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    • 专利摘要:
    NEW OXINTOMODULIN DERIVATIVES AND PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF OBESITY UNDERSTANDING THE SAME. The present invention relates to a new peptide that exhibits excellent activities at a glucagon-like peptide-1 receptor and a greater glucagon receptor than native oxintomodulin and a composition for the prevention or treatment of obesity comprising the peptide as an active ingredient. . Unlike native oxintomodulin, the new peptide of the present invention reduces food intake, suppresses gastric emptying and facilitates lipolysis with reduced side effects, also demonstrating excellent receptor activating effects. Thus, it can be widely used to treat obesity safely and effectively.
    公开号:BR112013031794B1
    申请号:R112013031794-9
    申请日:2012-06-07
    公开日:2020-11-10
    发明作者:Sung Youb Jung；Myung Hyun Jang；Ling Ai Shen；Young Kyung Park；Young Jin Park；Se Chang Kwon
    申请人:Hanmi Science Co., Ltd；
    IPC主号:
    专利说明:

    TECHNICAL FIELD
    [001] The present invention relates to a new peptide that exhibits excellent activities at a glucagon-like peptide receptor 1 and a glucagon receptor greater than native oxintomodulin and a composition for the prevention or treatment of obesity comprising the peptide as an active ingredient. BACKGROUND OF THE TECHNIQUE
    [002] Recently economic growth and changes in lifestyle have led to changes in eating habits. The main causes of the increase in overweight and obesity rates in current populations are the consumption of high-calorie foods, such as fast food and lack of exercise. The World Health Organization (WHO) estimates that more than 1 billion people worldwide are overweight and at least 300 million of these are pathologically obese. In particular, 250,000 people die every year in Europe and more than 2.5 million people worldwide die as a result of being overweight (World Health Organization, Global Strategy on Diet, Physical Activity and Health, 2004).
    [003] Being overweight and being obese increases blood pressure and cholesterol levels, causing an exacerbation of various diseases, such as cardiovascular disease, diabetes and arthritis, and are also the main causes of the increased incidence rates of arteriosclerosis , hypertension, hyperlipidemia or cardiovascular diseases in children and adolescents, as well as among adults.
    [004] Obesity is a serious condition that causes several diseases worldwide. It is thought that it can be overcome with individual effort and it is also thought that obese patients have poor self-control. However, it is difficult to treat obesity because it is a complex disorder, which involves the regulation of appetite and energy metabolism. For the treatment of obesity, it is necessary to treat the anomalous actions associated with the regulation of appetite and energy metabolism in conjunction with the efforts of obese patients. Many attempts have been made to develop drugs capable of treating anomalous actions. As a result of these efforts, drugs such as Rimonabant (Sanofi- Aventis), Sibutramine (Abbott), Contrave (Takeda) and Orlistat (Roche) have been developed, but these have the disadvantage of causing serious side effects or having very weak anti-obesity effects. For example, Rimonabant (Sanofi- Aventis) has been reported to have side effects on the central nervous system, Sibutramine (Abbott) and Contrave (Takeda) have cardiovascular side effects and with Orlistat (Roche) there has been a weight loss of only 4 pounds when taken for 1 year. Unfortunately, there are no therapeutic agents for obesity that can be safely prescribed to obese patients.
    [005] Many studies have been conducted to develop therapeutic agents for obesity that do not have the problems of anti-obesity drugs. Recently, glucagon derivatives have received a lot of attention. Glucagon is produced in the pancreas when blood glucose drops as a result of other medications or diseases, hormonal or enzymatic deficiencies. Glucagon stimulates glycogen fractionation in the liver and facilitates the release of glucose to increase blood glucose to normal levels. In addition to the effect of increasing blood glucose, glucagon suppresses appetite and activates adipocyte hormone-sensitive lipase (LSH) to facilitate lipolysis, thus revealing anti-obesity effects. One of the glucagon derivatives, the glucagon-like peptide-1 (GLP-1) is in development as a therapeutic agent for hyperglycemia in patients with diabetes and works by stimulating the synthesis and secretion of insulin, inhibiting the secretion of glucagon, decreasing the gastric emptying, increasing the use of glucose and inhibiting food intake. Exendin-4 is isolated from lizard venom that shares a homology of approximately 50% amino acids with GLP-1 and has also been described as a GLP-1 receptor activator, thus improving hyperglycemia in patients with diabetes. However, anti-obesity drugs including GLP-2 have been experiencing side effects such as vomiting and nausea.
    [006] Therefore, as an alternative to GLP-1, attention has been focused on oxintomodulin, a peptide derivative of a precursor glucagon, pre-glucagon that binds to the receptors of two peptides, GLP-1 and glucagon. Oxytomodulin represents a powerful anti-obesity therapy because it inhibits the ingestion of foods like GLP-2, promotes satiety and has lipolytic activity like glucagon.
    [007] Based on the dual function of the oxintomodulin peptide it has been actively studied as a drug for the treatment of obesity. For example, Korean patent No. 925017 discloses a pharmaceutical composition including oxintomodulin as an active ingredient for the treatment of overweight humans, being administered orally, parenterally, mucosally, rectally, subcutaneously or transdermally. However, it has been reported that this anti-obesity drug with oxintomodulin has a short in vivo half-life and poor therapeutic efficacy, even when administered at high doses three times a day. Thus, many efforts have been made to improve the in vivo half-life or the therapeutic effect of oxintomodulin on obesity by modifying it.
    [008] For example, an oxintomodulin (Merck) double agonist is prepared by substituting L-serine for D-serine at position 2 of the oxintomodulin to increase resistance to dipeptyl peptidase-IV (DPP-IV) and associating a cholesterol fraction in terminal C to increase blood half-life at the same time. ZP2929 (Zealand) is prepared by replacing L-serine with D-serine in position 2 to increase resistance to DPP-IV, replacing arginine with alanine in position 17, to increase resistance to protease, replacing methionine with lysine in position 27 in order to increase oxidative stability and replacing glutamine with aspartic acid and alanine at positions 20 and 24 and asparagine with serine at position 28 to increase the stability of deamidation. However, although the half-life of the double agonist oxintomodulin (Merck) has been increased, with a half-life of 8 ~ 12 minutes longer than native oxintomodulin, it is still a very short half-life of 1.7 hours and the respective half-life. administration dose is also several mg / kg. Unfortunately, oxintomodulin or its derivatives have the disadvantages of daily administration of a high dose due to the short half-life and poor efficacy. DISCLOSURE TECHNICAL PROBLEM
    [009] Thus, the authors of the present invention developed an oxintomodulin derivative prepared from modifying the amino acid sequence of native oxintomodulin in order to intensify its therapeutic effects on obesity and to reduce the respective dose of administration. Thus, they found that an oxintomodulin derivative reveals more excellent activities at the glucagon receptor and a GLP-1 receptor than native oxintomodulin, thus completing the present invention. TECHNICAL SOLUTION
    [010] An object of the present invention is to present a new peptide with excellent therapeutic effects on obesity.
    [011] Another object of the present invention is to present a composition for the prevention or treatment of obesity, comprising the peptide.
    [012] Yet another object of the present invention is to provide a method for the prevention or treatment of obesity by administering the peptide or composition to a subject.
    [013] Yet another object of the present invention is to provide the use of the peptide in the preparation of drugs intended for the prevention or treatment of obesity. ADVANTAGE EFFECTS
    [014] Unlike native oxintomodulin, the new peptide of the present invention reduces food intake, suppresses gastric emptying and facilitates lipolysis without side effects, also demonstrating excellent receptor activating effects. Thus, it can be widely used to treat obesity safely and effectively. DESCRIPTION OF THE FIGURES
    [015] FIG. 1 is a graph showing changes in food intake according to the administered dose of oxytomodulin or oxytomodulin derivative. BEST MODE
    [016] In one aspect to achieve the stated objectives, the present invention features new peptides including the amino acid sequence of the following formula 1. R1 -X1-X2-GTFTSD-X3-X4-X5-X6-X7-X8-X9 -X10-X11 -X12-X13-X14-X15- X16-X17-X18-X19-X20-X21-X22-X23-X24-R2 (SEQ ID NO 1) (Formula 1) where R1 is histidine, deamination- histidyl, dimethyl-histidyl (N-dimethyl-histidyl), beta-hydroxydidazopropionyl, 4-imidazoacetyl, beta-carboxy imidazopropionyl or tyrosine; XI is Aib (aminoisobutyric acid), d-alanine, glycine, Sar (N-methylglycine), serine or d-serine; X2 is glutamic acid or glutamine; X3 is leucine or tyrosine; X4 is serine or alanine; X5 is lysine or arginine; X6 is glutamine or tyrosine; X7 is leucine or methionine; X8 is aspartic acid or glutamic acid; X9 is glutamic acid, serine, alpha-methyl-glutamic acid or is eliminated; X10 is glutamine, glutamic acid, lysine, arginine, serine or is eliminated; XII is alanine, arginine, valine or is eliminated; X12 is alanine, arginine, serine or is eliminated; X13 is lysine, glutamine, arginine, alpha-methyl-glutamic acid or is eliminated; X14 is aspartic acid, glutamic acid, leucine or is eliminated; X15 is phenylalanine or is eliminated; X16 is isoleucine, valine or is eliminated; X17 is alanine, cysteine, glutamic acid, lysine, glutamine, alpha-methyl-glutamic acid or is eliminated; X18 is tryptophan or is eliminated; X19 is alanine, isoleucine, leucine, serine, valine or is eliminated; X20 is alanine, lysine, methionine, glutamine, arginine or is eliminated; X21 is asparagine or is eliminated; X22 is alanine, glycine, threonine or is eliminated; X23 is cysteine, lysine or is eliminated; X24 is a peptide with 2 to 10 amino acids consisting of combinations of alanine, glycine and serine or is eliminated and R2 is KRNRNNIA (SEQ ID NO. 32), GPSSGAPPPS (SEQ ID NO. 33), GPSSGAPPPSK (SEQ ID NO. 34) , HSQGTFTSDYSKYLD (SEQ ID NO. 35), HSQGTFTSDYSRYLDK (SEQ ID NO. 36), HGEGTFTSDLSKQMEEEAVK (SEQ ID NO. 37) or is deleted (excluded if the Formula 1 amino acid sequence is identical to SEQ ID NO. 1) .
    [017] As used herein the term "peptide" means a compound of two or more α-amino acids linked by a peptide bond. With respect to the objects of the present invention it means a peptide that activates both the GLP-1 receptor and the glucagon receptor to reveal anti-obesity effects. The peptide according to the present invention includes peptides, peptide derivatives or peptide mimetics that are prepared by adding, removing or replacing oxyntomodulin amino acids in order to activate both the GLP-1 receptor and the glucagon receptor at a high level, compared to native oxintomodulin.
    [018] The cited amino acids are abbreviated according to the IUPAC-IUB nomenclature as follows: Alanine A Arginine R Asparagine N Aspartic acid D Cysteine C Glutamic acid And Glutamine Q Glycine G Histidine H Isoleucine 1 Leucine L Lysine K Methionine M Phenylalanine F Proline P Serina S Threonine T Tryptophan W Tyrosine Y Valina V
    [019] In the present invention, the peptide encompasses any peptide that is prepared by means of post-translation substitutions, additions, deletions or modifications (eg methylation, acylation, ubiquitination, intramolecular covalent bonding) in the amino acid sequence of the oxintomodulin (HSQGTFTSDYSKYLDSRRAQDNN , SEQ ID NO. 1) in order to activate the glucagon and GLP-1 receptors simultaneously. With the substitution or addition of amino acids, any of the 20 amino acids commonly found in human proteins can be used, as well as atypical or unnatural amino acids. Sources of atypical amino acids for sale include Sigma-Aldrich, ChemPep Inc. and Genzyme Pharmaceuticals. Peptides including these amino acids and atypical peptide sequences can be synthesized and purchased from commercial suppliers, for example American Peptide Company or Bachem (USA) or Anygen (Korea).
    [020] In order to increase the activity of oxintomodulin for the glucagon receptor and for the GLP-1 receptor, the peptide of the present invention can be replaced by 4-imidazoacetyl where the alpha carbon of histidine at position 1 of the amino acid sequence represented by SEQ ID NO 1 is eliminated, deamino-histidyl where the N-terminal amino group is eliminated, dimethyl-histidyl (n-dimethyl-histidyl) where the N-terminal amino group is modified with two methyl groups, beta-hydroxyimidazopropionyl where the group N-terminal amino is replaced by a hydroxyl group or an imidazopropionyl beta-carboxy where the N-terminal amino group is replaced by a carboxyl group. In addition, the GLP-1 receptor binding region can be replaced by amino acids that enhance hydrophobic and ionic bonds or combinations thereof. A portion of the oxintomodulin sequence can be replaced by the amino acid sequence of GLP-1 or exendin-4 to increase activity at the GLP-1 receptor.
    [021] In addition, a part of the oxintomodulin sequence can be replaced by an alpha helix stabilizing sequence. Preferably, the amino acids at positions 10, 14, 16, 20, 24 and 28 of the amino acid sequence of formula 1 can be replaced by amino acids or derivatives of amino acids consisting of Tyr (4-Me), Phe, Phe (4-Me) , Phe (4-CI), Phe (4-CN), Phe (4-NC> 2), Phe (4-NH2), Phg, Pal, Nal, Ala (2-thienyl) and Ala (benzothienyl) which are known to stabilize the alpha helix and there are no limitations on the type and number of amino acids or derivatives of stabilizing amino acids of the alpha helix to be inserted. Preferably, the amino acids at positions 10 and 14, 12 and 16, 16 and 20, 20 and 24 and 24 and 28 can also be replaced by glutamic acid or lysine respectively, in order to form rings and the number of rings to be inserted it is unlimited. More preferably, the peptide can be a peptide with an amino acid sequence selected from the following formulas 2 to 6.
    [022] In a specific embodiment, the peptide of the present invention is an oxintomodulin derivative, including the amino acid sequence of the following formula 2, wherein the amino acid sequence of oxintomodulin is replaced by that of exendin or GLP-1. R1-A-R3 (SEQ ID NO 52) (Formula 2)
    [023] In another specific embodiment, the peptide of the present invention is an oxintomodulin derivative, including the amino acid sequence of the following formula 3, which is prepared by linking a part of the amino acid sequence of the oxintomodulin and a part of the sequence of GLP-1 amino acids through a suitable amino acid linker. R1-B-C-R4 (SEQ ID NO 53) (Formula 3)
    [024] In yet another specific embodiment, the peptide of the present invention is an oxintomodulin derivative, including the amino acid sequence of the following formula 4, wherein a part of the amino acid sequence of the oxintomodulin is replaced by an amino acid capable of enhancing the binding affinity to the GLP-1 receptor, for example, Leu at position 26 which binds to the GLP-1 receptor by hydrophobic interaction, is replaced by the hydrophobic residue lie or Val. R1-SQGTFTSDYSKYLD-D1-D2-D3-D4-D5-LFVQW-D6-D7-N-D8-R3 (SEQ ID NO 54) (Formula 4)
    [025] In yet another specific embodiment, the peptide of the present invention is an oxintomodulin derivative, including the amino acid sequence of the following formula 5, in which a part of the amino acid sequence is deleted, added or replaced by another amino acid in order to to increase the activities of native oxintomodulin at the GLP-1 receptor and glucagon receptor. R1 -E1-QGTFTSDYSKYLD-E2-E3-RA-E4-E5-FV-E6-WLMNT-E7-R5 (SEQ ID NO 55) (Formula 5)
    [026] In formulas 2 to 5, R1 is the same as the description of formula 1; A is selected from the group consisting of SQGTFTSDYSKYLDSRRAQDFVQWLMNT (SEQ ID NO. 38), SQGTFTSDYSKYLDEEAVRLFIEWLMNT (SEQ ID NO. 39), SQGTFTSDYSKYLDERRAQDFVAWLKNT (SEQ ID NO. 40), GQGTFTSDYSRYLEEEAVRLFIEWLKNG (SEQ ID NO. 41), GQGTFTSDYSRQMEEEAVRLFIEWLKNG (SEQ ID NO. 42 ), GEGTFTSDLSRQMEEEAVRLFIEWAA (SEQ ID NO. 43) eSQGTFTSDYSRQMEEEAVRLFIEWLMNG (SEQ ID NO. 44); B is selected from the group consisting of SQGTFTSDYSKYLDSRRAQDFVQWLMNT (SEQ ID NO. 38), SQGTFTSDYSKYLDEEAVRLFIEWLMNT (SEQ ID NO. 39), SQGTFTSDYSKYLDERRAQDFVAWLKNT (SEQ ID NO. 40), GQGTFTSDYSRYLEEEAVRLFIEWLKNG (SEQ ID NO. 41), GQGTFTSDYSRQMEEEAVRLFIEWLKNG (SEQ ID NO. 42 ), GEGTFTSDLSRQMEEEAVRLFIEWAA (SEQ ID NO. 43), SQGTFTSDYSRQMEEEAVRLFIEWLMNG (SEQ ID NO. 44), GEGTFTSDLSRQMEEEAVRLFIEW (SEQ ID NO. 45) and SQGTFTSDYSLDRY (SEQ ID NO. 46); C is a peptide with 1 to 10 amino acids consisting of combinations of alanine, glycine and serine; D1 is serine glutamic acid or arginine; D2 is glutamic acid or serine arginine; D3 is arginine, alanine or valine; D4 is arginine, valine or serine; D5 is glutamine, arginine or lysine; D6 is isoleucine, valine or serine; D7 is methionine, arginine or glutamine; D8 is threonine, glycine or alanine; E1 is serine, Aib, Sar, d-alanine or d-serine; E2 is serine or glutamic acid; E3 is arginine or lysine; E4 is glutamine or lysine; E5 is aspartic acid or glutamic acid; E6 is glutamine, cysteine or lysine; E7 is cysteine, lysine or is eliminated; R3 is KRNRNNIA (SEQ ID NO. 32), GPSSGAPPPS (SEQ ID NO. 33) or GPSSGAPPPSK (SEQ ID NO. 34); R4 is HSQGTFTSDYSKYLD (SEQ ID NO. 35), HSQGTFTSDYSRYLDK (SEQ ID NO. 36) or HGEGTFTSDLSKQMEEEAVK (SEQ ID NO. 37) and R5 is KRNRNNIA (SEQ ID NO. 32), GPSSGAPPPS (SEQ ID NO. 32), GPSSGAPPPS (SEQ ID NO. (SEQ ID NO. 34) or is deleted (excluded if the Formula 2 to 5 amino acid sequences are identical to SEQ ID NO. 1).
    [027] Preferably, the new peptide of the present invention can be a peptide of the following formula 6. R1 -X1-X2-GTFTSD-X3-X4-X5-X6-X7-X8-X9-X10-X11 -X12-X13- X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24-R2 (SEQ ID NO 56) (Formula 6) wherein R1 is histidine, deamin-histidyl, 4-imidazoacetyl or tyrosine; XIII is Aib (aminoisobutyric acid), glycine or serine; X2 is glutamic acid or glutamine; X3 is leucine or tyrosine; X4 is serine or alanine; X5 is lysine or arginine; X6 is glutamine or tyrosine; X7 is leucine or methionine; X8 is aspartic acid or glutamic acid; X9 is glutamic acid, alpha-methyl-glutamic acid or is eliminated; X10 is glutamine, glutamic acid, lysine, arginine or is eliminated; XIV is alanine, arginine or is eliminated; X12 is alanine, valine or is eliminated; X13 is lysine, glutamine, arginine, alpha-methyl-glutamic acid or is eliminated; X14 is aspartic acid, glutamic acid, leucine or is eliminated; X15 is phenylalanine or is eliminated; X16 is isoleucine, valine or is eliminated; X17 is alanine, cysteine, glutamic acid, glutamine, alpha-methyl-glutamic acid or is eliminated; X18 is tryptophan or is eliminated; X19 is alanine, isoleucine, leucine, valine or is eliminated; X20 is alanine, lysine, methionine, arginine or is eliminated; X21 is asparagine or is eliminated; X22 is threonine or is eliminated; X23 is cysteine, lysine or is eliminated; X24 is a peptide with 2 to 10 amino acids consisting of glycine or is deleted and R2 is KRNRNNIA (SEQ ID NO. 32), GPSSGAPPPS (SEQ ID NO. 33), GPSSGAPPPSK (SEQ ID NO. 34), HSQGTFTSDYSKYLD (SEQ ID NO. 35), HSQGTFTSDYSRYLDK (SEQ ID NO. 36), HGEGTFTSDLSKQMEEEAVK (SEQ ID NO. 37) or is deleted (excluded if the Formula 6 amino acid sequence is identical to that of SEQ ID NO. 1).
    [028] More preferably, the peptide of the present invention can be selected from the group consisting of the peptides of SEQ ID NOs 1 to 31. More preferably, the peptide of the present invention can be an oxintomodulin derivative described in table 1 of example 2-1 .
    [029] Oxytomodulin has activities of two peptides, GLP-1 and glucagon. GLP-1 lowers blood glucose, reduces food intake and suppresses gastric emptying and glucagon increases blood glucose, facilitates lipolysis and decreases body weight by increasing energy metabolism. The different biological effects of the two peptides can cause unwanted effects such as increased blood glucose if glucagon has a more dominant effect than GLP-1 or can cause nausea and vomiting if GLP-1 shows a more dominant effect than glucagon . Therefore, the oxintomodulin derivatives of the present invention are not only geared towards increasing these activities, for example, amino acids at position 1 and 11 of oxintomodulin that suppress glucagon activity, can be modified to balance the rates of glucagon and GLP-1.
    [030] The authors of the present invention performed in vitro experiments to demonstrate that the peptide of the present invention shows excellent activity at the GLP-1 receptor and at the glucagon receptor compared to oxintomodulin. Thus, it is suggested that the peptide of the present invention activates the GLP-1 receptor and the glucagon receptor to show more excellent therapeutic effects on obesity than conventional oxintomodulin. In addition, its inhibitory effects on in vivo food intake were examined, revealing more excellent inhibitory effects on food intake than conventional oxytomodulin (FIG. 1).
    [031] It will be apparent to one skilled in the art that when the oxintomodulin derivatives of the present invention are modified using typical techniques, including modification with polymers, such as PEG and the sugar chain or fusion with albumin, transferin, fatty acid and immunoglobulin in order to improve the therapeutic effects of oxintomodulin derivatives, will demonstrate therapeutic effects superior to those of native oxintomodulin. Therefore, oxintomodulin derivatives are also included within the scope of the present invention.
    [032] In another aspect, the present invention features a polynucleotide encoding the peptide.
    [033] The term "homology", as used at present, indicates sequence similarity between wild type amino acid sequences or wild type nucleotide sequences and includes a genetic sequence that is 75% or more identical, preferably 85 % or more, more preferably 90% or more and even more preferably 95% or more to the polynucleotide sequence encoding the peptide. The homology assessment can be performed with the naked eye or using a program for sale. With a computer program for sale, the homology between two or more sequences can be expressed as a percentage (%) and the homology (%) between the sequences can be evaluated. The polynucleotide encoding the peptide is inserted into a vector and expressed in order to obtain a large amount of the peptide.
    [034] In yet another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of obesity, comprising the peptide.
    [035] As used today, the term "prevention" means all actions in which the symptoms of diabetes are contained or the occurrence of obesity is controlled or delayed by administration of the peptide and the term "treatment" means all actions in which the symptoms of obesity improve or change favorably through administration of the peptide of the composition.
    [036] As used at present, the term "administration" means the introduction of a predetermined amount of a substance into a patient through a certain suitable method. The composition of the present invention can be administered via any of the common routes as long as it is possible to reach the desired tissue, for example, but without limitation, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrapulmonary or intrarectal. However, since peptides are digested for oral administration, the active ingredients of a composition intended for oral administration must be coated or formulated to protect against degradation in the stomach.
    [037] As currently used, the term “obesity” implies the accumulation of an excessive amount of adipose tissue in the body and a body mass index (body weight (kg) divided by the square of height (m))) greater than 25 should be considered with obesity. Obesity is usually caused by an energy imbalance, when the amount of food intake exceeds the amount of energy expended over a long period of time. Obesity is a metabolic disease that affects the whole body and increases the risk of diabetes, hyperlipidemia, sexual dysfunction, arthritis and cardiovascular diseases and, in some cases, is associated with the incidence of cancer.
    [038] The pharmaceutical composition of the present invention can further include a pharmaceutically acceptable carrier, excipient or diluent. As used herein, the term "pharmaceutically acceptable" means that the composition is sufficient to achieve therapeutic effects without negative side effects and can be easily determined depending on the type of disease, age of the patient, body weight, health status, sex and sensitivity to the drug, route of administration, mode of administration, frequency of administration, duration of treatment, drugs used in combination or coincident with the composition of this invention and other factors known in medicine.
    [039] The pharmaceutical composition including the derivatives of the present invention can further include a pharmaceutically acceptable carrier. In the case of oral administration, the vehicle may include, without limitation, a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersing agent, a stabilizer, a suspension promoting agent, a coloring agent and a flavoring agent. For injectable preparations, the vehicle may include a buffering agent, a preservative, an analgesic, a solubilizer, an isotonic agent and a stabilizer. For preparations intended for topical administration, the carrier may include a base, an excipient, a lubricant and a preservative.
    [040] The pharmaceutical composition of the present invention can be formulated in a variety of dosage forms in combination with said pharmaceutically acceptable carriers. For example, in the case of oral administration, the pharmaceutical composition can be formulated into tablets, troches, capsules, elixirs, suspensions, syrups or pills. In the case of injectable preparations, the pharmaceutical composition can be formulated in an ampoule as a single dose form or in a multidose container. The pharmaceutical composition can also be formulated in solutions, suspensions, tablets, pills, capsules and long-acting preparations.
    [041] On the other hand, examples of the vehicle, excipient and diluent suitable for pharmaceutical formulations include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, phosphate calcium, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oils. In addition, pharmaceutical formulations may also include fillers, anticoagulants, lubricants, wetting agents, flavorings and antiseptics.
    [042] In addition, the pharmaceutical composition of the present invention can take any formulation selected from the group consisting of tablets, pills, powder, granules, capsules, suspensions, liquids for internal use, emulsions, syrups, sterile aqueous solutions, non-aqueous solvents, formulations lyophilized and suppositories.
    [043] In addition, the composition can be formulated in a galenic form and in a single dose suitable for the patient's body and is preferably formulated in a preparation useful for peptide drugs according to the typical method in the pharmaceutical field, in order to be administered orally. or parenteral, such as through the skin, intravenously, intramuscularly, intraarterial, intramedullary, intraventricular, pulmonary, transdermal, subcutaneous, intraperitoneal, intranasal, intracolonic, topical, sublingual, vaginal or rectal, without these being any limitation .
    [044] The peptide can be used by mixing with a variety of pharmaceutically acceptable carriers, such as saline or organic solvents. To increase stability or ease of absorption, carbohydrates such as glucose, sucrose or dextrans, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers can be used.
    [045] The dose and frequency of administration of the pharmaceutical composition of the present invention are determined by the type of active ingredient, together with several factors such as the disease being treated, the route of administration, the age of the patient, sex and body weight and severity disease.
    [046] The total effective dose of the composition of the present invention can be administered to the patient in a single dose or can be administered over an extended period of time divided into multiple doses according to the fractional treatment protocol. In the pharmaceutical composition of the present invention, the content of the active ingredient can vary depending on the severity of the disease. Preferably, the total daily dose of the peptide of the present invention can be approximately 0.0001 µg to 500 mg per 1 kg of a patient's body weight. However, the effective dose of the peptide is determined taking into account several factors, including the patient's age, body weight, health status, sex, severity of the disease, diet and secretion rate, in addition to the route of administration and frequency of treatment of the pharmaceutical composition. Accordingly, one skilled in the art can easily determine an effective dose suitable for the particular use of the pharmaceutical composition of the present invention. The pharmaceutical composition according to the present invention is not particularly limited to the formulation and route of administration and method, as long as it has the effects of the present invention.
    [047] The pharmaceutical composition of the present invention shows an excellent in vivo duration of efficacy and titer, thus considerably reducing the number and frequency of its administration.
    [048] In addition, the pharmaceutical composition can be administered alone or in combination or concurrently with other pharmaceutical formulations that reveal prophylactic or therapeutic effects on obesity. Pharmaceutical formulations that reveal prophylactic or therapeutic effects on obesity are not particularly limited and may include a GLP receptor agonist, a leptin receptor agonist, a DPP-IV inhibitor, a Y5 receptor antagonist, a hormone receptor antagonist melanin concentrator (MCH), a Y2 / 3 receptor antagonist, an MC3 / 4 receptor agonist, a gastric / pancreatic lipase inhibitor, a 5HT2c agonist, an β3A receptor agonist, an amulin receptor agonist, an amulin receptor agonist ghrelin and / or a ghrelin receptor antagonist.
    [049] In yet another aspect, the present invention provides a method of preventing or treating obesity, comprising the stage of administration to a subject of the peptide or pharmaceutical composition that includes it.
    [050] In the present invention, the term "subject" means someone suspected of suffering from obesity, which means mammals, including humans, mice and cattle with obesity or with the possibility of suffering from obesity. However, any subject to be treated with the peptide or pharmaceutical composition of the present invention is included without limitation. The pharmaceutical composition that includes the peptide of the present invention is administered to a subject suspected of suffering from obesity, thereby treating the subject effectively. Obesity is described above.
    [051] The therapeutic method of the present invention may include the stage of administration of the composition which includes the peptide in a pharmaceutically effective amount. The total daily dose should be determined by appropriate medical assessment and administered once or several times. With regard to the objects of the present invention, the dosage level with specific therapeutic efficacy for any particular patient can vary depending on several well-known factors, including the type and degree of response that is to be achieved, concrete compositions according to the eventual concomitant use of other agents, the patient's age, body weight, health status, sex and diet, the time and route of administration, the rate of secretion of the composition, the duration of therapy, other drugs used in combination or concomitantly with the composition of the present invention and similar factors well known in medicine.
    [052] In yet another aspect, the present invention provides a use of the peptide or pharmaceutical composition including the same in the preparation of drugs for the prevention or treatment of obesity. MODE FOR THE INVENTION
    [053] Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are illustrative only and it is not intended to limit the invention by these examples. EXAMPLE 1. PRODUCTION OF IN VITRO ACTIVATED CELL LINE EXAMPLE 1-1: CELL LINE LINE PRODUCTION DISPLAYING CAMP RESPONSE TO GLP-1
    [054] PCR was performed using a region corresponding to the ORF (Open Reading Frame) in cDNA (OriGene Technologies, Inc. USA) of the human GLP-1 receptor gene as a model and the direct and inverse primers, including each of the Hindi 11 and EcoRI restriction sites in order to obtain a PGR product.
    [055] 5'-CCCGGCCCCCGCGGCCGCTATTCGAAATAC-3 'direct primer (SEQ ID NO. 47)
    [056] 5'-GAACGGTCCGGAGGACGTCGACTCTTAAGATAG-3 'reverse primer (SEQ ID NO. 48)
    [057] The PCR product was cloned into a known animal cell expression vector xOGC / dhfr to prepare a recombinant vector x0GC / GLP1 R.
    [058] The CHO DG44 cell line cultured in DMEM / F12 medium (10% FBS) was transfected with the recombinant vector x0GC / GLP1R using Lipofectamine (Invitrogen, USA) and cultured in a selection medium containing 1 mg / mL G418 and 10 nM methotraxate. From here, single clone cell lines were selected using the limited dilution technique and finally a cell line with excellent cAMP response to GLP-1 was selected in a concentration-dependent manner. EXAMPLE 1-2: PRODUCTION OF CELL LINES WITH CAMP RESPONSE TO GLUCAGON
    [059] PCR was performed using a region corresponding to the ORF in human glucagon cDNA (OriGene Technologies, Inc. USA) as the model and the forward and reverse primers, including each of the EcoRI and Xhol restriction sites to obtain a PCR product.
    [060] 5'-CAGCGACACCGACCGTCCCCCCGTACTTAAGGCC- 3 'direct primer (SEQ ID NO. 49)
    [061] 5'-CTAACCGACTCTCGGGGAAGACTGAGCTCGCC- 3 'reverse primer (SEQ ID NO. 50)
    [062] The PCR product was cloned into a known animal cell expression vector xOGC / dhfr to prepare a recombinant xOGC / GCGR vector.
    [063] The CHO DG44 cell line grown in DMEM / F12 medium (10% FBS) was transfected with the xOGC / GCGR recombinant vector using Lipofectamine and cultured in a selection medium containing 1 mg / mL G418 and 10 nM methotraxate. From here, single clone cell lines were selected using the limited dilution technique and finally a cell line with excellent cAMP response to glucagon was selected in a concentration-dependent manner. EXAMPLE 2. ANALYSIS OF OXINTOMODULIN DERIVED IN VITRODO ACTIVITY EXAMPLE 2-1: OXINTOMODULIN DERIVATIVE SYNTHESIS
    [064] In order to measure in vitrode activities derived from oxintomodulin, derivatives with oxintomodulin were synthesized with the following amino acid sequences (Table 1). TABLE 1 OXINTOMODULIN AND OXINTOMODULIN DERIVATIVES


    [065] In Table 1, the amino acids in bold and underlined represent a ring formation and the amino acids represented by X mean a non-native amino acid, alpha methyl-glutamic acid. In addition, CA represents 4-imidazoacetyl and DA represents deaminohistidyl. EXAMPLE 2-2: ANALYSIS OF ACTIVITY IN VITRODES DERIVED FROM OXINTOMODULIN In order to measure the anti-obesity efficacy of the oxintomodulin derivatives synthesized in example 2-1, cell activity was measured in vitroutizing the cell lines prepared in examples 1-1 and 1-2. Cell lines were prepared by transfection of CHO (Chinese Hamster Ovary) to express the human GLP-1 receptor gene and the glucagon receptor gene respectively. Thus, they are suitable for measuring GLP-1 and glucagon activities. Therefore, the activity of each oxintomodulin derivative was measured using each transformed cell line. Specifically, each cell line was subcultured two or three times a week and aliquoted in each well of a 96-well plate at a density of 1 X 105, followed by culture for 24 hours. The cultured cells were washed with KRB buffer and suspended in 40 ml of KLB buffer containing 1 mM of IBMX and left at room temperature for 5 minutes. Oxytomodulin (SEQ ID NO 1) and oxytomodulin derivatives (represented by SEQ ID NO 2-6, 8, 10-13, 17, 18, 23-25, 27-30 and 31) were diluted from 1000 nM to 0 , 02 nM through a five-fold dilution, adding each 40 mL to the cells and culturing at 37 ° C for 1 hour in an incubator under CO2. Then, 20 ml of cell lysis buffer was added and the cell lysates were applied in a cAMP analysis kit (Molecular Device, USA) to measure cAMP concentrations. The EC50 values were calculated and compared. ECso values are shown in Table 2. TABLE 2
    [066] Comparison of in vitro activities for the GLP-1 receptor and glucagon receptor between oxintomodulin and oxintomodulin derivatives


    [067] As shown in Table 2, oxintomodulin derivatives with excellent in vitro activity were detected at different rates of activity at the GLP-1 receptor and glucagon receptor compared to the native oxintomodulin of SEQ ID NO 1.
    [068] It is known that oxintomodulin activates both GLP-1 and glucagon receptors to suppress appetite, facilitate lipolysis and promote satiety, thus revealing anti-obesity effects. The oxintomodulin derivatives according to the present invention show even higher in vitro activities at both GLP-1 and glucagon receptors compared to wild-type oxintomodulin and, therefore, can be used as a therapeutic agent against obesity more effectively than known oxytomodulin. EXAMPLE 3. ANALYSIS OF THE IN VIVO ACTIVITY OF OXINTOMODULIN DERIVATIVES
    [069] In order to measure the in vivo therapeutic activity of oxintomodulin derivatives, changes in food intake were examined by administering oxintomodulin derivatives to ob / ob mice, using native oxintomodulin as a control.
    [070] Specifically, obese ob / ob mice, commonly used in trials of the effectiveness of therapeutic agents against obesity and diabetes, were fasted for 16 hours and 1 or 10 mg / kg of oxintomodulin or 0.02 is administered , 0.1 or 10 mg / kg of the oxintomodulin derivative of SEQ ID NO 2. Then food intake was examined for 2 hours (FIG. 1). FIG. 1 is a graph showing changes in food intake according to the administered dose of oxytomodulin or oxytomodulin derivative. As shown in FIG. 1, the administration of 1 mg / kg of oxintomodulin derivative revealed inhibitory effects of food intake more excellent than the administration of 10 mg / kg of oxintomodulin.
    [071] Taken together, the oxintomodulin derivatives of the present invention have far superior anti-obesity effects than wild-type oxintomodulin, even if administered at lower doses, indicating improvement over the problems of wild-type oxintomodulin which exhibits anti-obesity effects. - lower obesity and should be administered in larger doses, three times a day.
    权利要求:
    Claims (10)
    [0001]
    1. Peptide characterized by comprising the amino acid sequence selected from the group consisting of SEQ ID NOs. 2 and 23 to 31.
    [0002]
    2. Peptide according to claim 1, characterized in that the peptide is an oxintomodulin derivative capable of activating the GLP-1 receptor and the glucagon receptor.
    [0003]
    3. Peptide according to claim 1, characterized in that the peptide has anti-obesity effects.
    [0004]
    Peptide according to claim 1, characterized in that one or more pairs of amino acids at positions 12 and 16 and 16 and 20 of the peptide form rings.
    [0005]
    Polynucleotide characterized by encoding the peptide of claim 1.
    [0006]
    6. Pharmaceutical composition characterized by being intended for the prevention or treatment of obesity, comprising the peptide according to any one of claims 1 to 4 as an active ingredient.
    [0007]
    Pharmaceutical composition according to claim 6, characterized in that it also contains a pharmaceutically acceptable carrier.
    [0008]
    Pharmaceutical composition according to claim 6, characterized in that the composition is administered alone or in combination or concomitantly with other pharmaceutical formulations that reveal prophylactic or therapeutic effects on obesity.
    [0009]
    Pharmaceutical composition according to claim 8, characterized in that the pharmaceutical formulation that reveals prophylactic or therapeutic effects on obesity is selected from the group consisting of a GLP-1 receptor agonist, a leptin receptor agonist, a DPP- IV, a Y5 receptor antagonist, a melanin concentrating hormone (MCH) receptor antagonist, a Y2 / 3 receptor antagonist, an MC3 / 4 receptor agonist, a gastric / pancreatic lipase inhibitor, a 5HT2c agonist, a β3A receptor agonist, an amylin receptor agonist, a ghrelin antagonist and a ghrelin receptor antagonist.
    [0010]
    Use of the peptide according to any one of claims 1 to 4, or of the composition according to claim 6, characterized in that it is intended for the preparation of drugs for the prevention or treatment of obesity.
    类似技术:
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    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-03-19| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-07-02| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|
    2019-10-08| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2020-03-03| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2020-06-23| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-11-10| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 07/06/2012, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    KR20110056472|2011-06-10|
    KR10-2011-0056472|2011-06-10|
    PCT/KR2012/004494|WO2012169798A2|2011-06-10|2012-06-07|Novel oxyntomodulin derivatives and pharmaceutical composition for treating obesity comprising the same|
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