Triple activator having activity on all of GLP-1, GIP, and glucagon receptors, and pharmaceutical composition for preventing or treating lipid metabolic diseases comprising same

Abstract

The present invention relates to a use of a novel triple activator, having activity on all of GLP-1, GIP, and glucagon receptors, for preventing or treating lipid metabolic diseases.

Description

Triple activator having activity at all GLP-1, GIP, and glucagon receptors and pharmaceutical composition for preventing or treating lipid metabolism diseases comprising the same

[0001] The present invention relates to a triple activator having activity at all GLP-1, GIP, and glucagon receptors and uses thereof.

[0002]

[0003] GLP-1 (Glucagon-like peptide-1) and GIP (Glucose-dependent insulinotropic polypeptide) are representative gastrointestinal hormones and neurohormones that regulate blood glucose levels in response to food intake. GLP-1 is a hormone secreted from the small intestine in response to food intake. It stimulates insulin secretion from the pancreas in a blood glucose concentration-dependent manner and suppresses glucagon secretion, thereby helping to lower blood glucose levels.

[0004] In addition, GIP, one of the gastrointestinal hormones secreted in response to food intake along with GLP-1, is a hormone composed of 42 amino acids secreted from K cells in the small intestine. It performs the function of promoting insulin secretion from the pancreas in a blood sugar concentration-dependent manner and helping to lower blood sugar concentration, and its effects of increasing the activity of GLP-1 and anti-inflammatory effects have been reported.

[0005] Glucagon is a peptide hormone secreted by the pancreas. Along with the two substances mentioned above, it plays a role in regulating blood sugar levels. Glucagon is produced by the pancreas when blood sugar levels begin to drop due to medication, disease, or hormone or enzyme deficiencies. Glucagon signals the liver to break down glycogen and release glucose, thereby raising blood sugar levels to normal levels. Furthermore, glucagon has been reported to suppress appetite in animals and humans, activate hormone-sensitive lipase in fat cells, promote fat breakdown, and promote energy expenditure, thus exhibiting anti-obesity effects.

[0006]

[0007] Compared to single agonists for the GLP-1 receptor, GIP receptor, or glucagon receptor known in the past, the need for substances that can simultaneously act on the above receptors to increase efficacy or improve side effects has recently emerged, and peptides and conjugates thereof that can act on the GLP-1, GIP, and glucagon receptors have been developed (WO2017-116204; WO2017-116205).

[0008]

[0009] Meanwhile, lipids include cholesterol and triglycerides, of which cholesterol is divided into low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol. Representative examples of lipid metabolism-related diseases caused by excess or deficiency of these lipids compared to normal levels include hyperlipidemia, dyslipidemia, hypercholesterolemia, and hypertriglyceridemia.

[0010] The most important factors in lipid metabolism-related diseases are high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), and triglycerides. HDLc and LDLc play a role in transporting cholesterol between the liver and cells, and are necessary for cell membrane formation, hormones, and vitamin D production. However, excessive cholesterol in the blood is known to promote arteriosclerosis. Triglycerides function as an energy source, but if they are not maintained at an appropriate level, they are highly likely to cause cardiovascular disease or develop complications, so early diagnosis and treatment are required. When low-density lipoprotein cholesterol and / or triglycerides in the blood are abnormally high, they can accumulate on the blood vessel walls, causing inflammation, which can result in cardiovascular disease, cerebrovascular diseases, and peripheral arterial disease. Cardiovascular disease and cerebrovascular disease are the three leading causes of death in Korea, along with cancer.

[0011] The causes of lipid metabolism-related disorders include genetic factors, as well as dietary and lifestyle habits. However, low-density lipoprotein cholesterol (LDL), a major contributor to atherosclerosis and complications, is difficult to control with diet alone, and appropriate medication is often required.

[0012] To treat these lipid metabolism-related disorders, significant efforts are being made to improve lipid levels. Representative therapeutic agents include statins, which act as HMG-CoA reductase (HMGCR) inhibitors and inhibit cholesterol synthesis. However, high-dose or long-term use can cause liver toxicity and myopathy.

[0013]

[0014] There is a need to develop therapeutic agents that can improve lipid metabolism and treat related diseases.

[0015]

[0016] One object of the present invention is to provide a pharmaceutical composition for preventing or treating lipid metabolism diseases, comprising a peptide active against a GLP-1 (Glucagon-like peptide-1) receptor, a GIP (Glucose-dependent insulinotropic polypeptide) receptor, and a glucagon receptor.

[0017] Another object of the present invention is to provide a method for preventing or treating a lipid metabolism disease, comprising a step of administering the peptide or pharmaceutical composition to a subject in need thereof.

[0018] Another object of the present invention is to provide a use of the peptide or pharmaceutical composition for preventing or treating lipid metabolism diseases.

[0019] Another object of the present invention is to provide a use of the peptide or pharmaceutical composition for providing a drug for preventing or treating a lipid metabolism disease.

[0020]

[0021] The peptide of the present invention having activity against the GLP-1 (Glucagon-like peptide-1) receptor, the GIP (Glucose-dependent insulinotropic polypeptide) receptor, and the glucagon receptor can have an excellent preventive or therapeutic effect on lipid metabolism diseases by activating the three receptors simultaneously.

[0022]

[0023] Figure 1 is a diagram confirming the blood sugar lowering effect of the triple activator of sequence numbers 1 to 6 according to the present invention.

[0024] FIG. 2 is a diagram showing the results of measuring total cholesterol (T-CHO), low-density lipoprotein cholesterol (LDL-c), the ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol (HDL-c / LDL-c), and triglyceride (TG) in blood following administration of the triple activator of sequence numbers 1 to 6 according to the present invention.

[0025]

[0026] One aspect of the present invention is a pharmaceutical composition comprising a peptide having activity against a GLP-1 (Glucagon-like peptide-1) receptor, a GIP (Glucose-dependent insulinotropic polypeptide) receptor, and a glucagon receptor.

[0027] As a specific example, the peptide is characterized by being represented by the following general formula 1:

[0028] X1-Aib-X3-GTFTSDYS-X12-X13-LDE-X17-X18-AK-X21-FVQWLLD-X29-HPSSGQPPPS (general formula 1, sequence number 29)

[0029] In the above general formula 1,

[0030] X1 is histidine or tyrosine;

[0031] X3 is glutamine or histidine;

[0032] X12 is lysine or an acylated amino acid;

[0033] X13 is alpha-methyl-leucine (αMeL), tyrosine, or alanine;

[0034] X17 is lysine or an acylated amino acid;

[0035] X18 is alanine or arginine;

[0036] X21 is aspartic acid or glutamic acid;

[0037] X29 is histidine or glutamine;

[0038] The above - represents a peptide bond, and the peptide does not contain cysteine.

[0039] As another specific example, the peptide is

[0040] In the above general formula 1,

[0041] X13 is tyrosine;

[0042] X18 is characterized as being alanine.

[0043] As another specific example, the peptide is

[0044] In the above general formula 1,

[0045] X1 is tyrosine;

[0046] X3 is glutamine;

[0047] X13 is tyrosine;

[0048] X18 is characterized by being arginine.

[0049] As another specific example, the peptide is

[0050] In the above general formula 1,

[0051] It is characterized by X3 being histidine.

[0052] As another specific example, the peptide is

[0053] In the above general formula 1,

[0054] X29 is characterized by being glutamine.

[0055] As another specific example, the peptide is characterized by having a structure of the following general formula 2:

[0056] [General Formula 2]

[0057]

[0058] In the above general formula 2,

[0059] The above n is 16 or 18,

[0060] X1 is histidine or tyrosine;

[0061] X3 is glutamine or histidine;

[0062] X13 is alpha-methyl leucine, tyrosine, or alanine;

[0063] X18 is alanine or arginine;

[0064] X21 is aspartic acid or glutamic acid;

[0065] X29 is histidine or glutamine.

[0066] A composition according to any one of the preceding specific examples, wherein the composition is characterized in that it is a pharmaceutical composition for preventing or treating a lipid metabolism disease, comprising the peptide in a pharmaceutically effective amount.

[0067] A composition according to any one of the preceding specific examples, wherein the peptide is characterized in that it has a higher relative activity against the GLP-1 receptor and the GIP receptor than the native GLP-1 and GIP, respectively, compared to the relative activity against the glucagon receptor compared to the native glucagon.

[0068] A composition according to any one of the preceding specific examples, wherein the peptide is characterized in that the relative activity against the GLP-1 receptor and the GIP receptor, respectively, is at least 4 times higher than the relative activity against the glucagon receptor compared to the native GLP-1 and GIP, respectively.

[0069] A composition according to any one of the preceding specific examples, wherein the peptide is characterized in that an acyl group is attached directly or through a linker to one or more amino acids of the peptide.

[0070] A composition according to any one of the preceding specific examples, wherein the linker is selected from the group consisting of AEEA ((2-(2-aminoethoxy)ethoxy)acetic acid), GABA (4-Aminobutyric acid), Ava (5-Aminovaleric acid), Ahx (Aminohexanoic acid), triazole, and polyethylene glycol (PEG).

[0071] A composition according to any one of the preceding specific examples, wherein the linker comprises AEEA ((2-(2-aminoethoxy)ethoxy)acetic acid).

[0072] A composition according to any one of the preceding specific examples, wherein the linker is gammaGlu-(AEEA)2.

[0073] A composition according to any one of the preceding specific examples, wherein the linker comprises 0 to 3 AEEAs, and 0 to 3 gamma-Glutamates are linked to the AEEAs.

[0074] A composition according to any one of the preceding specific examples, wherein the acylated amino acid is any one of the amino acids represented by K(1) or K(2):

[0075]

[0076] .

[0077] A composition according to any one of the preceding specific examples, wherein the peptide is characterized in that the C-terminus is amidated.

[0078] A composition according to any one of the preceding specific examples, wherein the peptide is characterized in that it is acylated with a C1-C30 straight or branched chain acyl group comprising one or two carboxylic acids.

[0079] A composition according to any one of the preceding specific examples, wherein the acyl group is a C4 to C30 fatty acid or a dicarboxylic acid.

[0080] A composition according to any one of the preceding specific examples, wherein the peptide is characterized in that it is acylated at an amino acid or lysine residue located at the N-terminus or C-terminus.

[0081] A composition according to any one of the preceding specific examples, wherein the peptide comprises any one sequence selected from the group consisting of amino acid sequences of SEQ ID NOs: 1 to 28.

[0082] A composition according to any one of the preceding specific examples, wherein the peptide is characterized in that amino acids 16 and 20 from the N-terminus form a ring.

[0083] A composition according to any one of the preceding specific examples, wherein the peptide is characterized by having any one of the following structures (i) to (iv):

[0084] (i)

[0085] ;

[0086] (ii)

[0087] ;

[0088] (iii)

[0089] ;

[0090] (iv)

[0091] .

[0092] A composition according to any one of the preceding specific examples, characterized in that the composition further comprises a pharmaceutically acceptable carrier.

[0093] A composition according to any one of the preceding specific examples, wherein the lipid metabolism disease is any one selected from the group consisting of hyperlipidemia, dyslipidemia, hypercholesterolemia, and hypertriglyceridemia.

[0094] A composition according to any one of the preceding specific examples, wherein the hypertriglyceridemia is characterized as severe hypertriglyceridemia (SHTG) or mild-to-moderate hypertriglyceridemia.

[0095] A composition according to any one of the preceding specific examples, wherein the composition exhibits at least one of the following properties (i) to (iv) when administered to a subject:

[0096] (i) Reduction of total cholesterol (T-CHO) in the blood;

[0097] (ii) reduction of low-density lipoprotein cholesterol (LDL-c) in the blood;

[0098] (iii) increased high-density lipoprotein cholesterol to low-density lipoprotein cholesterol ratio (HDL-c / LDL-c); and

[0099] (iv) Reduction of triglycerides (TG) in the blood.

[0100] A composition according to any one of the preceding specific examples, wherein the composition exhibits a blood sugar lowering effect when administered to a subject.

[0101] Another aspect of the present invention is a method for preventing or treating a lipid metabolism disease, comprising administering the peptide or a composition comprising the same.

[0102] Another aspect of the present invention is the use of the peptide or a composition comprising the same for the prevention or treatment of lipid metabolism diseases.

[0103] Another aspect of the present invention is the use of the peptide or a composition comprising the same to provide a drug for preventing or treating a lipid metabolism disease.

[0104]

[0105] The following is a detailed description of the implementation of the present invention. Each description and embodiment disclosed herein can also be applied to other descriptions and embodiments. In other words, all combinations of the various elements disclosed herein fall within the scope of the present invention. Furthermore, the scope of the present invention is not limited by the specific descriptions described below.

[0106]

[0107] Throughout this specification, the conventional one-letter and three-letter codes for naturally occurring amino acids are used, as well as the generally accepted three-letter codes for other amino acids, such as Aib (2-aminoisobutyric acid), Sarcosine (N-methylglycine), α-methyl-glutamic acid, α-methyl-leucine (αMeL), etc. In addition, amino acids referred to by abbreviations herein are described according to the IUPAC-IUB nomenclature.

[0108]

[0109] Alanine A Arginine R

[0110] Asparagine N Aspartic acid D

[0111] Cysteine ​​C Glutamic Acid E

[0112] Glutamine Q Glycine G

[0113] Histidine H Isoleucine I

[0114] Leucine L Lysine K

[0115] Methionine M Phenylalanine F

[0116] Proline P Serine S

[0117] Threonine T Tryptophan W

[0118] Tyrosine Y Valine V

[0119]

[0120] One aspect of the present invention is a pharmaceutical composition for preventing or treating a lipid metabolism disease, comprising a peptide active against a GLP-1 (Glucagon-like peptide-1) receptor, a GIP (Glucose-dependent insulinotropic polypeptide) receptor, and a glucagon receptor. The peptide or peptides active against the GLP-1, GIP, and glucagon receptors may be used in combination as a triple activator in the present invention.

[0121] These triple activators include various substances, such as various peptides, that have significant levels of activity against GLP-1, GIP, and glucagon receptors.

[0122] Although not particularly limited thereto, the triple activator having a significant level of activity against the GLP-1, GIP, and glucagon receptors may exhibit in vitro activity against one or more of the GLP-1, GIP, and glucagon receptors, specifically two or more receptors, and more specifically all three receptors, of about 0.1% or more, about 1% or more, about 2% or more, about 3% or more, about 4% or more, about 5% or more, about 6% or more, about 7% or more, about 8% or more, about 9% or more, about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more of the native ligand of the corresponding receptor (native glucagon, native GLP-1, and native GIP).

[0123] Meanwhile, the triple active agent according to the present invention is characterized by possessing one or more activities, specifically significant activities, among the following i) to iii):

[0124] i) activation of GLP-1 receptors; ii) activation of GIP receptors; and iii) activation of glucagon receptors.

[0125] Here, activating a receptor means, for example, that the in vitro activity for the receptor is about 0.1% or more, about 1% or more, about 2% or more, about 3% or more, about 4% or more, about 5% or more, about 6% or more, about 7% or more, about 8% or more, about 9% or more, about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more compared to the native type. However, the present invention is not limited thereto.

[0126] In the present invention, the term "about" includes all ranges including ±0.5, ±0.4, ±0.3, ±0.2, ±0.1, etc., and includes all numerical values ​​in a range equal to or similar to the numerical value following the term "about," but is not limited thereto.

[0127] The activity of such a triple activator can be measured using methods known in the art and is not limited to a specific method. For example, it can be measured using a method such as that disclosed in Experimental Example 1, but is not limited thereto.

[0128] The triple activator of the present invention may have activity against all of the GLP-1, GIP, and glucagon receptors, while the ratio of relative activity against each receptor may vary. Specifically, the triple activator according to the present invention may have higher relative activity against both the GLP-1 receptor and the GIP receptor compared to native GLP-1 and GIP than the relative activity against the glucagon receptor compared to native glucagon. The degree of activity exhibited against each receptor is important in determining the in vivo activity and efficacy of the triple activator, and the triple activator of the present invention exhibits relatively high activity against the GLP-1 and GIP receptors, making it effective in the treatment of lipid metabolic diseases, while simultaneously exhibiting activity against the glucagon receptor, so that a synergistic effect in the treatment of lipid metabolic diseases can be expected.

[0129] Specifically, the triple activator may have a relative activity against the GLP-1 receptor of at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, or at most 30 times, respectively, compared to the relative activity against the glucagon receptor of native glucagon, but is not limited thereto. In addition, the triple activator may have a relative activity against the GIP receptor of at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 10 times, at least 15 times, or at least 20 times, respectively, compared to the relative activity against the glucagon receptor of native glucagon, but is not limited thereto.

[0130] Based on the relative activity (a) of the triple activator against the glucagon receptor compared to native glucagon, the relative activity (b) against the GLP-1 receptor compared to native GLP-1; and the relative activity (c) against the GIP receptor compared to native GIP (i.e., (b) / (a); and (c) / (a)) may each independently appear in different ratios, and more specifically, the relative activity against the GIP receptor and the GLP-1 receptor compared to native GIP and GLP-1 may be higher than the relative activity against the glucagon receptor compared to native glucagon. Without being limited thereto, the triple activator may have a relative activity against the GIP receptor and the GLP-1 receptor compared to native GIP and GLP-1, respectively, that is four times or more than the relative activity against the glucagon receptor compared to native glucagon.

[0131]

[0132] In addition, the triple activator may have an increased half-life in the body compared to any one of natural GLP-1, natural GIP, and natural glucagon, but is not particularly limited thereto. The triple activator of the present invention exhibits activity on all of the GLP-1 receptor, GIP receptor, and glucagon receptor, but has a relatively low activity on the glucagon receptor in particular, and at the same time, can maintain its efficacy for a long time due to the increased half-life in the body, so it can be used as an effective treatment for lipid metabolism diseases.

[0133]

[0134] Although not specifically limited to this, these triple activators may be non-naturally occurring.

[0135]

[0136] The pharmaceutical composition of the present invention comprising the above triple active agent may exhibit a preventive or therapeutic effect on lipid metabolism diseases.

[0137]

[0138] In the present invention, lipid metabolism disease refers to a condition in which the levels of low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and triglycerides (TG) in the blood are not properly maintained, and is a general term for all diseases caused by lipid abnormalities. Examples of lipid metabolism diseases include, but are not limited to, hyperlipidemia, dyslipidemia, hypercholesterolemia, and hypertriglyceridemia.

[0139] Low-density lipoprotein cholesterol (LDL-C) transports cholesterol from the liver to cells, but excessively high levels are a major cause of arteriosclerosis. High-density lipoprotein cholesterol (HDL-C) transports cholesterol from cells to the liver, removing it from the blood vessels and thus helping prevent cardiovascular disease. Furthermore, triglycerides, insoluble fats that are essential for energy, are known to induce the production of low-density lipoprotein cholesterol (LDL-C) when levels are high.

[0140] It is necessary to maintain the levels of low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and triglycerides (TG) in the blood at appropriate levels because if these lipoproteins are not maintained at appropriate levels, it causes cardiovascular diseases such as arteriosclerosis, angina pectoris, myocardial infarction, and stroke. Although there are differences depending on the country, time, and risk factor level, it is generally recommended to maintain total cholesterol below 200 mg / dL, high-density lipoprotein cholesterol above 60 mg / dL (40 mg / dL or more in men, 50 mg / dL or more in women), low-density lipoprotein cholesterol below 130 mg / dL, and triglycerides below 200 mg / dL. If even one of these levels is exceeded, it is considered that there is a lipid metabolism disease or that there is a risk.

[0141]

[0142] In the present invention, the lipid metabolism disease may be used interchangeably with terms such as lipid metabolism disorder, lipid dyslipidemia, and metabolic lipid disease.

[0143]

[0144] In lipid metabolism diseases, they can be categorized as hyperlipidemia, dyslipidemia, hypercholesterolemia, and hypertriglyceridemia, depending on the specific values ​​of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides and the patterns of deviation from normal levels.

[0145]

[0146] Dyslipidemia is a condition in which the concentration of cholesterol (low-density lipoprotein cholesterol and high-density lipoprotein cholesterol) and triglycerides in the blood is outside the normal range (both increased and decreased). It can refer to a broader condition than hyperlipidemia, which refers to a condition in which there is a lot of low-density lipoprotein cholesterol or triglycerides in the blood.

[0147] The known causes of dyslipidemia include genetic problems in the process of metabolizing fat, a diet high in fat, lack of exercise, and aging.

[0148] Although it may vary depending on the individual's family history, medical history, age, and presence of risk factors, if any of the following is true, dyslipidemia can be diagnosed: total cholesterol 240 mg / dL or higher, low-density lipoprotein cholesterol 160 mg / dL or higher, high-density lipoprotein cholesterol less than 40 mg / dL, and triglycerides 200 mg / dL or higher.

[0149] The triple active agent of the present invention may exhibit a preventive or therapeutic effect on dyslipidemia by exhibiting one or more of the effects of reducing total blood cholesterol (T-CHO); reducing blood low-density lipoprotein cholesterol (LDL-c) concentration; increasing the blood low-density lipoprotein to high-density lipoprotein cholesterol ratio (HDL-c / LDL-c); and reducing blood triglyceride (TG) concentration, but is not limited thereto.

[0150]

[0151] Hyperlipidemia is a condition in which excessive amounts of lipoproteins are present in the blood, meaning that either low-density lipoprotein cholesterol or triglycerides, or both, are high.

[0152] Although hyperlipidemia is often caused by increased levels of certain lipids in the blood due to genetic factors, it can also be caused by other factors such as eating habits and lack of exercise.

[0153] Although it may vary depending on the individual's family history, medical history, age, and presence of risk factors, if total cholesterol is 200 mg / dL or higher, triglyceride is 200 mg / dL or higher, or low-density lipoprotein cholesterol is 130 mg / dL or higher, it can be diagnosed as hyperlipidemia.

[0154] The triple active agent of the present invention may exhibit a preventive or therapeutic effect on hyperlipidemia by exhibiting one or more of the effects of reducing total blood cholesterol (T-CHO); reducing blood low-density lipoprotein cholesterol (LDL-c) concentration; increasing the ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol (HDL-c / LDL-c); and reducing blood triglyceride (TG) concentration, but is not limited thereto.

[0155]

[0156] Hypercholesterolemia refers to a condition in which the total cholesterol level in the blood is high, and the causes are known to be genetics, eating habits, exercise, lifestyle, drinking, stress, disease, or medication.

[0157] It may vary depending on the individual's family history, medical history, age, and presence of risk factors, but is usually diagnosed as hypercholesterolemia when low-density lipoprotein cholesterol is 160 mg / dL or higher, but is not limited to this.

[0158] The triple active agent of the present invention may exhibit an effect of reducing the concentration of low-density lipoprotein cholesterol (LDL-c) in the blood, thereby exhibiting a preventive or therapeutic effect on hypercholesterolemia, but is not limited thereto.

[0159]

[0160] Hypertriglyceridemia is a condition in which total cholesterol and low-density lipoprotein cholesterol are within the normal range, but triglyceride levels are particularly high. It is known that individuals with only high triglyceride levels are at high risk of coronary artery disease.

[0161] It may vary depending on the individual's family history, medical history, age, and presence of risk factors, but if the triglyceride level is 150 mg / dL or higher, it can be diagnosed as hypertriglyceridemia, but is not limited thereto.

[0162] Hypertriglyceridemia can be classified as severe hypertriglyceridemia (SHTG) or mild-to-moderate hypertriglyceridemia depending on the level of triglycerides. Specifically, severe hypertriglyceridemia is diagnosed when triglycerides are 885 mg / dL or higher. It is known to occur due to overproduction of very low-density lipoproteins (VLDL) due to saturation or dysfunction of lipoprotein lipase (LPL), inadequate removal of triglycerides, and accumulation of chylomicrons and VLDL, leading to the development of the disease. Individuals with severe hypertriglyceridemia have triglyceride levels more than three times the normal triglyceride level, and are associated with serious diseases such as acute pancreatitis and cardiovascular disease. When triglycerides are between 150 and 885 mg / dL, it is diagnosed as mild or moderate hypertriglyceridemia, and very low-density lipoproteins are overproduced by the liver, but the amount produced by the intestines is minimal compared to individuals with severe hypertriglyceridemia.

[0163] The triple active agent of the present invention may exhibit an effect of reducing the concentration of blood triglycerides (TG) and thus may exhibit a preventive or therapeutic effect on hypertriglyceridemia, but is not limited thereto.

[0164]

[0165] The above hyperlipidemia, dyslipidemia, hypercholesterolemia, and hypertriglyceridemia may occur independently depending on the individual levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides, but may also be diagnosed as one or more diseases at the same time.

[0166]

[0167] Hyperlipidemia, dyslipidemia, hypercholesterolemia, and hypertriglyceridemia are summarized as follows.

[0168]

[0169]

[0170]

[0171] In order to treat lipid metabolic disorders such as hyperlipidemia, dyslipidemia, hypercholesterolemia, and hypertriglyceridemia, it is most important to manage the levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides in the blood that are above normal levels. In particular, low-density lipoprotein cholesterol and triglycerides are direct factors that cause arteriosclerosis, and low-density lipoprotein cholesterol is well known as bad cholesterol, so its levels must be lowered. In addition, high-density lipoprotein cholesterol transports cholesterol in the blood to the liver for excretion, so the lower its level, the higher the risk of arteriosclerosis. Therefore, it is important to maintain the ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol at an appropriate level.

[0172] The triple active agent of the present invention can improve lipid metabolism of an individual by lowering total cholesterol, low-density lipoprotein cholesterol, and triglycerides, and increasing the ratio of high-density lipoprotein cholesterol to low-density lipoprotein, and further, can exhibit preventive or therapeutic effects on hyperlipidemia, dyslipidemia, hypercholesterolemia, and / or hypertriglyceridemia, but is not limited thereto.

[0173] Specifically, the triple activator of the present invention may exhibit any one of the following effects (i) to (iv) through its action on the GLP-1 receptor, GIP receptor, and glucagon receptor, but is not limited thereto:

[0174] (i) Reduction of total cholesterol (T-CHO) in the blood;

[0175] (ii) reduction of low-density lipoprotein cholesterol (LDL-c) in the blood;

[0176] (iii) increased high-density lipoprotein cholesterol to low-density lipoprotein cholesterol ratio (HDL-c / LDL-c); and

[0177] (iv) Reduction of triglycerides (TG) in the blood.

[0178] The effect of showing one or more of the above (i) to (iv) is called improvement in lipid metabolism, and through the improvement in lipid metabolism, the triple active agent of the present invention can show a preventive or therapeutic effect on lipid metabolism diseases.

[0179] In an embodiment of the present invention, the lipid improvement effect was confirmed in a hamster model induced by a high-fat and high-fructose diet, and it was confirmed that total cholesterol (T-CHO), low-density lipoprotein cholesterol (LDL-c), the ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol (HDL-c / LDL-c), and triglyceride (TG) in the blood were all improved by the triple activator of the present invention.

[0180]

[0181] Additionally, the triple activator of the present invention may exhibit a blood sugar lowering effect through an active action on a GLP-1 receptor, a GIP receptor, and a glucagon receptor, but is not limited thereto.

[0182] In an embodiment of the present invention, an intraperitoneal glucose tolerance test (ipGTT) was performed on normal mice, and it was confirmed that the triple activator of the present invention had a blood sugar lowering effect.

[0183]

[0184] In the present invention, “subject” may refer to mammals including rats, livestock, etc., including patients with lipid metabolism diseases or humans at risk of developing lipid metabolism diseases, and is not particularly limited as long as beneficial effects can be obtained through improvement of lipid metabolism.

[0185]

[0186] The pharmaceutical composition of the present invention can exhibit an effect of improving lipid metabolism through an action on a GLP-1 receptor, a GIP receptor, and a glucagon receptor, including a triple activator, and in particular, since the relative activity of the GLP-1 receptor and the GIP receptor compared to native GLP-1 and GIP is relatively higher than the relative activity of the glucagon receptor compared to native glucagon, it can exhibit an excellent preventive or therapeutic effect on lipid metabolism diseases, but is not limited thereto. Specifically, the triple activator of the present invention exhibits simultaneous activity with an optimized activity ratio for the GLP-1 receptor, the GIP receptor, and the glucagon receptor, and thus has an advantage of excellent blood sugar lowering effect, and this blood sugar lowering effect can exhibit an excellent effect in the prevention and treatment of lipid metabolism diseases by preventing excess sugar in the blood from becoming a source of lipid production.

[0187]

[0188] As one specific embodiment of the present invention, the triple active agent included in the composition may be a peptide comprising an amino acid sequence represented by the following general formula 1:

[0189] X1-Aib-X3-GTFTSDYS-X12-X13-LDE-X17-X18-AK-X21-FVQWLLD-X29-HPSSGQPPPS (general formula 1, sequence number 29)

[0190] In the above general formula 1,

[0191] X1 is histidine or tyrosine;

[0192] X3 is glutamine or histidine;

[0193] X12 is lysine or an acylated amino acid;

[0194] X13 is alpha-methyl-leucine (αMeL), tyrosine, or alanine;

[0195] X17 is lysine or an acylated amino acid;

[0196] X18 is alanine or arginine;

[0197] X21 is aspartic acid or glutamic acid;

[0198] X29 is histidine or glutamine;

[0199] The above - represents a peptide bond, and the peptide does not contain cysteine.

[0200]

[0201] Examples of triple activators according to the present invention include, but are not limited to, those comprising an amino acid sequence of any one of SEQ ID NOs: 1 to 28, and those consisting (essentially) of an amino acid sequence of any one of SEQ ID NOs: 1 to 28.

[0202]

[0203] More specifically, the triple activator is, in the general formula 1,

[0204] X13 is tyrosine;

[0205] X18 may be, but is not limited to, an alanine peptide.

[0206]

[0207] Examples of the above triple activator include, but are not limited to, those comprising an amino acid sequence of any one of SEQ ID NOs: 1, 3, 6, 9, 10, 13, 15, 17, 20, 22, 24, and 27, and those consisting (essentially) of an amino acid sequence of any one of SEQ ID NOs: 1, 3, 6, 9, 10, 13, 15, 17, 20, 22, 24, and 27.

[0208]

[0209] Alternatively, the triple activator in the general formula 1,

[0210] X1 is tyrosine;

[0211] X3 is glutamine;

[0212] X13 is tyrosine;

[0213] X18 may be, but is not limited to, an arginine peptide

[0214]

[0215] Examples of the above triple activator include, but are not limited to, those comprising an amino acid sequence of any one of SEQ ID NOs: 2, 4, 7, 8, 11, 14, 16, 18, 21, 23, 25, and 28, and those consisting (essentially) of an amino acid sequence of any one of SEQ ID NOs: 2, 4, 7, 8, 11, 14, 16, 18, 21, 23, 25, and 28.

[0216]

[0217] Alternatively, the triple activator in the general formula 1,

[0218] X29 may be, but is not limited to, a glutamine peptide.

[0219]

[0220] Examples of the triple activator include, but are not limited to, those comprising an amino acid sequence of any one of SEQ ID NOs: 3, 5, 6, 7, 10, 12, 13, 14, 17, 19, 20, 21, 24, 26, 27, and 28, and those consisting (essentially) of an amino acid sequence of any one of SEQ ID NOs: 3, 5, 6, 7, 10, 12, 13, 14, 17, 19, 20, 21, 24, 26, 27, and 28.

[0221]

[0222] Alternatively, the triple activator in the general formula 1,

[0223] X3 may be a peptide containing histidine, but is not limited thereto.

[0224]

[0225] Examples of the above triple activator include, but are not limited to, those comprising an amino acid sequence of any one of SEQ ID NOs: 6, 13, 20, and 27, and those consisting (essentially) of an amino acid sequence of any one of SEQ ID NOs: 6, 13, 20, and 27.

[0226]

[0227] In another specific embodiment, the triple activator may be a peptide comprising an amino acid sequence represented by the following general formula 2:

[0228] [General Formula 2]

[0229] .

[0230]

[0231] In the above general formula 2,

[0232] wherein n is 16 to 20, specifically 16 or 18,

[0233] X1 is histidine or tyrosine;

[0234] X3 is glutamine or histidine;

[0235] X13 is alpha-methyl leucine, tyrosine, or alanine;

[0236] X18 is alanine or arginine;

[0237] X21 is aspartic acid or glutamic acid;

[0238] X29 is histidine or glutamine.

[0239] Here, the peptide including the amino acid sequence represented by the general formula 2 may not include cysteine.

[0240]

[0241] The peptide portion of the above general formula 2 may be the same as the peptide portion of the above general formula 1, and the description regarding the general formula 1 may also be applied to the general formula 2.

[0242]

[0243] As an example of the triple active substance of the above general formulae 1 and 2, glutamic acid and lysine, which are amino acids at positions 16 and 20, may be in the form of a ring, specifically a lactam ring, but are not particularly limited thereto.

[0244]

[0245] In another specific embodiment, the triple activator may have a higher relative activity against the GIP receptor and the GLP-1 receptor compared to native GIP and GLP-1 than the relative activity against the glucagon receptor compared to native glucagon, and more specifically, the triple activator may have a relative activity against the GIP receptor and the GLP-1 receptor compared to native GIP and GLP-1 that is at least four times higher than the relative activity against the glucagon receptor compared to native glucagon.

[0246] Specific examples include, but are not limited to, those comprising an amino acid sequence of any one of SEQ ID NOs: 1, 3 to 7, and 9, those consisting essentially of an amino acid sequence of any one of SEQ ID NOs: 1, 3 to 7, and 9. More specific examples include, but are not limited to, those comprising an amino acid sequence of any one of SEQ ID NOs: 1, 3, 6, and 9, those consisting essentially of an amino acid sequence of any one of SEQ ID NOs: 1, 3, 6, and 9.

[0247]

[0248] Additionally, in the present invention, the triple active agent may be an acylated peptide, but is not limited thereto. In the present invention, the triple active agent may refer to either an acylated or non-acylated triple active agent.

[0249]

[0250] Acylation is known as a method for improving the pharmacokinetic and pharmacodynamic properties of peptide drugs. Peptide drugs have a problem in that they have difficulty exerting their efficacy due to enzymatic degradation in the body. Therefore, acylation of the peptide, which attaches a fatty acid to the peptide, blocks the enzyme action site, thereby increasing the stability of the peptide drug and increasing its half-life. For the purposes of the present invention, the triple active agent of the present invention may be in an acylated form to increase its half-life. The acylated triple active agent of the present invention exhibits activity at all three receptors, the GLP-1 receptor, the GIP receptor, and the glucagon receptor, while also having an increased half-life in the body, making it an effective therapeutic agent.

[0251]

[0252] In the present invention, even if it is described as a “triple active substance” or “peptide” without description of whether it is acylated or not, the acylated form is not excluded, and it can be used interchangeably with “acylated triple active substance” and “acylated peptide”.

[0253]

[0254] The acylated triple active agent of the present invention may be one in which an acyl group is directly linked to an amino acid of a triple active agent peptide, or an acyl group is attached via a linker. Although not limited thereto, the linker may be a linker selected from the group consisting of AEEA ((2-(2-aminoethoxy)ethoxy)acetic acid), GABA (4-Aminobutyric acid), Ava (5-Aminovaleric acid), Ahx (Aminohexanoic acid), triazole, and polyethylene glycol (PEG), but is not limited thereto.

[0255] As a specific example, the linker may include AEEA ((2-(2-aminoethoxy)ethoxy)acetic acid), and more specifically, gamma-Glutamate may be further linked, but is not limited thereto. As a specific example of the linker, (gammaGlu) m -(AEEA) n , and the above m and n may each independently be an integer of 0, 1, 2, 3, or more, but are not limited thereto.

[0256] As another example, the linker may be, but is not limited to, polyethylene glycol having a maleimide reactive group (maleimide-PEG).

[0257] As another example, the triple active peptide and the acyl group may be linked via a click chemistry reaction, but is not limited thereto.

[0258] An acyl group can be bonded to an amine group, a hydroxyl group, a thiol group, a carboxyl group, etc. of an amino acid of a triple active substance through an amine group, a hydroxyl group, a thiol group, etc. of the above linker. However, as long as the acyl group can be bonded to the triple active substance to contribute to the structural stability and increase of the half-life of the triple active substance, it is not limited to a specific type or length. In addition, the linker can be covalently bonded to an acyl group, and can be linked to an acyl group in 1, 2, 3, or more repetitions, but is not limited thereto.

[0259]

[0260] The acyl group may be a carbon chain of any length and may be linear or branched. Specifically, the chain may include a linear aliphatic chain, a branched aliphatic chain, a chain containing a cyclic alkyl moiety, a hydrophobic natural product such as a steroid, an aralkyl chain, or an alkyl chain containing an acyl moiety.

[0261] Although not limited thereto, the acylated triple activator may be acylated with a C1-C30 straight chain or branched chain acyl group comprising one or more, two or more, specifically one or two carboxylic acids, and as an example, the acyl group may be a fatty acid or dicarboxylic acid, specifically, but not limited to, a C4 to C30 fatty acid or dicarboxylic acid. As a more specific example, the acyl group may be a C16, C18, C20, C22, C24, C26, C28, or C30 fatty acid or dicarboxylic acid. Other examples of acyl groups include, but are not limited to, bile acids such as cholic acid, chenodeoxycholic acid, deoxycholic acid, lithocholic acid, taurocholic acid, glycocholic acid, cholesteric acid, succinic acid or succinic acid derivatives, maleic acid or maleic acid derivatives, and the like.

[0262] In one specific embodiment, the acyl group may be a fatty acid or fatty diacid having a carbon number of C18 or higher or a derivative thereof, and more specifically, may be octadecanoic acid, octadecanodiic acid, linoleic acid, linolenic acid, oleic acid, etc., but is not limited thereto.

[0263] In another specific embodiment, the acyl group may be a fatty acid or fatty diacid having a C20 or higher number, or a derivative thereof, and more specifically, may be eicosanoic acid, docosanoic acid, icosapentaenoic acid, adrenic acid, etc., but is not limited thereto.

[0264]

[0265] The acylated triple active agent of the present invention may be one in which an acyl group is attached to the triple active agent by a method known in the art, or may be one prepared by synthesizing a peptide using an acylated amino acid, but is not limited thereto.

[0266]

[0267] In the present invention, the acylated triple activator may be in a form in which an acyl group is directly attached to an amino acid residue included in the triple activator. For example, the acyl group may be attached via an ester, thioester, or amide bond, but is not limited thereto. Specifically, the acylated triple activator may be one in which acylation is performed on an amino acid residue having an amine, hydroxyl, or thiol group. For example, the acylated triple activator may be one in which acylation is performed on an amino acid or lysine residue located at the N-terminus or C-terminus, but is not limited thereto.

[0268]

[0269] The term "acylated amino acid" of the present invention refers to an amino acid to which an acyl group is attached. The amino acid of the acylated amino acid may be a natural or unnatural amino acid, and may also include isomers thereof, and is not limited to a specific amino acid as long as an acyl group can be attached. For example, the amino acid may be an amino acid having an amine, hydroxyl, or thiol group, or a carboxyl group to which an acyl group can be attached, more specific examples include, but are not limited to, lysine, glutamine, asparagine, or arginine. Alternatively, the acyl group may be linked to the N-terminus of a triple active moiety, but is not limited thereto.

[0270]

[0271] In the present invention, the acylated triple active substance or the acylated amino acid of general formula 1 may include, but is not limited to, any one of the amino acids represented by K(1) or K(2) below:

[0272]

[0273] .

[0274]

[0275] The above acylated amino acid may be linked to another amino acid within the peptide. Specifically, the lysine of K(1) and K(2) may be linked to another adjacent amino acid of the triple active agent via a carboxyl group and / or an amino group, and may be linked to a linker and an acyl group via a side chain. It is apparent that even forms linked to other amino acids are included within the scope of K(1) and K(2) of the present invention.

[0276]

[0277] The triple active agent of the present invention may be in the form of acylation at one or more amino acids at positions 1 to 39 from the N-terminus, or at the N-terminus, or at the C-terminus, but the position of acylation or the number of acylated amino acids is not limited as long as it retains activity as a triple active agent.

[0278] As a specific example, the acylated triple activator of the present invention may include, but is not limited to, an amino acid acylated at any one or more of positions 12, 17, and 20.

[0279] In one specific embodiment of the acylated triple active agent of the present invention, it may include an amino acid acylated at position 12. Specifically, it may include K(1) at position 12, and more specifically, it may include an amino acid sequence of any one of SEQ ID NOs: 1 to 7, or it may include K(2) at position 12, and more specifically, it may include an amino acid sequence of any one of SEQ ID NOs: 8 to 14, but is not limited thereto.

[0280] In another specific embodiment of the acylated triple active agent of the present invention, the acylated amino acid may be included at position 17. Specifically, it may include K(1) at position 17, and more specifically, it may include an amino acid sequence of any one of SEQ ID NOs: 15 to 21, or it may include K(2) at position 17, and more specifically, it may include an amino acid sequence of any one of SEQ ID NOs: 22 to 28, but is not limited thereto.

[0281]

[0282] In another specific embodiment, the triple activator may comprise, or consist essentially of, any one of the amino acid sequences of SEQ ID NOs: 1 to 28, but is not limited thereto.

[0283] Even if it is described in this application as a ‘peptide composed of a specific sequence number’, if it has the same or corresponding activity as a peptide composed of the amino acid sequence of the sequence number, it does not exclude meaningless sequence additions before and after the amino acid sequence of the sequence number, mutations that may occur naturally, or silent mutations thereof, and it is clear that even if it has such sequence additions or mutations, it falls within the scope of this application.

[0284]

[0285] In addition, the triple active agent of the present invention may include an amino acid sequence having 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or more homology or identity to the amino acid sequence of SEQ ID NOs: 1 to 28, but is not limited thereto as long as it can act on the GLP-1 receptor, the GIP receptor, and the glucagon receptor, and can exhibit a preventive or therapeutic effect on lipid metabolism diseases.

[0286]

[0287] In the present invention, the term 'homology' or 'identity' means the degree to which two given amino acid sequences or base sequences are related to each other, and may be expressed as a percentage.

[0288] Sequence homology or identity of conserved polypeptides is determined by standard alignment algorithms, and may be combined with default gap penalties established by the program being used. In practice, homologous or identical sequences can generally hybridize with all or part of the sequence under moderate or high stringency conditions. It should be appreciated that hybridization also includes hybridization with polynucleotides containing common codons or codons that take codon degeneracy into account.

[0289] The terms homology and identity are often used interchangeably.

[0290] Whether any two peptide sequences are homologous, similar or identical can be determined using known computer algorithms such as the "FASTA" program using default parameters, for example as in Pearson et al (1988) [Proc. Natl. Acad. Sci. USA 85]: 2444. Alternatively, it can be determined using the Needleman-Wunsch algorithm (Needleman and Wunsch, 1970, J. Mol. Biol. 48: 443-453) as performed in the Needleman program of the EMBOSS package (EMBOSS: The European Molecular Biology Open Software Suite, Rice et al., 2000, Trends Genet. 16: 276-277) (version 5.0.0 or later) (GCG program package (Devereux, J., et al, Nucleic Acids Research 12: 387 (1984)), BLASTP, BLASTN, FASTA (Atschul, [S.] [F.,] [ET AL, J MOLEC BIOL 215]: 403 (1990); Guide to Huge Computers, Martin J. Bishop, [ED.,] Academic Press, San Diego, 1994, and [CARILLO ETA / .] (1988) SIAM J Applied Math 48: 1073). For example, homology, similarity, or identity can be determined using BLAST or ClustalW of the National Center for Biotechnology Information database.

[0291] Peptide homology, similarity, or identity can be determined by comparing sequence information, for example, using the GAP computer program, as disclosed in Smith and Waterman, Adv. Appl. Math (1981) 2:482, or, for example, Needleman et al. (1970), J Mol Biol. 48: 443. In brief, the GAP program defines the total number of symbols in the shorter of the two sequences as the number of similarly arranged symbols (i.e., nucleotides or amino acids). Default parameters for the GAP program include (1) a unary comparison matrix (containing values ​​of 1 for identity and 0 for non-identity) and (2) a univariate comparison matrix, as disclosed in Schwartz and Dayhoff, eds., Atlas Of Protein Sequence And Structure, National Biomedical Research Foundation, pp. 353-358 (1979), as disclosed in Gribskov et al. (1986) Nucl. Acids Res. 48: 443. 14: 6745 weighted comparison matrix (or EDNAFULL (EMBOSS version of NCBI NUC4.4) substitution matrix); (2) a penalty of 3.0 for each gap and an additional penalty of 0.10 for each symbol in each gap (or a gap opening penalty of 10, a gap extension penalty of 0.5); and (3) no penalty for terminal gaps. Therefore, as used herein, the term "homology" or "identity" refers to the relevance between sequences.

[0292]

[0293] A specific example of the above triple activator may be a peptide having any one of the structures (i) to (iv) below, but is not limited thereto:

[0294] (i)

[0295] ;

[0296] (ii)

[0297] ;

[0298] (iii)

[0299] ;

[0300] (iv)

[0301] .

[0302]

[0303] Meanwhile, the triple active agent included in the composition of the present invention may be characterized by not including cysteine ​​(or a derivative thereof) inside the peptide or at both terminals, and being composed of natural or unnatural amino acid residues excluding cysteine.

[0304]

[0305] In addition, the triple active substance according to the present invention may be a peptide whose N-terminus and / or C-terminus is not modified, but a form in which the N-terminus and / or C-terminus is chemically modified or protected with an organic group, or an amino acid is added to the peptide terminus, etc. to protect it from protein cleavage enzymes in the body and increase stability, is also included in the scope of the present invention.

[0306] In particular, in the case of chemically synthesized peptides, since the N- and C-terminals are charged, the N-terminus may be acetylated and / or the C-terminus amidated to remove the charge, but is not particularly limited thereto.

[0307]

[0308] The triple active agent according to the present invention may have an unmodified C-terminus or an amidated C-terminus, but is not limited thereto.

[0309]

[0310] Meanwhile, the triple active agent of the present invention may include an intramolecular bridge (e.g., a covalent bridge or a non-covalent bridge), and may be in a form specifically including a ring, for example, a ring may be formed between amino acids 16 and 20 of the triple active agent, and / or between amino acids 17 and 21, but is not particularly limited thereto.

[0311] Non-limiting examples of the above ring may include a lactam ring.

[0312] The triple active agent of the present invention includes all those modified to include a ring, or an amino acid capable of forming a ring at a desired position.

[0313] For example, the triple activator of the present invention may have, but is not limited to, glutamic acid or lysine capable of forming a ring at amino acid pairs 16 and 20 and / or amino acid pairs 17 and 21.

[0314] Such a ring may be formed between the side chains of amino acids within the triple active substance, for example, a lactam ring may be formed between the side chain of lysine and the side chain of glutamic acid, but is not particularly limited thereto.

[0315]

[0316] In addition, but not particularly limited thereto, the triple active substance of the present invention may have some amino acids substituted with other amino acids or non-natural compounds to avoid recognition by enzymes that decompose the active substance in order to increase the half-life in the body.

[0317] Specifically, it may be a peptide that increases the half-life in the body by avoiding the recognition action of a decomposition enzyme through a substitution of the second amino acid sequence among the amino acid sequences of the above triple activator, but amino acid substitutions or changes for avoiding the recognition action of a decomposition enzyme in the body are included without limitation.

[0318]

[0319] In addition, the triple active agent of the present invention may include all modified ones using L- or D-type amino acids, and / or non-natural amino acids; and / or modified ones by modifying the native sequence, for example, by modifying side chain functional groups, by forming intramolecular covalent bonds, such as ring formation between side chains, by methylation, acylation, ubiquitination, phosphorylation, aminohexaoxidation, biotinylation, etc.

[0320] Additionally, the triple active agent of the present invention may include one or more amino acids added to the amino and / or carboxy termini.

[0321] The amino acids to be substituted or added above may be the 20 amino acids commonly observed in human proteins as well as atypical or non-naturally occurring amino acids, and atypical amino acids and peptides containing amino acids and typical peptide sequences can be commercially synthesized and purchased.

[0322] Amino acid derivatives can also be obtained in a similar manner, such as 4-imidazoacetic acid or alpha-methyl-leucine (αMeL), to name just a few.

[0323]

[0324] Unless otherwise indicated herein, the description or claims of the invention regarding the triple active agent according to the present invention apply to a category that includes not only the triple active agent but also a salt of the peptide (triple active agent) (e.g., a pharmaceutically acceptable salt of the peptide), or a solvate thereof. Accordingly, the description in the specification also applies to the specific salt, the specific solvate, and the specific solvate of the specific salt. The salt form may be, for example, a form using any pharmaceutically acceptable salt. The type of the salt is not particularly limited. However, it is preferable that it be a form that is safe and effective for a subject, such as a mammal, but is not particularly limited thereto.

[0325] The above term, “pharmaceutically acceptable” means a substance that can be effectively used for the intended purpose without causing excessive toxicity, irritation, or allergic reaction within the scope of pharmaceutical judgment.

[0326] As used herein, the term "pharmaceutically acceptable salt" includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Salts derived from suitable bases may include alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium.

[0327] Additionally, the term "solvate" used in the present invention refers to a triple active substance according to the present invention, or a salt thereof, formed in a complex with a solvent molecule.

[0328]

[0329] The triple active substance of the present invention can be synthesized by a method well known in the art, for example, an automatic peptide synthesizer, depending on its length, and can also be produced by genetic engineering techniques.

[0330] Specifically, the triple activator of the present invention can be prepared by standard synthetic methods, recombinant expression systems, or any other method known in the art. Accordingly, the triple activator of the present invention can be synthesized by a number of methods, including, for example, the following:

[0331] (a) a method of synthesizing a peptide stepwise or by fragment assembly by means of a solid-phase or liquid-phase method, and isolating and purifying the final peptide product; or

[0332] (b) a method of expressing a nucleic acid construct encoding a peptide in a host cell and recovering the expression product from the host cell culture; or

[0333] (c) a method for performing cell-free in vitro expression of a nucleic acid construct encoding a peptide and recovering the expression product; or

[0334] A method for obtaining fragments of a peptide by any combination of (a), (b) and (c), then linking the fragments to obtain a peptide, and recovering the peptide.

[0335]

[0336] The above may be applied to other specific examples or other aspects of the present invention, but is not limited thereto.

[0337]

[0338] A pharmaceutical composition for preventing or treating a lipid metabolism disease comprising the triple active agent of the present invention may contain the triple active agent in a pharmaceutically effective amount. In addition, the triple active agent of the composition may also include an acylated form.

[0339] An example of a triple active agent included in the above composition includes, but is not limited to, a peptide comprising any one of the amino acid sequences of SEQ ID NOs: 1 to 28.

[0340] The above triple activator can exhibit an effect of improving lipid metabolism through its action on the GLP-1 receptor, the GIP receptor, and the glucagon receptor, and in particular, since the relative activity of the GLP-1 receptor and the GIP receptor compared to natural GLP-1 and GIP is relatively higher than the relative activity of the glucagon receptor compared to natural glucagon, it can exhibit an excellent preventive or therapeutic effect on lipid metabolism diseases, but is not limited thereto.

[0341]

[0342] Including the above triple active agent in a pharmaceutically effective amount means the extent to which the desired pharmacological activity (e.g., prevention, improvement, or treatment of lipid metabolism disease) can be achieved, and may also mean a pharmaceutically acceptable level where no or minimal toxicity or side effects occur in the administered subject, but is not limited thereto. Such a pharmaceutically effective amount can be determined comprehensively considering the number of administrations, the administered subject, the formulation, etc.

[0343]

[0344] In the present invention, the term "prevention" means any action that inhibits or delays the onset of a desired disease, such as a lipid metabolism disease, by administering the triple active agent (including an acylated form) or a composition containing the same, and "treatment" means any action that improves or benefits the symptoms of a desired disease, such as a lipid metabolism disease, by administering the triple active agent (including an acylated form) or a composition containing the same.

[0345] In the present invention, the term "administration" means introducing a given substance into an individual by any appropriate method, and the route of administration of the composition is not particularly limited thereto, but the composition may be administered through any general route that can reach the target in the body, and examples thereof include intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, and rectal administration.

[0346]

[0347] The pharmaceutical composition of the present invention may additionally include a pharmaceutically acceptable carrier, excipient, or diluent. The term "pharmaceutically acceptable" as used herein means a sufficient amount to exhibit a therapeutic effect and not causing side effects, and can be easily determined by those skilled in the art based on factors well known in the medical field, such as the type of disease, the age, weight, health, sex of the subject, the subject's sensitivity to drugs, the route of administration, the method of administration, the number of administrations, the duration of treatment, and drugs used in combination or concurrently.

[0348] The pharmaceutical composition including the triple active agent of the present invention may further comprise a pharmaceutically acceptable carrier. The carrier is not particularly limited thereto, but may include, for oral administration, a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a pigment, a fragrance, etc.; for injections, a buffer, a preservative, an analgesic, a solubilizer, an isotonic agent, a stabilizer, etc. may be mixed and used; and for topical administration, a base, an excipient, a lubricant, a preservative, etc. may be used.

[0349] The composition of the present invention can be prepared in various forms by mixing it with the pharmaceutically acceptable carriers described above. For example, for oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and for injections, it can be prepared in the form of unit dose ampoules or multiple doses. In addition, it can be formulated in the form of solutions, suspensions, tablets, pills, capsules, sustained-release preparations, etc.

[0350] Meanwhile, examples of carriers, excipients, and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, or mineral oil. In addition, fillers, anticoagulants, lubricants, wetting agents, fragrances, preservatives, and the like may be additionally included.

[0351] In addition, the pharmaceutical composition of the present invention may have any one dosage form selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, liquids, emulsions, syrups, sterilized aqueous solutions, non-aqueous solutions, lyophilized preparations, and suppositories.

[0352]

[0353] In addition, the composition is formulated into a unit dosage form suitable for administration into the body of an individual according to a conventional method in the pharmaceutical field, specifically, into a form of a formulation useful for administration of a peptide drug, and can be administered by a parenteral route including, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intraventricular, pulmonary, transdermal, subcutaneous, intraperitoneal, intranasal, intragastric, topical, sublingual, vaginal, or rectal route using an administration method conventionally used in the art.

[0354] In addition, the triple active agent can be used by mixing with various carriers acceptable as pharmaceuticals, such as saline or organic solvents, and carbohydrates such as glucose, sucrose or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low-molecular-weight proteins or other stabilizers can be used as pharmaceuticals to increase stability or absorbability.

[0355] The dosage and frequency of administration of the pharmaceutical composition of the present invention are determined according to the type of drug as the active ingredient, along with various related factors such as the disease to be treated, the route of administration, the age, sex and weight of the subject, and the severity of the disease.

[0356] Although not particularly limited thereto, the pharmaceutical composition of the present invention may contain the above-mentioned ingredient (active ingredient) in an amount of 0.01 to 99% by weight to volume.

[0357]

[0358] The total effective amount of the composition of the present invention can be administered to an individual as a single dose, or can be administered by a fractionated treatment protocol in which multiple doses are administered over a long period of time. The pharmaceutical composition of the present invention can have different contents of the active ingredient depending on the severity of the disease. Specifically, the administration cycle of the triple active agent of the present invention can be from one day to one month, for example, one day, one week, two weeks, three weeks, four weeks, or one month, and the dosage administered per week can be about 0.005 to 1.5 mg per kg of body weight of the individual, but is not limited thereto. In the case of an acylated triple active agent, the dosage can be determined based on the mass value excluding the mass of the fatty acid moiety in the triple active agent, i.e., the sum of the masses of only the polypeptide moieties. However, since the dosage of the triple active agent is determined as an effective dosage for an individual by taking into consideration various factors such as the route of administration and number of treatments of the pharmaceutical composition as well as the age, weight, health status, sex, severity of the disease, diet, and excretion rate of the individual, taking these into consideration, a person having ordinary skill in the art will be able to determine an appropriate effective dosage according to a specific use of the composition of the present invention. The pharmaceutical composition according to the present invention is not particularly limited in its formulation, route of administration, and method of administration as long as it exhibits the effects of the present invention.

[0359] The pharmaceutical composition of the present invention may have excellent in vivo persistence and potency, and may exhibit a lower number and frequency of administrations compared to other drugs, but is not particularly limited thereto.

[0360]

[0361] Another embodiment of the present invention provides a method for preventing or treating a lipid metabolism disease, comprising administering to a subject the triple active agent or a composition comprising the same.

[0362] The triple active agent, the composition containing the same, lipid metabolism disease, prevention, and treatment are as described above.

[0363] In the present invention, the subject is a subject suspected of having a lipid metabolism disease, and the subject suspected of having a lipid metabolism disease refers to mammals including humans, rats, livestock, etc. that have developed or may develop the disease. However, any subject treatable with the triple active agent of the present invention or the composition containing the same is included without limitation. The lipid metabolism disease is as described above.

[0364] The method of the present invention may comprise administering a pharmaceutical composition comprising a triple active agent in a pharmaceutically effective amount. The appropriate total daily dosage may be determined by the treating physician within the scope of sound medical judgment, and may be administered once or in several divided doses. However, for the purposes of the present invention, it is preferable that a specific therapeutically effective amount for a specific subject be applied differently depending on various factors including the type and degree of response to be achieved, the specific composition including whether other agents are used in some cases, the age, weight, general health, sex, and diet of the subject, the time of administration, the route of administration, and the excretion rate of the composition, the duration of treatment, drugs used together or concurrently with the specific composition, and similar factors well known in the medical field.

[0365] The method of the present invention can be administered through a general route that can reach the target in a living body, such as intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, or rectal administration.

[0366]

[0367] Another embodiment of the present invention provides a use of the triple active agent or the composition for the prevention or treatment of lipid metabolism diseases.

[0368] The triple activator, composition, lipid metabolism disease, prevention, and treatment are as described above.

[0369]

[0370] Another embodiment of the present invention provides a use of the triple active agent or the composition in the manufacture of a drug (or pharmaceutical composition) for the prevention or treatment of a lipid metabolism disease.

[0371] The triple activator, composition, lipid metabolism disease, prevention, and treatment are as described above.

[0372]

[0373] Meanwhile, unless the context otherwise requires in this specification, it should be understood that the expressions “includes,” “including,” “containing,” etc. mean the inclusion of a specified integer or group of integers, but not the exclusion of other integers or sets of integers.

[0374]

[0375] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and the scope of the present invention is not limited by these examples.

[0376]

[0377] Example: Preparation of a triple activator

[0378]

[0379] The synthesis of the triple active substance of the present invention was performed using an automatic peptide synthesizer (Symphony X, Gyros Protein Tech.) utilizing a solid-phase synthesis method. Rink amide resin was used for amidation of the C-terminus, and each amino acid was synthesized in order from the C-terminus to the N-terminus.

[0380] Amino acids were sequentially coupled using Fmoc (9H-fluoren-9-ylmethoxycarbonyl) protected amino acids (4 equivalents relative to peptide-resin), HOBt (1-hydroxybenzotriazole, 4 equivalents relative to peptide-resin), and DIC (diisopropylcarbodiimide, 8 equivalents relative to peptide-resin). The same method was used when coupling acylated amino acids, K(1) or K(2).

[0381]

[0382]

[0383]

[0384] The Fmoc protecting group was removed by adding 8 mL of 20% piperidine / DMF to the resin-containing reaction vessel in an automated synthesizer for 5 min each. After each step, six washes with 12 mL of DMF for 10 s each were performed to remove any remaining impurities. The protecting group that was not removed was deprotected along with the peptide when it was cleaved from the resin.

[0385]

[0386] The sequence of the triple activator manufactured through this process is shown in Table 2 below.

[0387]

[0388]

[0389]

[0390] In Table 2 above, K(1) and K(2) represent acylated amino acids K(1) and K(2) having the above structures, respectively. The underlined amino acids (glutamic acid at position 16 and lysine at position 20) represent those that form a lactam ring with each other.

[0391]

[0392] The purified triple-activator was purified using reverse-phase chromatography. The synthesized peptide was purified using RP-HPLC (reactive phase high-performance liquid chromatography). Purities greater than 90% were deemed acceptable for further experiments. Furthermore, the molecular weight and other information of the peptide were confirmed using liquid chromatography / mass spectrometry (LC / MS).

[0393] The synthesized peptides were stored at -20°C until used in the experiments.

[0394]

[0395] Experimental Example 1: In vitro activity confirmation of triple activator

[0396]

[0397] In order to measure the activity of the triple activator manufactured in the above example, cell activity was measured in vitro using cell lines each transfected with a GLP-1 receptor, a GIP receptor, and a glucagon (GCG) receptor.

[0398]

[0399] Each of the above cell lines was transformed into CHO (Chinese Hamster Ovary) to express human GLP-1 receptor, human GCG receptor, and human GIP receptor genes, respectively, and the activities for GLP-1, GIP, and GCG were measured using each transformed cell line.

[0400]

[0401] In order to measure the activity of the triple activator of the present invention on the GLP-1 receptor, human GLP-1 was serially diluted from 4 nM to 0.00007 nM in 3-fold increments, and the triple activator of SEQ ID NOS: 1 to 9 was serially diluted from 40 nM to 0.00068 nM in 3-fold increments. The culture medium was removed from the CHO cells expressing the GLP-1 receptor, and 10 μl of each serially diluted substance was added to the cells, followed by incubation at room temperature for 15 minutes. Afterwards, 5 μl of Eu-cAMP tracer mix and anti-cAMP detection mix containing cell lysis buffer were sequentially added to lyse the cells, and the cells were reacted at room temperature for 60 minutes under light-shielding conditions. The cAMP accumulated in the cell lysate after the reaction was completed was measured by fluorescence, and the EC 50 After calculating the values, they were compared with each other. The relative titers compared to GLP-1 are shown in Table 3 below.

[0402]

[0403] In order to measure the activity of the triple activator of the present invention against the GCG (glucagon) receptor, human GCG was serially diluted from 4 nM to 0.00007 nM in three-fold increments, and the triple activator of SEQ ID NOS: 1 to 9 was serially diluted from 40 nM to 0.00068 nM in three-fold increments. The culture medium was removed from the CHO cells expressing the GCG receptor, and 10 μl of each serially diluted substance was added to the cells, followed by incubation at room temperature for 15 minutes. Afterwards, 5 μl of Eu-cAMP tracer mix and anti-cAMP detection mix containing cell lysis buffer were sequentially added to lyse the cells, and the cells were reacted at room temperature for 60 minutes under light-shielding conditions. The cAMP accumulated in the cell lysate after the reaction was completed was measured by fluorescence, and the EC 50After calculating the values, they were compared with each other. The relative titers compared to GCG are shown in Table 3 below.

[0404]

[0405] In order to measure the activity of the triple activator of the present invention against the GIP receptor, human GIP was serially diluted from 4 nM to 0.00007 nM in three-fold increments, and the triple activator of SEQ ID NOS: 1 to 9 was serially diluted from 40 nM to 0.00068 nM in three-fold increments. The culture medium was removed from the CHO cells expressing the GIP receptor, and 10 μl of each serially diluted substance was added to the cells, followed by incubation at room temperature for 15 minutes. Afterwards, 5 μl of Eu-cAMP tracer mix and anti-cAMP detection mix containing cell lysis buffer were sequentially added to lyse the cells, and the cells were reacted at room temperature for 60 minutes under light-shielding conditions. The cAMP accumulated in the cell lysate after the reaction was completed was measured by fluorescence, and the EC 50 After calculating the values, they were compared with each other. The relative titers compared to GIP are shown in Table 3 below.

[0406]

[0407]

[0408]

[0409] Through this, it was confirmed that the triple activator of the present invention (SEQ ID NOs: 1 to 9) has activity against all three receptors: GLP-1, GIP, and glucagon receptors.

[0410]

[0411] Experimental Example 2: Hypoglycemic effect of triple activator in normal mice

[0412]

[0413] In order to confirm the blood sugar lowering effect of the triple activator of sequence numbers 1 to 6 of the present invention, an intraperitoneal glucose tolerance test (ipGTT) was performed on normal mice.

[0414]

[0415] For this purpose, each triple activator of sequence numbers 1 to 6 was administered subcutaneously once at a dose of 0.25 mg / kg the day before the test. On the day of the test, glucose was injected into the peritoneal cavity of mice that had fasted for 4 hours, and the degree of blood glucose change was measured. Blood glucose was measured by taking a drop of whole blood from the tail vein 1 hour before the test and 0, 0.25, 0.5, 1, and 2 hours after the glucose load (1 g / kg). The area under the concentration curve was calculated based on the blood glucose change graph, and the blood glucose lowering effect was confirmed through % ​​comparison with the vehicle control group, and one-way ANOVA was used for statistical analysis (***p<0.001 vs. general mouse vehicle control group).

[0416]

[0417] As a result, as shown in Fig. 1, it was confirmed that each triple activator had a statistically significant blood sugar lowering effect compared to the excipient administration group. Specifically, it was confirmed that the AUC of the triple activator administration group of sequence number 6 was reduced by 58.17% compared to the excipient control group.

[0418]

[0419] Experimental Example 3: Lipid-improving effect of triple activator in a hamster model induced by a high-fat and high-fructose diet.

[0420]

[0421] The triple activator (SEQ ID NOs: 1 to 6) prepared in Experimental Example 1 was repeatedly administered subcutaneously (40 nmol / kg, Q2D) to a hamster model of Golden Syrian hamsters fed a high fat-high fructose diet (HFFH diet) for two weeks. After two weeks of repeated administration, total cholesterol (T-CHO), low-density lipoprotein cholesterol (LDL-c), the ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol (HDL-c / LDL-c), and triglyceride (TG) in the blood were measured.

[0422]

[0423] As a result, as shown in Fig. 2, total cholesterol and low-density lipoprotein cholesterol showed significant improvement in all triple activator (SEQ ID NOs: 1 to 6) administration groups compared to the control group. Neutral fat also showed significant improvement in the triple activator (SEQ ID NOs: 1 to 6) administration groups compared to the control group (*p<0.05, **p<0.01, ***p<0.001, by Oneway ANOVA).

[0424] Specifically, total cholesterol was confirmed to be 769.17 mg / dL in the control group (high-fat and high-fructose diet model) while it was 303.17 mg / dL in the triple activator group of sequence number 6 (normal diet group was 158 mg / dL).

[0425] Low-density lipoprotein cholesterol was 298.62 mg / dL in the control group (high-fat and high-fructose diet model), while it was 76.88 mg / dL in the triple activator group of sequence number 6 (normal diet group was 23.98 mg / dL).

[0426] The ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol was 0.64 in the control group (high-fat and high-fructose diet model), while it was 2.97 in the triple activator group of sequence number 6 (4.75 in the normal diet group).

[0427]

[0428] Neutral fat was confirmed to be 604.67 mg / dL in the control group (high-fat and high-fructose diet model) while it was 61 mg / dL in the triple activator group of sequence number 6 (normal diet group was 109.83 mg / dL).

[0429]

[0430] From the above examples, it was confirmed that the triple activator manufactured in the present invention can be used as a useful therapeutic agent for lipid metabolism-related diseases (hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia) by acting on the GLP-1 receptor, GIP receptor, and glucagon receptor, thereby improving total cholesterol (T-CHO), low-density lipoprotein cholesterol (LDL-c), the ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol (HDL-c / LDL-c), and triglycerides (TG) in the blood.

[0431]

[0432] It was confirmed that the triple active agent of the present invention has a preventive or therapeutic effect on lipid metabolism diseases due to its lipid metabolism improving effect.

[0433]

[0434] From the above description, those skilled in the art will understand that the present invention can be implemented in other specific forms without altering its technical spirit or essential characteristics. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be interpreted as encompassing all changes or modifications derived from the meaning and scope of the following claims, and their equivalent concepts, rather than the detailed description described above.

Claims

A pharmaceutical composition for preventing or treating lipid metabolism diseases, comprising a peptide active against a GLP-1 (Glucagon-like peptide-1) receptor, a GIP (Glucose-dependent insulinotropic polypeptide) receptor, and a glucagon receptor, The composition wherein the peptide comprises an amino acid sequence represented by the following general formula 1: X1-Aib-X3-GTFTSDYS-X12-X13-LDE-X17-X18-AK-X21-FVQWLLD-X29-HPSSGQPPPS (general formula 1, sequence number 29) In the above general formula 1, X1 is histidine or tyrosine; X3 is glutamine or histidine; X12 is lysine or an acylated amino acid; X13 is alpha-methyl leucine, tyrosine, or alanine; X17 is lysine or an acylated amino acid; X18 is alanine or arginine; X21 is aspartic acid or glutamic acid; X29 is histidine or glutamine, The above - represents a peptide bond, and the peptide does not contain cysteine. In claim 1, the composition has a higher relative activity against the GIP receptor and GLP-1 receptor than the relative activity against the glucagon receptor compared to the native GIP and GLP-1, respectively. A composition according to claim 1 or 2, wherein the peptide has a relative activity against the GIP receptor and the GLP-1 receptor that is at least 4 times higher than the relative activity against the glucagon receptor compared to the native GIP and GLP-1, respectively. In any one of claims 1 to 3, in the general formula 1, A composition wherein X3 is histidine. In any one of claims 1 to 4, in the general formula 1, X13 is tyrosine; X18 is alanine, composition. In any one of claims 1 to 5, in the general formula 1, X1 is tyrosine; X3 is glutamine; X13 is tyrosine; X18 is arginine, composition. In any one of claims 1 to 6, in the general formula 1, X29 is a composition containing glutamine. A composition according to any one of claims 1 to 7, wherein the peptide has an acyl group attached to one or more amino acids of the peptide through a linker selected from the group consisting of AEEA ((2-(2-aminoethoxy)ethoxy)acetic acid), GABA (4-Aminobutyric acid), Ava (5-Aminovaleric acid), Ahx (Aminohexanoic acid), triazole, and polyethylene glycol (PEG). A composition according to claim 8, wherein the linker comprises AEEA. A composition according to claim 8 or 9, wherein the linker comprises 0 to 3 AEEAs. A composition according to any one of claims 1 to 10, wherein the acylated amino acid is an amino acid represented by K(1) or K(2): . A composition according to any one of claims 1 to 11, wherein the peptide is amidated at the C-terminus. A composition according to any one of claims 1 to 12, wherein the peptide has any one of the following structures (i) to (iv): (i) ; (ii) ; (iii) ; (iv) . A composition according to any one of claims 1 to 13, wherein the peptide comprises any one sequence selected from the group consisting of amino acid sequences of SEQ ID NOs: 1 to 28. A composition according to any one of claims 1 to 14, wherein amino acids 16 and 20 from the N-terminus of the general formula 1 form a ring with each other. A composition according to any one of claims 1 to 15, wherein the peptide has a structure of the following general formula 2: [General Formula 2] In the above general formula 2, The above n is 16 or 18, X1 is histidine or tyrosine; X3 is glutamine or histidine; X13 is alpha-methyl leucine, tyrosine, or alanine; X18 is alanine or arginine; X21 is aspartic acid or glutamic acid; X29 is histidine or glutamine. A composition according to any one of claims 1 to 16, wherein the lipid metabolism disease is any one selected from the group consisting of hyperlipidemia, dyslipidemia, hypercholesterolemia, and hypertriglyceridemia. A composition according to any one of claims 1 to 17, wherein the composition further comprises a pharmaceutically acceptable carrier. A composition according to any one of claims 1 to 18, wherein the composition exhibits at least one of the following characteristics (i) to (iv) upon administration: (i) Reduction of total cholesterol (T-CHO) in the blood; (ii) reduction of low-density lipoprotein cholesterol (LDL-c) in the blood; (iii) increased high-density lipoprotein cholesterol to low-density lipoprotein cholesterol ratio (HDL-c / LDL-c); and (iv) Reduction of triglycerides (TG) in the blood.

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