OA18548A - Peptide having anti-diabetic and anti-obesity effects and use thereof. - Google Patents
Peptide having anti-diabetic and anti-obesity effects and use thereof. Download PDFInfo
- Publication number
- OA18548A OA18548A OA1201700421 OA18548A OA 18548 A OA18548 A OA 18548A OA 1201700421 OA1201700421 OA 1201700421 OA 18548 A OA18548 A OA 18548A
- Authority
- OA
- OAPI
- Prior art keywords
- peptide
- seq
- obesity
- complex
- diabètes
- Prior art date
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Abstract
A peptide and a peptide complex of the present invention exhibit an anti-obesity effect by inhibiting fat accumulation and decomposing already accumulated fat, and exhibit an excellent effect with respect to diabetes by effectively reducing blood sugar. The peptide and the peptide complex of the present invention decrease the expression of PPARy, ACC, and aP2, which are adipogenic markers, increase the expression of pHSL, AMPK- α1, CGI-58, and ATGL, which are lipolytic factors, and reduce the size of fat cells and blood cholesterol values. The peptide and the peptide complex of the present invention, which have excellent activity and safety, can be advantageously applied to drugs and quasi-drugs.
Description
PEPTIDE WITH ANTI-OBESITY AND ANTI-DIABETES ACTIVITY AND USE THEREOF
Technical Field
This application daims priority to Korean Patent Application No.10-2015-0059648, filed April 28, 2015, to the KIPO. The content of incorporated by reference in invention
The présent anti-obesity and thereof.
filed April 28, the above applications their entirety.
relates to a peptide anti-diabetes activity, and are with use
Background
In
Art
Korea, with westernization diseases such increased of dietary fat the growth diet life, obesity, diabètes, and intake has of economy and onset of recently and the metabolic hyperlipidemia, fatty
In as arteriosclerosis, to insufficient exercise, aesthetic problem to people to slim body types as various disorders. therapeutic agents for into drugs that act who well liver addition, generally as being obesity may be on the central
Drugs placed on the the serotonin fenfluramine, noradrénaline and on hypertension, increased due obesity is an tend to prefer associated with
To date, largely divided nervous System to affect appetite and drugs that act on the gastrointestinal· tract to inhibit uptake. acting on the central· nervous System were market as anti-obesity drugs which work on (5-HT) in the nervous System such as dexfenfluramine and the like, on the nervous System such as ephedrine and caffeine, both the serotonin and the noradrenaline nervous System such as recently developed sibutramine, as classified by acting mechanisms. Représentative of anti-obesity drugs acting on the gastrointestinal tract is orlistat,
Z
approved as a therapeutic agent for obesity, which inhibits intestinal lipase to reduce fat uptake. There are problems with some of the pre-existing drugs. For example, fenfluramine and the like hâve been prohibited 5 from being marketed due to the side effect of incurring primary pulmonary hypertension or valvular heart disease, and other drugs cannot be applied to patients with heart failure or kidney failure due to the occurrence of blood pressure réduction or lactic 10 acidosis.
Diabètes is a group of metabolic disorders caused when insulin is insufficiently secreted or in does that do not enable normal function (DeFronzo, 1988) and is characterized by hyperglycemia, that is, high blood 15 sugar levels over a prolonged period, which causes various symptoms and syndromes, with glucose in urine. In recent years, the prevalence of obesity, particularly, abdominal obesity has increased, leading to the explosion of the prevalence of diabètes.
As of 2000, diabètes patients were estimated to be
170 million worldwide and expected to increase to 370 million people in 2030. However, a 2008 analysis report showed that the number of diabètes patients may hâve already reached 350 million worldwide (Danaei et al., 25 2011), with far more significant aggregation than expectation. It is reported that more than about 80 % of type 1 diabètes patients are obese whereas only less than 10 % of (non-)obese patients hâve diabètes (Harris et al.. 1987). The corrélation between diabètes and 30 obesity is attributed to the fact that adipokines and free fatty acids are irregularly secreted to induce fatty acids to accumulate in insulin-sensitive tissues such as beta cells, kidneys, liver, heart, etc., resulting in lipotoxicity. If left without suitable treatment, chronic hyperglycemia may be prone to incurring various pathological symptoms including retinopathy, rénal dysfunction, neuropathy, and vascular disorder. Indispensable for preventing such complications is effective blood sugar management.
Nowadays, the control of blood sugar levels is accomplished by lifestyle improvement (diet therapy, exercise therapy), and médications. However, diet therapy or exercise therapy is difficult to strictly manage and practice, with limitations of the effects thereof. Hence, most patients with diabètes rely on the control of blood sugar levels by médications such as insulin, insulin secretagogues, insulin sensitizer, and hypoglycémie agents, as well as lifestyle improvement.
Insulin produced using a recombinant method is used as a drug indispensable to type 1 diabètes patients and type 2 diabètes patients which fail to control blood sugar levels, and is advantageous in blood sugar control. However, it suffers from the disadvantage of repulsion to syringe needles, difficulty in administration, hypoglycémie risk, and weight gain.
Meglitinides, a kinds of insulin secretagogues, are short-acting agents and are taken before meals. Among them are NovoNorm (repaglinide) , Fastic (nateglinide), and Glufast (mitiglinide). Insulin sensitizers are characterized by almost no hyperglycémie incurrence when taken alone, and may be exemplified by biguanide drugs, such as metformin, and thiazolidinedione drugs such as Avanida (rosiglitazone) and Actos (pioglitazone).
Recently, GLP-1 agonists hâve been developed using the action of glucagon-like peptide-1, which is an insulin secretion-stimulating hormone, and include exenatide and Victoza (liraglutide). In addition, DDP-4 inhibitors, which inhibit the action of DPP (dipeptidyl peptidase-4), an enzyme responsible for the rapid
inactivation of GLP-1, are newly developed drugs and are representatively exemplified by Januvia (ingrédient name : sitagliptin). However, those drugs are reported to hâve side effects of hepatoxicity, gastrointestinal 5 disorders, cardiovascular disorders, and carcinogenicity. Another problem with the drugs is a high annual treatment cost, which is a barrier to the treatment of diabètes. Indeed, health care costs of prediabetes and diabètes approached about 200 trillion won 10 in the USA as of 2007 (Dali et al., 2010), and health care costs of obesity are also near 150 trillion won only in the USA as of 2008 (Finkelstein et al., 2009). Therefore there is an urgent need for the development of a drug that can effectively lower blood glucose levels 15 and can be applied to both diabètes and obesity-induced diabètes, with less side effects.
For this, the présent inventors hâve recently paid attention to energy metabolism-regulating mechanisms in order to find an improved method for the treatment of 20 obesity, and hâve made research of signais responsible for lipid accumulation and proteins affecting lipid accumulation upon the intake of high-fat diets in humans, with the premise that the compound to be developed should of higher safety (lower toxicity). As a 25 resuit of research on signais for suppressing the expression of proteins responsible for fat accumulation and for degrading accumulated fat and on proteins involved in the signaling, the présent inventors succeeded in developing peptides that promote lipolysis.
In addition, the peptides of the présent invention exhibit outstanding therapeutic efficacy on diabètes and obesity-induced diabètes. The fat accumulation induced by high-fat diets, the suppression of insulin signaling attributed to fat accumulation in the liver or muscle, and resulting insulin tolérance are causes of diabètes.
Each and complexes of the peptides according to the présent invention are therapeutically effective for such diabètes and obesity-induced diabètes.
Throughout this spécification, reference is made to many papers and patent documents, with citations thereof indicated. The disclosures of the cited papers and patent documents are herein entirely incorporated by reference and thus the level of technical field to which the présent invention belong and contents of the présent invention are explained more definitely.
Detaiied Description of the Invention
Technical Probiem
Culminating in the présent invention, intensive and thorough research on the development of plural outstanding peptides having biologically effective activity, conducted by the présent inventors, led to the finding that peptides having the amino acid sequences of SEQ ID NOS: 1 to 7 exhibit not only anti-obesity effects by suppressing high-fat diet-induced fat accumulation and degrading already accumulated fat, but also high therapeutic effects on diabètes and obesity-induced diabètes, and diabètes complications.
Accordingly, an object of the présent invention is to provide peptides having the amino acid sequences of SEQ ID NOS: 1 to 7.
Another object of the présent invention is to provide a peptide having anti-obesity or anti-diabetes activity.
A further object of the présent invention is to provide a peptide complex having anti-obesity or antidiabetes activity
A still further object of the présent invention is to provide a pharmaceutical composition for the prévention or treatment of obesity.
Still another object of the présent invention to provide a pharmaceutical composition for the prévention or treatment of diabètes.
Other purposes and advantages of the présent invention will become clarified by the following detailed description of the invention, daims, and drawings.
Technical Solution
One embodiment of the présent invention provides a peptide having one selected from the group consisting of the amino acid sequences of SEQ ID NOS: 1 to 7.
Another embodiment of the présent invention provides a peptide of anti-obesity and anti-diabetes activity having one selected from the group consisting of the amino acid sequences of SEQ ID NOS: 1 to 7.
Provided according to another embodiment of the présent invention is a peptide complex of anti-obesity and anti-diabetes activity, composed of the following peptide combination:
| (a) | a | peptide | having | the | amino | acid | sequence | of | |
| SEQ | ID NO: | 1 | f | ||||||
| (b) | a | peptide | having | the | amino | acid | sequence | of | |
| SEQ | ID NO: | 2 | or 3 ; and | ||||||
| (c) | a | peptide | having | the | amino | acid | sequence | of | |
| SEQ | ID NO: | 6 | or 7. |
As a resuit of the effort of the présent inventors to develop plural outstanding peptides having biologically effective activity, it was found that peptides having the amino acid sequences of SEQ ID NOS: 1 to 7 suppress high-fat diet-induced fat accumulation and dégradé already accumulated fat, thus exhibiting an anti-obesity effect and a therapeutic effect on diabètes and obesity-induced diabètes, or diabètes complications.
As used herein, the term peptide refers to a linear molécule of amino acid residues linked by peptide bonds. The peptides of the présent invention may be prepared using chemical synthesis methods known in the art, especially solid-phase synthesis techniques (Merrifield, J. Amer. Chem. Soc. 85:2149-54(1963); Stewart, et al., Solid Phase Peptide Synthesis, 2nd. ed., Pierce Chem. Co.: Rockford, 111(1984)) or a liquidphase synthesis method (US Pat. No. 5,516,891).
In order to select régions of the amino acid sequences thereof and increase the activity thereof, the peptides of the présent invention may be modified at Nor C-terminals thereof. Through such modification, the peptides of the présent invention may be imparted with a prolonged half-life after in vivo administration.
Further, C-terminals of the peptides of the présent invention may be modified with a hydorxy group (-OH), an amino group (-NH2), an azide group (-NHNH2), etc. while N-terminals may be coupled with a protecting radical consisting of the group consisting of acetyl, fluorenyl methoxy carbonyl, formyl, palmitoyl, myristyl, stearyl, and polyethylene glycol (PEG).
Through the above stated amino acid modification, the peptides of the présent invention can greatly increase in stability. As used herein, the term stability is intended to refer to both in vivo stability and storage stability (e.g., stability during storage at room température). The protecting group acts to protect the peptides of the présent invention against the attack of protéinases in vivo.
According to one embodiment of the présent invention, the peptides of the présent invention exhibit the effect of suppressing high-fat diet-induced fat accumulation and degrading already accumulated fat, decrease the expression of the adipogénie markers PPARy, ACC, and aP2, increase the expression of the lipolytic
factors pHSL, AMPK-al, CGI-58, and ATGL, reduce the size of adipose cells, and lower blood cholestérol levels. These results indicate that the peptides of the présent invention hâve excellent therapeutic effects on obesity, 5 diabètes, and obesity-induced diabètes.
Not only individual peptides of SEQ ID NOS: 1 to 7, but also a complex thereof exhibits excellent antiobesity and anti-diabetes activity.
According to the présent invention, the peptides 10 of SEQ ID NOS: 3, 5, and 7 correspond respectively to those of SEQ ID NOS: 2, 4, and 6, with the exception that the Cys residue is substituted with the Ser residue. The corresponding paired peptides are almost identical in terms of anti-obesity and anti-diabetes 15 activity.
In accordance with an embodiment of the présent invention, the peptide complex exhibiting anti-obesity or anti-diabetes activity is composed of a peptide having the amino acid sequence of SEQ ID NO: 1; a 2 0 peptide having the amino acid sequence of SEQ ID NO: 2 or 3; and a peptide having the amino acid sequence of SEQ ID NO: 6 or 7.
According to another embodiment of the présent invention, the peptide complex of the présent invention 25 is composed of peptides having the respectively amino acid sequences of SEQ ID NOS: 1, 3, and 7.
Contemplated in accordance with another aspect of the présent invention is a pharmaceutical composition comprising the peptide or peptide complex of the présent 30 invention as an effective ingrédient for preparing or treating obesity.
Superior in terms of anti-adipogenetic and lipolytic functions, the peptide or peptide complex of the présent invention can be useful for the prophylaxie 35 or therapy of obesity.
A further aspect of the présent invention provides a pharmaceutical composition comprising the peptide or peptide complex of the présent invention as an effective ingrédient for preventing or treating diabètes.
Functioning to effectively lower an increased blood sugar level in diabètes animal models, the peptide or peptide complex of the présent invention can find applications in the prophylaxis or therapy of diabètes.
According to some particular embodiments of the présent invention, the composition of the présent invention is a pharmaceutical composition comprising:
(a) a pharmaceutically effective amount of the peptide or peptide complex of the présent invention; and a pharmaceutically acceptable carrier.
The term pharmaceutically effective amount, as used herein, means a sufficient amount to achieve the above-stated efficacy or activity of the peptide.
The pharmaceutically acceptable carrier contained in the pharmaceutical composition of the présent invention may be that commonly used in drug formulations and include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium carbonate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnésium stéarate, and minerai oil. In addition to those ingrédients, the pharmaceutical composition of the présent invention may further comprise a lubricant, a humectant, a sweetener, a flavorant, an emulsifier, a suspending agent, and a preservative. With regard to pharmaceutically acceptable carriers and agents suitable for use, reference may be made to Remington's Pharmaceutical Sciences (19th ed., 1995).
The pharmaceutical composition of the présent invention may be administered orally or parenterally. For parentéral administration, intramuscular, intravenous, subcutaneous, intraperitoneal, topical, or transcutaneous routes may be used.
The dosage of the pharmaceutical composition according to the présent invention may vary depending on various factors, including dosage form, administration modality, the patient's âge, weight, gender, state of health, diet, the time of administration, the route of administration, excrétion rate, sensitivity, etc. For example, the pharmaceutical composition according to the présent invention may be administered at a daily dose in the range of 0.0001 to 1, 000 pg.
The pharmaceutical composition according to the présent invention may be prepared in single-dose forms or in multi-dose packages using a pharmaceutically acceptable carrier and/or excipient according to a method that may be easily carried out by those skilled in the art. Herein, the formulation of the pharmaceutical composition may be a solution, suspension or émulsion of the pharmaceutical composition in oil or aqueous medium, or an extract, powder, granule, tablet or capsule containing the pharmaceutical composition, and may further comprise a dispersing agent or a stabilizer.
Advantageous Effects
Features and advantages of the présent invention are summarized as follows:
(i) the peptides and présent invention exhibit effect by suppressing fat already accumulated fats, therapeutic effect the peptide complex of the not only an anti-obesity accumulation and degrading but also an outstanding on diabètes by effectively reducing blood sugar levels.
(ii) the peptides and the peptide complex of the présent invention decrease the expression of the adipogénie markers PPARy, ACC, and aP2, increase the expression of the lipolytic factors pHSL, AMPK-al, CGI58, and ATGL, thus reducing adipocyte sizes and blood cholestérol levels.
(iii) the peptides and the peptide complex of the présent invention hâve excellent activity and safety and thus can be advantageously applied to drugs and quasidrugs.
Brief Description of the Drawings
FIG. 1 shows lipids accumulated after treatment with peptides of the présent invention, as analyzed by Oil red O staining: (a) peptide of SEQ ID NO: 1, (b) peptide of SEQ ID NO: 3, and (c) peptide of SEQ ID NO:
5.
FIG. 2 shows results of lipid accumulation after treatment with the peptide complex of the présent invention, as analyzed by Oil red O staining.
FIG. 3 shows measurement results of the expression levels of the gene aP2, which is invol ved in adipogenesis, after treatment with the peptides of the présent invention: (a) peptide of SEQ ID NO: 1, (b) peptide of SEQ ID NO: 3, and (c) peptide of SEQ ID NO:
5.
FIG. 4 shows measurement results of expression levels of PPARy, ACC, and aP2 genes, which play an important rôle in adiapgenesis, after treatment with various concentrations of the peptide complex of the présent invention.
FIG. 5 shows measurement results of expression levels of PPARy and phospho-HSL, which play an important rôle in adipogenesis, after various concentrations of the peptide complex of the présent invention.
FIG. 6 shows measurement results of expression levels of AMPK-otland CGI58 genes, which are involved in the dégradation of accumulated fats, after treatment with the peptides and peptide complex of the présent 5 invention: (a) peptide of SEQ ID NO: 1, (b) peptide of SEQ ID NO: 3, (c) peptide of SEQ ID NO: 5, and (d) a complex of peptides of SEQ ID NOS: 1, 3, and 7.
FIG. 7 shows measurement results of ATGL, a protein involved in the dégradation of accumulated fats, 10 after treatment with various concentrations of the peptide complex of the présent invention.
FIG. 8 shows results of expression levels of the Phospho-HSL protein involved in the dégradation of accumulated fats, after treatment with the peptides of 15 the présent invention: (a) peptide of SEQ ID NO: 1, (b) peptide of SEQ ID NO: 3, (c) peptide of SEQ ID NO: 5, and (d) a complex of peptides of SEQ ID NOS: 1, 3, and
7, as measured by immunostaining.
FIG. 9 shows measurement results of glycerol produced after treatment with various concentrations of the peptides complex of the présent invention.
FIG. 10a shows adipose tissues degraded in obese mouse experiment models after treatment with the peptide complex of the présent invention. FIG. 10b shows sizes 25 and numbers of the adipose tissues degraded in obese mouse experiment models after treatment with the peptide complex of the présent invention.
FIG. 11 shows results of the expression levels of the Phospho-HSL protein which is involved in the 30 dégradation of accumulated fats after treatment with the peptide complex of the présent invention, as measured by immunostaining.
FIG. 12 shows changes in body weight (g) and diet intake of obese mice after treatment with the peptide 35 complex of the présent invention.
FIG. 13 shows images of obese mice after treatment of the peptide complex of the présent invention.
FIG. 14 shows results of fat distribution in obese mouse models induced by feeding a high-fat diet to the 5 experimental animal model C57BL/6, as analyzed by microCT.
FIG. 15 shows images of the adipocyte tissues extracted from obese mouse models induced by feeding a high-fat diet to the experimental animal model C57BL/6, 10 after treatment with the peptide complex of the présent invention.
FIG. 16a shows morphological images of the adipocytes in adipose tissues taken from obese mouse models induced by feeding a high-fat diet to the 15 experimental animal model C57BL/6, after treatment with the peptide complex of the présent invention. FIG. 16b shows size results of the adipocytes in the adipose tissues taken from obese mouse models induced by feeding a high-fat diet to the experimental animal model 20 C57BL/6, after treatment with the peptide complex of the présent invention.
FIG. 17 shows measurement results of the expression levels of the phosphor-HSL protein, which is involved in lipolysis, in adipocytes of adipose tissues 25 taken from obese mouse models induced by feeding a highfat diet to the experimental animal model C57BL/6, after treatment with the peptide complex of the présent invention.
FIG. 18 shows measurement results of cholestérol 30 levels in blood samples taken from obese mouse models induced by feeding a high-fat diet to the experimental animal model C57BL/6, after treatment with the peptide complex of the présent invention.
FIG. 19 shows measurement results of glucose 35 levels in blood samples taken from obese mouse models
induced by feeding a high-fat diet to the experimental animal model C57BL/6, after treatment with the peptide complex of the présent invention.
FIG. 20 shows changes in blood sugar level in obesity-induced DB/DB mouse models after treatment with the peptide complex of the présent invention.
FIG. 21 shows changes in blood cholestérol level in obesity-induced DB/DB mouse models after treatment with the peptide complex of the présent invention.
FIG. 22 shows changes in blood sugar level in obesity-induced DB/DB mouse models after treatment with the peptides of the présent invention: (a) peptide of SEQ ID NO: 1, (b) peptide of SEQ ID NO: 3, and (c) peptide of SEQ ID NO: 5.
FIG. 23 shows measurement résulte of expression levels of IGF-1 and insulin after treatment with the peptide of SEQ ID NO: 7.
FIG. 24 shows changes in blood sugar level in obesity-induced DB/Db mouse model after treatment with 20 the peptide of SEQ ID NO: 7.
FIGS. 25a-25d show changes in blood sugar levels in diabètes patients having high blood glucose levels after treatment with the peptide complex of the présent invention.
Mode for Carrying Out the Invention
Hereinafter, the présent invention will be described in further detail with reference to examples. It will be obvious to a person having ordinary skill in 30 the art that these examples are illustrative purposes only and are not to be construed to limit the scope of the présent invention. Thus, the substantial scope of the présent invention will be defined by the appended daims and équivalents thereof.
EXAMPLES
SYNTHESIS EXAMPLE 1: Peptide Synthesis
In a reactor, 700 mg of chlorotrityl chloride resins (CTL resins, Nova biochem Cat No. 01-64-0021) was 5 added with 10 ml of methylene chloride (MC) and stirred for 3 min. After removal of the solvent, 10 ml of dimethyl formamide (DMF) was added. The solution was stirred again for 3 min, and then the solvent was removed. To the reactor was added 10 ml of a 10 dichloromethane solution, followed by 200 mmole of FmocAsn(Trt)-OH (Bachem, Swiss) and 400 mmole of diisopropyl ethylamine (DIEA). The reactants were well dissolved and reacted while stirring for 1 hour. Thereafter, the solution was washed, and reacted with a solution of 15 methanol and DIEA (2:1) in DCM (dichloromethane) for 10 min. Subséquent to washing with an excess of DCM/DMF (1:1), the solvent was removed. Then, 10 ml of dimethyl formamide (DMF) was added, followed by stirring for 3 min. After removal of the solvent, 10 ml of a 20 deprotecting solution (20 % piperidine/DMF) was added to the reactor. Stirring at room température for 10 min was precedent to the removal of the solvent. The deprotecting solution was added in the same amount and then removed after 10 min of reaction. Washing was 25 performed twice with DMF, once with MC, and once with DMG for 3 min each wash to afford Asn-CTL resins. In another reactor, 200 mmole of Fmoc-Arg(Pbf)-OH(Bachem, Swiss) , 200 mmole of HoBt, and 200 mmole of Bop were added to 10 ml of a DMF solution and well dissolved by 30 stirring. To the reactor, 400 mmole of DIEA was added in two aliquots, followed by stirring for at least 5 min to the complété dissolution of the solid. The dissolved amino acid mixture solution was introduced into the reactor in which the deprotected resins were placed, 35 followed by stirring for 1 hour at room température for
reaction. After the reaction liquid was removed, stirring was carried three times for 3 min each time, together with a DMF solution which was then removed. A small amount of the reaction resins was taken and used in a Kaiser test (ninhydrin test) for examining an extent of the reaction. The same deprotection reaction was performed twice with the deprotecting solution to give Arg-Asn-CTL resins. The resins were sufficiently washed with DMF and MC before an additional Kaiser test.
The following amino acid attachment experiments were carried out in the same manner as described above. According to selected amino acid sequences, reactions were sequentially induced with Fmoc-Thr(tBu)-OH, FmocLys(Boc)-OH, and Fmoc-Leu-OH in that order. The Fmoc15 protecting group was removed by reacting twice with a deprotecting solution for 10 min for each reaction and then well washing. Acetic anhydride, DIEA, and HoBt were added and subjected to acétylation for 1 hour. The peptidyl resins thus obtained were washed with DMF, MC, and methanol three times each. The resins were dried with nitrogen gas slowly flowed and then were completely vacuum-dried under a P2O5 atmosphère. The resins were reacted for 2 hours at room température with 30 ml of a leaving solution (trifluoroacetic acid 81.5%, distilled water 5%, thioanisole 5%, phénol 5%, EDT 2.5%, and TIS 1%) while intermittently agitating. The resins were filtered and washed with a small volume of TFA solution, after which the filtrate was combined with the mother liquid. After distillation at a reduced pressure to reduce the total volume by two, 50 ml of cold ether was used to induce précipitation, and the précipitâtes thus formed were collected by centrifugation and washed twice with cold ether. After removal of the mother liquid, the remainder was sufficiently dried under a nitrogen atmosphère to afford 0.85 g of the unpurified peptide of
SEQ ID NO: 1 NH2-Leu-Lys-Thr-Arg-Asn-COOH (yield: 92%). Synthesis was made of NH2-Lys-Gly-Ala-Cys(Ser)-Thr-GlyTrp-Met-Ala-COOH in an amount of 0.7 8 g as peptides of SEQ ID NOS: 2 and 3 (yield: 82%), NH2-Ala-Cys (Ser) Thr5 Leu-Pro-His-Pro-Trp-Phe-Cys(Ser)-COOH in an amount of 0.92 g as peptides of SEQ ID NOS: 4 and 5 (yield: 85%), and NH2-Cys(Ser)-Asp-Leu-Arg-Arg-Leu-Glu-Met-TyrCys (Ser)-COOH in an amount of 0.7 6 g as peptides of SEQ ID NOS: 6 and 7 (yield: 88%). The peptides of SEQ ID
NOS: 1, 2, 4, and 6 were found to hâve molecular weights of 630.7 (cale.: 630.7), 924.5 (cale.: 924.1), 1236 (cale.: 1236.5), and 1301.5 (cale.: 1301.5), respectively, as measured by mass spectrometry.
TABLE 1
| Peptide | Amino Acid Sequence | Analysis (Mass spectrometry) | |
| Measured | Calculated | ||
| SEQ ID NO: 1 | 630.7 | 630.7 | |
| SEQ ID NO: 2 | KGACTGWMA | 924.5 | 924.1(908.0) |
| SEQ ID NO: 3 | KGASTGWMA | ||
| SEQ ID NO: 4 | ACYLPHPWFC | 1236 | 1236.5 (1269.4) |
| SEQ ID NO: 5 | ASYLPHPWFS | ||
| SEQ ID NO: 6 | CDLRRLEMYC | 1301.5 | 1301.5 |
| SEQ ID NO: 7 | SDLRRLEMYS |
Meanwhile, peptides of SEQ ID NOS: 1, 3, and 7 were mixed in equal amounts to give a peptide complex which was evaluated for efficacy.
EXAMPLE 1: Assay for Inhibitory Activity against Adipogenesis
1-1. Assay for suppression of lipid accumulation by use of pre-adipocyte (Oil red O staining)
The pre-adipocytes 3T3-L1 cells were grown to confluence and then incubated for two days with various concentrations of the peptides in a différentiation medium containing 10 pg/ml insulin, 0.1 μΜ dexamethasone, and 0.5 μΜ IBMX. The medium was exchanged every two days with a medium containing 10 pg/ml insulin. After différentiation was induced for 10 days, the génération of droplet in the cells was examined by Oil Red O staining. The prepared 3T3-L1 adipocytes were washed with PBS, fixed with 3.7% formalin for one hour, and washed with 60% isopropanol. The resulting cells were dyed with Oil Red O reagent at room température for 2 0 min. After removal of the Oil Red O reagent, the cells were washed three times with distilled water, and observed under a phase-contrast microscope. For quantitative analysis, fats were extracted from the cells using 100 % isopropanol, and the cells were transferred in an amount of 200 μΐ/well into 96-well plates and measured for optical density at 500 nm using an ELISA reader.
Experimental data showed that treatment with peptides of SEQ ID NOS: 1, 3, and 5 decreased extents of fat accumulation in cells, as measured by Oil red O staining (FIGS. la~c).
An extent of lipid accumulation in cells was also reduced when a complex of peptides of SEQ ID NOS: 1, 3, and 7 was applied by concentrations (FIG. 2).
1-2. Suppression of expression of genes involved in adipogenesis
3T3-L1 cells (pre-adipocytes) were seeded at a density of 3x105 cells/well into 6-well plates. After 24 hours of culturing, the cells were incubated at with predetermined concentrations (0.1, 1, and 10 pg/ml) of the peptides for 14 days in a 37°C incubator. Thereafter, the cells were harvested and treated with an
RNA extraction solution (Easy Blue, Intron) to préparé RNA from which cDNA was then synthesized using an RT premix (Intron). PCR was performed using primers for antigenic markers (PPARy, ACC, and aP2), and a PCR premix (Intron).
Target-specific primer sequences for PCR of adipogénie markers were as follows: PPARy forward primer sequence, 5'-TTTTCAAGGGTGCCAGTTTC-3' and PPARy reverse primer, 5'-AATCCTTGGCCCTCTGAGAT-3' (annealing température, 60°C); ACC forward primer sequence, 5'ACCTTACTGCCATCCCATGTGCTA-3' and ACC reverse primer, 5'GTGCCTGATGATCGCACGAACAAA-3' (annealing température, 60°C); aP2 forward primer sequence, 5'CATCAGCGTAAATGGGGATT-3' and aP2 reverse primer, 5'ACACATTCCACCACCAGCTT-3' (annealing température, 60°C).
PCR products were each loaded in a volume of 5 μΐ into a 1 % agarose gel, and electrophoresed, followed by identifying bands in a Gel-Doc.
In the mouse osteoblast cell line 3T3-L1 which was incubated with the peptide of SEQ ID NO: 1, 3, or 5 for three days, decreased expression levels of the adipogénie marker aP2 were observed (FIGS. 3a-c).
Also, when incubated for three days with concentrations of 0.1 pg/ml, 1 pg/ml, and 10 pg/ml of a complex of peptides of SEQ IS Nos: 1, 3 and 7, the mouse osteoblast cell line was observed to decrease in the expression of the adipogénie markers PPARy, ACC, and aP2, like the positive control cells treated with 100 ng/ml TNFa (FIG. 4).
1-3. Expression observation of adipogenesis and lipolysis inducing proteins by use of pre-adipocyte
3T3-L1 cells (pre-adipocytes) were seeded at a density of 3x105 cells/well into 6-well plates. After 24 hours of culturing, the cells were incubated for 14 days
with predetermined concentrations (0.1, 1, and 10 pg/ml) of the peptide complex in a 37°C incubator. Cell lysâtes obtained by treatment with a cell lysis buffer were used for protein quantitation, followed by Western blotting with an anti-PPARy antibody (Santa Cruz Biotechnology, USA), which is an antibody against an adipogénie marker, and an anti-pHSL antibody (Santa Cruz Biotechnology, USA), which is an antibody against an lipolytic marker.
When treated with the peptide complex by concentration, the cells were observed to decrease in the expression of the adipogénie marker PPARy in a dosedependent manner while ail increasing in the expression of the lipolysis marker pHSL (FIG. 5).
EXAMPLE 2: Assay for Lipolytic Activity
2-1. Increased expression of genes involved in lipolysis
3T3-L1 cells (pre-adipocytes ) were seeded at a density of 3x105 cells/well into 6-well plates. After 24 20 hours of culturing, the cells were incubated for 14 days with predetermined concentrations (0.1, 1, and 10 yg/ml) of the peptides in a 37°C incubator (positive control: 100 ng/ml TNFa (SIGMA) ) . The cells were harvested and treated with an RNA extraction solution (Easy Blue, 25 Intron) to préparé RNA from which cDNA was then synthesized using an RT premix (Intron). PCR was performed using primers for markers (AMPK-al and CGI5S), and a PCR premix (Intron).
Target-specific primer sequences for PCR of lipolytic markers were as follows: AMPK-al forward primer sequence, 5'-TGACCGGACATAAAGTGGCTGTGA-3'’ and AMPK-al reverse primer, 5'-TGATGATGTGAGGGTGCCTGAACA3'(annealing température, 60°C); CGI58 forward primer sequence, 5'-TGTGCAGGACTCTTACTTGGCAGT-3' and CGI58 35 reverse primer, 5' -GTTTCTTTGGGCAGACCGGTTTCT-3' (annealing
température, 60°C).
PCR products were each loaded in a volume of 5 μΐ into a 1 % agarose gel, and electrophoresed, followed by identifying bands in a Gel-Doc.
In ail of the pre-adipocytes (3T3-L1) which were incubated with the peptides, increased expression levels of the lipolytic markers AMPK-al and CGI-58 were detected (FIGS. 6a-c). In addition, treatment with the peptide complex was observed to increase the expression 10 of AMPK-al and CGI-58 in dose-dependent manners and to higher levels compared to the positive control TNFa 100 ng/ml treatment (FIG. 6d) .
2-2. Expression observation of lipolysis inducing proteins by use of pre-adipocyte
3T3-L1 cells (pre-adipocytes) were seeded at a density of 3x105 cells/well into 6-well plates. After 24 hours of culturing, the cells were incubated for 14 days with predetermined concentrations (0.1, 1, and 10 pg/ml) 20 of the peptide complex in a 37 °C incubator (positive control: 100 ng/ml TNFa(SIGMA)). Cell lysâtes obtained by treatment with a cell lysis buffer were used for protein quantitation, followed by Western blotting with an anti-ATGL antibody (Santa Cruz Biotechnology, USA) , 25 which is an antibody against an lipolytic marker.
The expression of the lipolytic marker ATGL was increased by treatment with the peptide complex (FIG. 7) .
2-3. Fluorescence microscopie observation of expression of lipolysis inducing protein by use of preadipocyte
3T3-L1 cells (pre-adipocytes) were seeded at a density of 3x105 cells/well into 6-well plates. After 24 35 hours of culturing, the cells were incubated for 14 days with the individual peptides or the peptide complex (1 pg/ml) in a 37°C incubator (positive control: 100 ng/ml TNFa (SIGMA)). Thereafter, the cells were fixed with 70 % éthanol and then subjected to immunostaining with an anti-phospho-HSL antibody (Santa Cruz Biotechnology, USA) to observe the cellular expression of phospho-HSL, a lipolytic marker.
From the experimental data, the peptides alone (FIGS. 8a-c) and the peptide complex (FIG. 8d) were both observed to increase the expression of the lipolytic marker phospho-HSL.
2-4. Quantitation of lipolysis product glycerol
After being taken from the abdomens of obesityinduced mice, adipose tissues were plated at a density of 100 mg/well into 24-well culture plates and cultured in a culture medium (1 ml Krebs-Ringer buffer containing 25 mM HEPES, 5.5 mM glucose, and 2 % (w/v) bovine sérum albumin). In this regard, the tissues were incubated for 48 hours with 0.1 pg/ml, 1 pg/ml, and 10 pg/ml of the peptide complex whereas 100 ng/ml of TNFa was used as a positive control. Glycerol produced during lipolysis was quantitatively analyzed.
As is understood from the experimental data, the amount of glycerol resulting from lipolysis by treatment with the peptide complex was increased in a dose-
| dépendent manner and greater than | that | produced | upon | |
| treatment with the positive | control | TNFa ( | FIG. 9). | |
| 2-5. Lysis effect on | adipose | tissue | isolated | from |
| obese mouse | ||||
| Adipose tissues are | divided | into | white fat | and |
brown fat by color and into subcutaneous fat, abdominal fat, mesentery fat (viscéral fat), and epididymal fat by tissue. After body anatomization, lipoectomy was
performed on the tissues. White fats were isolated, plated in an amount of 100 mg/well into 24-well plates, and then incubated for 72 hours with concentrations of the peptide complex in a culture medium (1 ml Krebs5 Ringer buffer containing 25 mM HEPES, 5.5 mM glucose, and 2 % (w/v) bovine sérum albumin) . The fats were sectioned into slices which were than dyed with hematoxylin and eosin. Sizes of adipocytes were compared under a microscope (TS100 Nikon) with lOOx 10 magnification.
Compared to the control, the fats treated with various concentrations of the peptides decreased in size (FIG. 10a). In addition, when treated with the peptide complex, adipose tissues having distinct cell membrane 15 compartments were observed in cell size, as measured by a program (FIG. 10b).
2-6. Observation of lipolytic marker in adipose tissue
An adipose tissue taken from the abdomen of an obesity-induced mouse was plated in an amount of 100 mg per well into 24-well culture plates and incubated for 48 hours with the peptide complex while TNFa 100 ng/ml was used as a positive control. The labeled lipolytic 25 marker phospho-HSL (green fluorescent) was detected.
Treatment with the peptide complex was observed to increase the expression level of the lipolytic marker phospho-HSL in adipose tissues (FIG. 11).
EXAMPLE 3: Adipogenesis-Suppressive and LipolysisPromotive Effect in Experimental Animal
Weight loss and adipogenesis suppression in highfat diet-fed animal
Models DIO (diets induced obesity), which had 35 become obese by feeding high-fat diets thereto, were
used for anti-obesity experiments in which TNFa 5 pg/ml was used as a positive control. For a control, a general diet, not a high-fat diet, was fed. In the experiment, a high-fat diet was fed for 12 weeks while the peptide 5 complex or the positive control was applied. During the experiment, the weight was monitored.
TNFa and the anti-obesity compounds were intraperitoneally injected at PM 3 - 4 o'clock every week for 12 weeks. Weights and meal sizes were measured 10 just before the initial injection and then regularly at intervals of one week. Blood samples were taken from tail veins after the experiments of drug injection and measured for blood sugar levels, using Accu-Check Active (Roche) and analyzed for cholestérol levels, using 15 Cholestérol calculation Kit (BioVision). Adipose tissues are divided into white fat and brown fat by color and into subcutaneous fat, abdominal fat, mesentery fat (viscéral fat), and epididymal fat by tissue. After lipoectomy, the fats thus obtained from the tissues were 20 observed. For histological examination, the fats were fixed with 10 % neutral buffered formalin, embedded in paraffin blocks, eut into 5 pm-thick sections, and dyed with hematoxylin and eosin. To analyze the phosphorylation of the lipolytic marker HSL, fluorescent 25 staining was carried out with an anti-pHSL antibody. A tissue sample was made, mounted on glycérine jell mounting media, and covered with a cover glass. The tissues were observed under a microscope (Nikon, TS100), with a built-in digital caméra taking images thereof.
Over 12 weeks from the initial stage to the final stage of the experiment, mice were measured to increase in weight from 20.9 g to 28.74 g when fed with a general diet and from 20.99 g to 49.5 g when fed with a high-fat diet. In the mice fed with a high-fat diet with the 35 peptide complex injected thereto, the weight gain was
reached only to 36.76 g after 12 weeks from the initial weight of 21.1 g, indicating a significant réduction of weight gain (174.2 %), compared to the high-fat diet-fed control (235.8%) (Table 2 and FIG. 12).
TABLE 2
Weight of Obese Mouse Model after Treatment with Peptide
Complex
Weight (g)
| Ganaral dlat (eontral)l | hiflh fat diet (contrai) | H.F+P/C | H.F*P.Camplex | |
| 0w | 20.09 | 20.99 | 22.41 | 21.1 |
| lw | 20.75 | 22.32 | 23 | 21.26 |
| 2w | 21.99 | 25.25 | 2612 | 23.72 |
| 3w | 18 23 | 27.35 | 27.45 | 24.36 |
| 4w | 23 26 | 30.2 | 30.51 | 2529 |
| 5w | 2316 | 32.76 | 32.76 | 28.65 |
| 6w | 23 28 | 36.78 | 3349 | 2879 |
| 7w | 24.71 | 38 31 | 3514 | 30 37 |
| âw | 25.84 | 40.12 | 3715 | 3153 |
| 9w | 25.59 | 42.14 | 38.97 | 32.59 |
| ICM· | 28.13 | 43.02 | 40.39 | 33.78 |
| llw | 27 9 | 45.7 | 41.35 | 35.33 |
| 12w | 28.74 | 49.S | 43.91 | 30.76 |
| General diet (ccntrol)l | hiah fat diet (cantrol) | H.F+P/C | H.F+PXompt«x | |
| Ow | îoo | 100 | 100 | 100 |
| lw | 103.3 | 106.3 | 1026 | 1008 |
| 2w | 1095 | 120.3 | 1166 | 1124 |
| 3w | 907 | 130.3 | 122 5 | 115 5 |
| 4w | 115.8 | 143.9 | 136.1 | 119.9 |
| 5w | 115.3 | 156.1 | 146.2 | 135 8 |
| 6w | 115.9 | 175.2 | 149.4 | 1364 |
| 7w | 123.0 | 182.5 | 1568 | 143 9 |
| 8w | 128.6 | 191.1 | 165.8 | 1494 |
| 9w | 127.4 | 200.8 | 173.9 | 1545 |
| 10w | 140.0 | 205.0 | 1802 | 1601 |
| llw | 138.9 | 217.7 | 1845 | 167.4 |
| 12w | 143.1 | 235.8 | 195.9 | 174.2 |
Weight (%)
After completion of the 12-week experiment, in addition, the mice treated with the peptide complex, were observed to maintain their body sizes in similar patterns to those of the normal mice (general diet), but 15 not to those of the high-fat diet-fed mice, as analyzed on the images (FIG. 13).
After 12 weeks of the experiment, the mice were subjected to micro-CT to examine fat distribution across the body. As a resuit of the micro-CT data of fats 20 (yellow) in the body, the fat distributed across the body was remarkably increased in the high-fat diet-fed mice, compared to the general diet-fed control while a significantly reduced level of fats distributed across the body was observed in the group which were treated with the peptide complex with the high-fat diet fed thereto (FIG. 14).
The mice which completed micro-CT imaging were anatomized to extract the adipose tissues distributed across the body. Volumes of the adipose tissues were compared. As a resuit, the fat extracted from the highfat diet-fed mice was greater than that from the general diet-fed mice, with a significant réduction in the fat volume in the mice treated with the peptide complex plus the high-fat diet (FIG. 15) .
Fats were isolated, and dyed with H&E to visualize fat sizes. Smaller sizes of fats were observed in the mice treated with both the high-fat diet and the peptide complex than in the high-fat diet-fed control (FIG. 16a) . Fat size analysis through a program showed that, when the fat size of the general diet-fed control was assumed to be 100 %, a fat size was increased to 127 % in the high-fat diet-fed group, but decreased to 97 % in the group treated with the high-fat diet and the peptide complex (FIG. 16b).
The fats were isolated and examined for the expression level of the lipolytic marker phospho-HSL in adipose tissues. The mice treated with both the high-fat diet and the peptide complex were observed to hâve an elevated expression level of phospho-HSL (FIG. 17).
Blood cholestérol levels in the mice after the experiment were measured. As a resuit, the blood cholestérol level was 2.52 pg/ml in the general diet-fed mice, 3.5 pg/ml in the high-fat diet-fed mice, and 2.86 pg/ml in the mice treated with both the high-fat diet and the peptide complex, indicating that the peptide complex reduced the cholestérol level that elevated with obesity (FIG. 18).
Blood sugar levels after completion of the experiment were 174 mg/dL in the general diet-fed mice, and increased to 235 mg/dL in the high-fat diet-fed mice. However, a blood sugar level of 183 mg/dL was measured in the mice treated with both the high-fat diet and the peptide complex, with a significant réduction therein (FIG. 19).
EXAMPLE 4 : Blood Sugar Control
Effect on blood sugar control
In this animal experiment, C57BL/6 (normal mouse) (purchased from Samtako Inc.) and female C57BLKS/JLepr (diabètes model mouse, db/db mouse) (purchased from Central Lab. Animal Inc.) were used, together with the peptide complex as an anti-diabetes and/or anti-obesity effective material, and sitagliptin as a positive control drug. In this Example, the anti-diabetes and/or anti-obesity effective complex was evaluated for acute anti-diabetes efficacy (single administration) in a normal mouse model and a genetically potential-diabetic model, using GTT (glucose tolérance test) , which is a représentative diagnostic method for diabètes. Mice were bred per cage at a température of 22-24’C and a relative humidity of 50-30%, with four per cage. The mice was under 150-300 Lux light from AM 8 o'clock to PM 8 o'clock with 12 light /12 dark cycles. They were given free access to a general diet (18 % protein, manufactured in 2018, Harlan Laboratories Inc, USA). To begin with, the mice were starved for 4 hours or longer before ITT experiment and for 12 hours before GTT experiment. The complex was orally administered by force with the aid of a disposable oral administration syringe one hour before GTT experiment. For GTT experiment, the mice were allowed to freely access to a high-fat diet on (zéro) hour after experiment started. After 40 min of free access to a high-fat diet, blood samples for use in examining blood glucose levels were taken from the tail vein at intervals of 0, 30, 60, 90, 120, and 180 min. Blood glucose levels were measured using Accu-Chek active (Roche). Sitagliptin, used as a therapeutic agent for diabètes, was selected as a positive control drug, and administered at a dose of 100 mg/kg. The complex selected as an anti-diabetes and/or anti-obesity effective candidate was administered at a dose of 100 mg/kg to experimental groups of four mice.
As a resuit, the peptide complex exhibited a reductive effect on blood sugar levels in which the blood sugar level increased by the high-fat diet was reduced by treatment with the peptide complex. In the diabetes-induced mouse models, the high blood sugar level was decreased by the complex (FIGS. 20a and 20b) . Further, lower blood cholestérol levels were detected in the group treated with both the high-fat diet and the peptide complex than the high-fat diet-fed control (FIG. 21) .
In addition, after starvation for 16 hours, DB/DB diabetes-induced mice were fed for 30 min and then administered with the peptides. Blood sugar levels were measured over times.
The blood sugar levels in the groups respectively treated with the peptides of SEQ ID NOS: 1, 3, and 5 were observed to decrease in a time-dependent manner (FIGS. 22a-22c).
EXAMPLE 5:
Promotion of Expression of
Insulin and
Insulin-like Growth Factor
Promotion of expression of insulin and insulinlike growth factor
3T3-L1 cells (pre-adipocytes) were seeded at a density of 3x105 cells/well into 6-well plates and grown for 24 hours. Subsequently, the cells were ïncubated with various concentrations (10 ng - 1 pg/ml) of the peptides for 14 days in a 37 °C incubator. Proteins were extracted from cell lysâtes which were obtained by treatment with cell lysis buffer, quantitatively analyzed, and subjected to Western blotting using an anti-IGF-1 antibody, which is an antibody against the lipolytic marker, and an insulin antibody (Santa Cruz Biotechnology, USA).
From the data, it was observed that the peptide of SEQ ID NO: 7 increased the expression of IGF-1 and insulin in dose-dependent manners (FIG. 23).
EXAMPLE 6: Observation of Blood Sugar Level Reducing Effect in Clinical Experiment
Réduction of blood sugar level by intake of the complex.
A brief clinical test was performed on persons 4565 years old who had a fasting blood glucose level of 170 mg/dL or higher. They were ingested with a complex formulation 30 min after meals. Blood samples were taken at intervals of 30, 60, 90, 120, 150, and 180 min from the persons, and measured for glucose level, using AccuChek active (Roche).
A réduction of blood sugar level by the complex formulation was observed in ail the tested persons (FIGS. 25a - 25d).
Although the présent invention has been described in detail with reference to the spécifie features, it will be apparent to those skilled in the art that this description is only for a preferred embodiment and does not limit the scope of the présent invention. Thus, the substantial scope of the présent invention will be defined by the appended daims and équivalents thereof.
Claims (16)
1. A peptide having one selected from the group consisting of the amino acid sequences of SEQ ID NOS: 1 to Ί.
2. A peptide, having one selected from the group consisting of the amino acid sequences of SEQ ID NOS: 1 to 7 and exhibiting anti-obesity or anti-diabetes activity.
3. The peptide of claim 2, wherein the peptide suppresses adipogenesis.
4. The peptide of claim 2, wherein the peptide reduces expression of PPARy (peroxisome proliferatoractivated receptor gamma), ACC (acetyl-CoA carboxylase), or aP2 (adipose-specific fatty acid-binding protein 2).
5. The peptide of claim 2, wherein the peptide promûtes lipolysis.
6. The peptide of claim 2, wherein the peptide increases expression of pHSL (phospho-hormone-sensitive lipase), AMPK-al (AMP-activated protein kinase al), CGI58 (comparative gene identification-58), or ATGL (adipose triglycéride lipase).
7. The peptide of claim 2, wherein the peptide reduces a blood sugar level.
8. A peptide complex, exhibiting anti-obesity or anti-diabetes activity and including the following peptide combination:
(a) a peptide of SEQ ID NO: 1;
(b) a peptide of SEQ ID NO: 3; and (c) a peptide of SEQ ID NO: 6 or 7.
9. The peptide complex of claim 8, wherein the peptide complex reduces sizes of adipocytes.
10. The peptide complex of claim 8, wherein the peptide complex reduces a blood cholestérol level.
11. A pharmaceutical composition, comprising the peptide of any one of claims 2 to 7 as an effective ingrédient for preventing or treating obesity.
12. A pharmaceutical composition, comprising the peptide complex of any one of claims 8 to 10 as an effective ingrédient for preventing or treating obesity.
13. A pharmaceutical composition, comprising the peptide of any one of claims 2 to 7 as an effective ingrédient for preventing or treating diabètes.
14. A pharmaceutical composition, comprising the peptide complex of any one of claims 8 to 10 as an effective ingrédient for preventing or treating diabètes.
15. A peptide according to any one of claims 2 to 7, or 8 or 10 for use in a method for preventing or treating obesity or diabètes.
16. Use of a peptide according to any one of claims 2 to 7, or 8 or 10 in the manufacture of a pharmaceutical composition for preventing or treating obesity or diabètes
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2015-0059648 | 2015-04-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA18548A true OA18548A (en) | 2018-12-14 |
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