 16 or 18

<400> 5

Tyr Ser 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> 6

<211> 39

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> D form Ser

<220>

<221> VARIANT

<222> (17)..(17)

<223> Lys is unmodified or there is a modification: ([ 2- (2-amino-ethoxy) -ethoxy ] -acetyl) a- (gammaglu) b-CO- (CH 2) c-CO2H conjugated to the epsilon-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, c is 16 or 18

<400> 6

Tyr Ser 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> 7

<211> 39

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (20)..(20)

<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> 21

<211> 39

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (20)..(20)

<400> 21

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> 22

<211> 39

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<400> 22

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> 23

<211> 39

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<400> 23

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> 24

<211> 39

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (20)..(20)

<400> 24

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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (20)..(20)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (20)..(20)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (20)..(20)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (17)..(17)

<400> 32

Tyr Ser 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> 33

<211> 29

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> D form Ser

<220>

<221> VARIANT

<222> (17)..(17)

<400> 33

Tyr Ser 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> 34

<211> 29

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (20)..(20)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (20)..(20)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (20)..(20)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (20)..(20)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (20)..(20)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (20)..(20)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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 (Artificial Sequence)

<220>

<221> VARIANT

<222> (2)..(2)

<223> Xaa is 2-aminoisobutyric acid (Aib)

<220>

<221> VARIANT

<222> (6)..(6)

<223> Xaa is α -Me- (2-F) -Phe

<220>

<221> VARIANT

<222> (17)..(17)

<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> Intelligent (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> Intelligent (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> Intelligent (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:

wherein Xaa1 is Tyr or His;

xaa2 is Ser, or Aib;

xaa3 is Gln, or His;

xaa6 is Phe, or α -Me- (2-F) -Phe;

xaa13 is Leu, tyr, or Ala;

xaa16 is Lys, glu, or Arg;

xaa17 is Lys, or Ile;

xaa19 is Gln, or Ala;

xaa20 is Arg, gln, lys, or His;

xaa21 is Asp, ala, or Glu;

xaa23 is Ile, or Val;

xaa25 is Trp, or Tyr;

xaa27 is Leu, or Glu;

xaa28 is Ala, ser, or Glu;

xaa29 is Gly, gln, or Ala;

r1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 2), pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 3), pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 4) or does not exist;

at least one of Xaa17 and Xaa20 is unmodified or modified Lys, and the modification is: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl group) _a -(γGlu) _b -CO-(CH ₂ ) _c -CO ₂ H is conjugated to the epsilon-amino group of the Lys side chain, wherein a is 1 or 2, b is 1 or 2, c is 16 or 18.

2. The compound of claim 1, wherein in formula I,

xaa1 is Tyr or His;

xaa2 is Ser, or Aib;

xaa3 is Gln or His;

xaa6 is Phe, or α -Me- (2-F) -Phe;

xaa13 is Leu, or Ala;

xaa16 is Lys, glu, or Arg;

xaa17 is Lys, or Ile;

xaa19 is Gln, or Ala;

xaa20 is Arg, gln, lys, or His;

xaa21 is Asp, ala, or Glu;

xaa23 is Ile, or Val;

xaa25 is Trp or Tyr;

xaa27 is Leu;

xaa28 is Ala, ser, or Glu;

xaa29 is Gly, or Ala;

r1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 2), pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 3), pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 4) or deleted;

3. The compound of claim 1, wherein in formula I,

xaa1 is Tyr or His;

xaa2 is Aib;

xaa3 is Gln, or His;

xaa6 is α -Me- (2-F) -Phe;

xaa13 is Leu;

xaa16 is Lys;

xaa17 is Lys modified as follows: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl group) _a -(γGlu) _b -CO-(CH ₂ ) _c -CO ₂ H is conjugated to the epsilon-amino group of the Lys side chain, wherein a is 1 or 2, b is 1 or 2, c is 16 or 18;

xaa19 is Gln;

xaa20 is Arg, gln, or His;

xaa21 is Asp;

xaa23 is Ile;

xaa25 is Trp;

xaa27 is Leu;

xaa28 is Ala, or Glu;

xaa29 is Gly;

r1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 2), pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 3), or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 4).

4. The compound of claim 1, wherein positions 1 to 29 of formula I are the following sequence:

YSQGTFTSDYSILLDKKAQRDFIEWLLAG(SEQ ID NO：32)；

Y(dS)QGTFTSDYSILLDKKAQRDFIEWLLAG(SEQ ID NO：33)；

Y-Aib-QGTFTSDYSILLDKKAQRDFIEWLLAG(SEQ ID NO：34)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLAG(SEQ ID NO：35)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQQDFIEWLLAG(SEQ ID NO：36)；

Y-Aib-QGTFTSDYSIYLDKKAQRAFVEWLLAQ(SEQ ID NO：37)；

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

Y-Aib-QGTFTSDYSIALDKKAQREFVEWLLSA(SEQ ID NO：38)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQRDFIEWLLAG(SEQ ID NO：39)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQRDFIEWLLEG(SEQ ID NO：40)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLEG(SEQ ID NO：41)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAAHEFIEWLLAG(SEQ ID NO：42)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEKAAQEFIEWLLAG(SEQ ID NO：43)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSIYLDKKAQQDFIEWLLEG(SEQ ID NO：44)；

Y-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLAG(SEQ ID NO：45)；

H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKIAAKDFIEWLLEG(SEQ ID NO：46)；

H-Aib-QGTFTSDYSILLDKIAAKDFIEWLLEG(SEQ ID NO：47)；

H-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQQDFIEWLLEG(SEQ ID NO：48)；

H-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQHDFIEWLLEG(SEQ ID NO：49)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAAKDFIEWLLEG(SEQ ID NO：50)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAQKAFIEYLLEG(SEQ ID NO：51)；

H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAAKAFIEYLLEG(SEQ ID NO：52)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQQDFIEWLLEG(SEQ ID NO：53)；

H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRIAAKDFIEWLLEG(SEQ ID NO：54)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRAFIEYLLAG(SEQ ID NO：55)；

Y-Aib-QGT- (α -Me- (2-F) -Phe) -TSDYSLDLKKAQRAFIEWLAG (SEQ ID NO: 56); or

Y-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRAFIEWLLAG(SEQ ID NO：57)；

Wherein the K at position 17 and/or 20 is unmodified or there is a modification: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl group) _a -(γGlu) _b -CO-(CH ₂ ) _c -CO ₂ H is conjugated to the epsilon-amino group of the K side chain, wherein a is 1 or 2, b is 1 or 2, c is 16 or 18;

r1 is GPSSGAPPPS (SEQ ID NO: 2), PSSGAPPPS (SEQ ID NO: 3), PSSGAPPPS (SEQ ID NO: 4) or null.

5. The compound of claim 1, wherein formula I is the following sequence:

YSQGTFTSDYSILLDKKAQRDFIEWLLAGGPSSGAPPPS(SEQ ID NO：5)；

Y(dS)QGTFTSDYSILLDKKAQRDFIEWLLAGGPSSGAPPPS(SEQ ID NO：6)；

Y-Aib-QGTFTSDYSILLDKKAQRDFIEWLLAGGPSSGAPPPS(SEQ ID NO：7)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLAGGPSSGAPPPS(SEQ ID NO：8)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQQDFIEWLLAGGPSSGAPPPS(SEQ ID NO：9)；

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

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

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

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQRDFIEWLLAGGPSSGAPPPS(SEQ ID NO：13)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQRDFIEWLLEGGPSSGAPPPS(SEQ ID NO：14)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLEGGPSSGAPPPS(SEQ ID NO：15)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAAHEFIEWLLAGGPSSGAPPPS(SEQ ID NO：16)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEKAAQEFIEWLLAGGPSSGAPPPS(SEQ ID NO：17)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSIYLDKKAQQDFIEWLLEGGPSSGAPPPS(SEQ ID NO：18)；

Y-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRDFIEWLLAGGPSSGAPPPS(SEQ ID NO：19)；

H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKIAAKDFIEWLLEGGPSSGAPPPS(SEQ ID NO：20)；

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

H-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQQDFIEWLLEGGPSSGAPPPS(SEQ ID NO：22)；

H-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQHDFIEWLLEGGPSSGAPPPS(SEQ ID NO：23)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAAKDFIEWLLEGGPSSGAPPPS(SEQ ID NO：24)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAQKAFIEYLLEGGPSSGAPPPS(SEQ ID NO：25)；

H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDEIAAKAFIEYLLEGGPSSGAPPPS(SEQ ID NO：26)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRKAQQDFIEWLLEGGPSSGAPPPS(SEQ ID NO：27)；

H-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDRIAAKDFIEWLLEGGPSSGAPPPS(SEQ ID NO：28)；

Y-Aib-QGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRAFIEYLLAGGPSSGAPPPS(SEQ ID NO：29)；

Y-Aib-QGT- (α -Me- (2-F) -Phe) -TSDYSLDLKKAQRAFIEWLAGLGSGAGPPPS (SEQ ID NO: 30); or

Y-Aib-HGT-(α-Me-(2-F)-Phe)-TSDYSILLDKKAQRAFIEWLLAGGPSSGAPPPS(SEQ ID NO：31)；

Wherein, is located at 1 stLysine in position 7 and/or 20 is unmodified or there is a modification: ([ 2- (2-amino-ethoxy) -ethoxy]-acetyl group) _a -(γGlu) _b -CO-(CH ₂ ) _c -CO ₂ H is conjugated to the epsilon-amino group of the lysine side chain, wherein a is 1 or 2, b is 1 or 2, c is 16 or 18.

6. A compound according to any one of claims 1-5 for use as an agonist of GLP-1, GCG, GIP receptors.

7. A composition comprising a compound of any one of claims 1-5.

8. The composition of claim 7, further comprising a pharmaceutically acceptable carrier, diluent or excipient.

9. Use of a compound according to any one of claims 1 to 5 and/or a composition according to any one of claims 7 to 8 for the manufacture of a medicament for the treatment and/or prevention of a metabolic disorder.

10. The use according to claim 9, wherein the metabolic disorder comprises diabetes, diabetes-related disorders, obesity, fatty liver disease, non-alcoholic steatohepatitis, dyslipidemia and disorders associated with metabolic syndrome.