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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
• • A23K1/1631—
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K20/00—Accessory food factors for animal feeding-stuffs
  • A23K20/10—Organic substances
  • A23K20/142—Amino acids; Derivatives thereof
  • A23K20/147—Polymeric derivatives, e.g. peptides or proteins
• • A23L1/3053—
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
  • A23L33/17—Amino acids, peptides or proteins
  • A23L33/18—Peptides; Protein hydrolysates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
  • C07K5/06043—Leu-amino acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06104—Dipeptides with the first amino acid being acidic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
  • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0802—Tripeptides with the first amino acid being neutral
  • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
  • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0802—Tripeptides with the first amino acid being neutral
  • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
  • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
  • C07K5/0823—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp and Pro-amino acid; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to a myoblast differentiation promoter comprising peptide molecule(s) or the like.
• an undifferentiated cell differentiates into a myoblast which is a cell derived from a muscle fiber.
• the myoblast further differentiates, and a protein that is specific to a muscle cell is expressed.
• a phenomenon characteristic of differentiation of a muscle cell is cell fusion, i.e., a phenomenon that myoblasts which are mononuclear cells fuse to differentiate into a myotube cell which is a multinucleate cell.
• cell fusion i.e., a phenomenon that myoblasts which are mononuclear cells fuse to differentiate into a myotube cell which is a multinucleate cell.
• muscle is completed.
• characteristic proteins such as tropomyosin and myosin heavy chain are generated, and these are used as differentiation markers (Non-Patent Literature 1).
• Patent Literature 1 describes that dipeptides such as Hyp-Gly have an osteoclast differentiation inhibiting effect, an alkaline phosphatase inhibiting effect, and so on.
• Non-Patent Literature 2 describes that peptides such as Hyp-Gly-Pro have an antioxidative effect.
• Patent Literature 2 describes that peptides such as Pro-Gly and Hyp-Gly which further have up to ten amino acids in their upstream region and/or in their downstream region, have effects of stimulating growth, maintenance and repair of bone or the like.
• Patent Literature 3 describes that Rosa roxburghii, a soybean peptide, a C12 peptide and the like have a myoblast activating effect. However, whether these peptide molecules have a myoblast differentiation promoting effect has not been known.
• Non-Patent Literature 3 shows the rate of change in muscle weight when American football players took in an equivalent mixture of a collagen peptide and a whey peptide for three months in combination with exercise.
• the muscle weight increased (FIG. 2)
• the body weight also increased (FIG. 1) after intake of this equivalent mixture, and the muscle, in terms of a ratio of the muscle weight to the body weight, was rather reduced in comparison with the starting point.
• the ratio of the muscle weight to the body weight significantly increases as described in later-described Test Example 2.
• the present inventors have found that peptide molecules Ala-Hyp-Gly, Hyp-Gly-Pro, Leu-Hyp, Glu-Hyp, Gly-Pro-Hyp, Pro-Ala, Hyp-Gly and Pro-Hyp have an excellent myoblast differentiation promoting effect, and have accomplished the present invention.
• the present invention is as follows.
• a myoblast differentiation promoter comprising a peptide selected from the group consisting of Ala-Hyp-Gly, Hyp-Gly-Pro, Leu-Hyp, Glu-Hyp, Gly-Pro-Hyp, Pro-Ala, Hyp-Gly and Pro-Hyp, or a pharmaceutically acceptable salt thereof.
• the myoblast differentiation promoter according to [1], comprising a peptide selected from the group consisting of Hyp-Gly and Pro-Hyp, or a pharmaceutically acceptable salt thereof.
• the myoblast differentiation promoter according to [1], comprising two or more peptides selected from the group consisting of Ala-Hyp-Gly, Hyp-Gly-Pro, Leu-Hyp, Glu-Hyp, Gly-Pro-Hyp, Pro-Ala, Hyp-Gly and Pro-Hyp, or pharmaceutically acceptable salts thereof.
• the myoblast differentiation promoter according to any one of [1] to [3], wherein the promoter is in the form of a preparation for oral administration, an injection for direct administration to muscle, a transdermal agent, a suppository, a nasal drop, or an inhalant.
• a beverage or food product or a feed comprising a peptide selected from the group consisting of Ala-Hyp-Gly, Hyp-Gly-Pro, Leu-Hyp, Glu-Hyp, Gly-Pro-Hyp, Pro-Ala, Hyp-Gly and Pro-Hyp, or a pharmaceutically acceptable salt thereof.
• the present invention can provide a myoblast differentiation promoter comprising a peptide molecule of Ala-Hyp-Gly, Hyp-Gly-Pro, Leu-Hyp, Glu-Hyp, Gly-Pro-Hyp, Pro-Ala, Hyp-Gly, and Pro-Hyp, that is superior to conventional arts.
• Peptides used in the present invention are Ala-Hyp-Gly, Hyp-Gly-Pro, Leu-Hyp, Glu-Hyp, Gly-Pro-Hyp, Pro-Ala, Hyp-Gly and Pro-Hyp, and these peptides can be in the form of a pharmaceutically acceptable salt.
• preferred peptides include Hyp-Gly and Pro-Hyp.
• Examples of the “pharmaceutically acceptable salt” include inorganic acid salts such as hydrochloride, sulfate and phosphate, organic acid salts such as methanesulfonate, benzenesulfonate, succinate and oxalate, inorganic basic salts such as a sodium salt, a potassium salt and a calcium salt, and organic basic salts such as a triethylammonium salt.
• inorganic acid salts such as hydrochloride, sulfate and phosphate
• organic acid salts such as methanesulfonate, benzenesulfonate, succinate and oxalate
• inorganic basic salts such as a sodium salt, a potassium salt and a calcium salt
• organic basic salts such as a triethylammonium salt.
• the present peptide can be synthesized, for example, by “a solid-phase synthesis method” and “a liquid-phase synthesis method” (for example, Japanese Patent Laying-Open No. 2003-183298).
• a solid-phase synthesis method for example, a Fmoc method and a Boc method are known, and the present peptide may be synthesized in any of these methods.
• One example of the solid-phase synthesis method will be concretely described below.
• a bead of polystyrene polymer gel having a diameter of about 0.1 mm whose surface is modified with an amino group is used as a solid phase, and diisopropylcarbodiimide is used as a condensing agent.
• the amino group of C-terminal amino acid is protected with a Fmoc group or a Boc group, and allowed to form a peptide bond with the amino group of the aforementioned polystyrene polymer gel.
• the solid phase is washed well with a solvent to clean and remove the remaining reagent and amino acid, and then the protecting group of the amino group of the amino acid bound to the solid phase is removed.
• a peptide is synthesized on the solid phase.
• the solid phase is digested in trifluoroacetic acid to detach the peptide from the solid phase, and thus the peptide can be synthesized.
• the present peptide can also be produced by hydrolyzing gelatin with a combination of two or more kinds of endoprotease and exoprotease. Also, the peptide mixture itself obtained by above hydrolysis, or a mixture obtained by partial purification of the peptide mixture can be used as a myoblast differentiation promoter.
• the present peptide may be chemically modified.
• Chemical modification can be carried out for an individual amino acid, for example, at the hydroxyl group of hydroxyproline, at the amino group of an N-terminal amino acid, and at the carboxyl group of a C-terminal amino acid.
• Such chemical modification enables dissolution under weak acidic to neutral conditions, and also allows improvement in compatibility with other active ingredient as described later.
• chemical modification at the hydroxyl group of hydroxyproline include, for example, O-acetylation.
• Chemical modification at the amino group of an N-terminal amino acid include, for example, polypeptidylation, succinylation, maleylation, acetylation, deamination, benzoylation, alkylsulfonylation, allylsulfonylation, dinitrophenylation, trinitrophenylation, carbamylation, phenylcarbamylation, and thiolation are recited.
• Chemical modification at the carboxyl group of a C-terminal amino acid include, for example, esterification and amidation. When the present peptide is cationated, ethylenediamination, spermination, and so on can be carried out.
• a usual chemical modification technique for peptide is applied.
• O-acetylation of the hydroxyl group of hydroxyproline can be achieved by allowing acetic anhydride to act in an aqueous solvent or in a nonaqueous solvent.
• esterification of the carboxyl group of a C-terminal amino acid can be achieved, for example, by aeration with a dry hydrogen chloride gas following suspension in methanol, and amidation thereof can be achieved by allowing carbodiimide or the like to act on the same.
• chemical modification techniques described in Patent Publication No. 62-44522 and Patent Publication No. 5-79046 can be applied.
• the present peptide or the like has a myoblast differentiation promoting effect as described in later-described Test Examples. Therefore, the present peptide or the like can be used for therapy or prevention of various diseases that require muscle enhancement.
• the myoblast differentiation promoter of the present invention can be used, for example, for therapy of locomotive syndrome, therapy of sarcopenia, improvement in the effect of training in athletes, students and so on, enhancement in physical strength of aged persons, long-stay inpatients and so on, and improvement in quality of meat of livestock.
• the myoblast differentiation promoter of the present invention can be administered orally or parenterally in pharmaceutical preparations of various forms.
• the forms include tablet, granule, capsule, powder, liquid, suspension and emulsion for oral administration, and injection, transdermal agent, suppository, nasal drop and inhalant for parenteral administration.
• Preferred examples include tablet, granule, capsule, and liquid to be directly administered to a diseased site such as muscle.
• the present peptide is preferably taken in by oral administration because it is little digested into amino acids in the digestive tract, but is rapidly absorbed in the intestinal tract. The present peptide may be taken in while it is mixed with a meal or a beverage.
• a dose of the present peptide varies depending on the condition or the body weight of the patient, the kind of the compound, the administration route and so on.
• oral administration per day for one adult for example, about 0.1 to 1000 mg, preferably about 1 to 500 mg, and more preferably about 30 to 200 mg are recited, and in the case of direct administration to a diseased part such as muscle, for example, about 0.01 to 200 mg, preferably about 0.1 to 100 mg, and more preferably about 1 to 50 mg are recited.
• Doses of preparations of other forms can be appropriately determined with reference to these doses. These preparations can be administered daily in one to several divided doses, or may be administered once every one to several days.
• the myoblast differentiation promoter of the present invention may appropriately comprise other active ingredient(s) and ingredient(s) for formulation as far as the effect of the present invention is not interfered.
• the other active ingredient include muscle-enhancing agents such as a male hormone, and muscle-enhancing supplements such as an amino acid mixture. Amounts of the other active ingredients formulated can be appropriately changed depending on the individual effects.
• Examples of a pharmaceutically acceptable carrier used in preparation into a pharmaceutical preparation can include a diluent, a binder (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone), an excipient (lactose, sucrose, cornstarch, potassium phosphate, sorbit, glycine), a lubricant (magnesium stearate, talc, polyethylene glycol, silica), a disintegrant (potato starch) and a humectant (sodium lauryl sulfate).
• the present pharmaceutical preparation can be produced by mixing the present peptide(s), other active ingredient(s), a pharmaceutically acceptable carrier and so on according to conventionally known techniques.
• the present peptide or the like is a peptide derived from gelatin, it is very safe for daily intake or application. Hence, it is also useful as a beverage or food product or a feed comprising the present peptide(s) or the like with the use of the excellent myoblast differentiation promoting effect of the present peptide(s) or the like.
• the present invention can be used for enhancement in physical strength of aged persons, long-stay inpatients and so on, improvement in effect of training in athletes, students and so on, and improvement in quality of meat of livestock.
• the content of the present peptide(s) or the like used in a beverage or food product or a feed of the present invention can be varied appropriately depending on the effect to be utilized.
• this collagen peptide contained the following respective peptides.
• Hyp-Gly 7573 ppm, Pro-Ala: 2541 ppm, Ala-Hyp-Gly: 331 ppm, Pro-Hyp: 184 ppm, Gly-Pro-Hyp: 85 ppm, Glu-Hyp: 72 ppm, Hyp-Gly-Pro: 7 ppm
• this collagen peptide contained the following respective peptides.
• D-MEM culture medium containing 10% FBS, 100 units/mL sodium penicillin G, 100 ⁇ g/mL streptomycin and 1.0 g /L NaHCO 3 (D-MEM culture medium (10% FBS, +P/S)) was used. Culture was conducted in an incubator at 37° C. containing 95% air and 5% CO 2 .
• the culture medium was replaced by a D-MEM culture medium including 2% horse serum (HS), 100 units/mL sodium penicillin G, 100 ⁇ g/mL streptomycin and 1.0 g/L NaHCO 3 (D-MEM culture medium (2% HS+P/S)), and then the D-MEM culture medium (2% HS+P/S) replacement was repeated every two days to lead to differentiation into myotube cells.
• D-MEM culture medium 2% HS+P/S
• the peptides of Examples 1 to 21 and Comparative Examples 1 to 3 were added in a final concentration of 100 ⁇ M to the culture medium every the culture medium replacement, and cells were continuously exposed thereto for eight days.
• the Western blotting method was conducted in the following procedure.
• the cells used for protein measurement were washed twice with PBS at the time of recovery, and the cells were scraped with a cell scraper and transferred to a tube, and centrifuged at 4° C. and at 250 ⁇ g for 3 minutes, and then PBS was completely removed.
• the cells were suspended in 100 ⁇ L of a buffer (20 mM HEPES-NaOH (pH 7.5), 0.5% NP-40, 1 mM EDTA, 100 ⁇ M AEBSF, 1 ⁇ g/mL aprotinin, 10 ⁇ g/mL leupeptin, 1 mM DTT, 1 mM sodium ortho-vanadate, 10 mM sodium fluoride, 10 ⁇ M ammonium molybdate, 10 mM sodium pyrophosphate), and then crushed under ice cooling for 5 seconds three times for each sample by using an ultrasonic disperser, followed by quantification of the amount of a protein.
• a buffer (20 mM HEPES-NaOH (pH 7.5), 0.5% NP-40, 1 mM EDTA, 100 ⁇ M AEBSF, 1 ⁇ g/mL aprotinin, 10 ⁇ g/mL leupeptin, 1 mM DTT, 1 mM sodium ortho-vanadate, 10
• Quantification of the amount of a protein was conducted according to the method of Bradford using bovine serum albumin as a standard protein. After end of SDS-PAGE, a blotting device was used to conduct electro-transferring at 1.5 mA per 1 cm 2 of a membrane for 1 hour on a PVDF membrane equilibrated with methanol and subjected to pre-wetting by infiltration with a transfer buffer (48 mM Tris, 39 mM glycine). After end of the transferring, the PVDF membrane was blocked with PBS ( ⁇ ) containing 6% skim milk for 1 hour. A primary antibody was diluted in the following manner, and an antigen-antibody reaction was conducted overnight at 4° C.
• a peroxidase-conjugated secondary antibody against each primary antibody was diluted in PBS ( ⁇ ) containing 6% skim milk in the ratios: mouse anti-myosin heavy chain monoclonal antibody (MF20) culture supernatant 1/2000, mouse anti-tropomyosin monoclonal antibody (CH1) culture supernatant 1/2000, rabbit anti-GAPDH polyclonal antibody 1/3000, peroxidase-conjugated anti-mouse IgG 1/5000, and peroxidase-conjugated anti-rabbit IgG 1/2000, allowed to react for 30 minutes, and washed three times with PBS ( ⁇ ) for 10 minutes.
• MF20 mouse anti-myosin heavy chain monoclonal antibody
• CH1 mouse anti-tropomyosin monoclonal antibody
• rabbit anti-GAPDH polyclonal antibody 1/3000 rabbit anti-GAPDH polyclonal antibody 1/3000
• Non-Patent Literature 1 tropomyosin and myosin heavy chain are used as myoblast differentiation markers.
• the above test results demonstrated that in the test of each peptide of Examples 1 to 8, larger quantities of tropomyosin and myosin heavy chain that are myoblast differentiation markers are generated in comparison with the control. Therefore, it is understood that these peptides have a myoblast differentiation promoting effect.
• peptide mixtures comprising two kinds of peptides selected from Ala-Hyp-Gly, Hyp-Gly-Pro, Leu-Hyp, Glu-Hyp, Gly-Pro-Hyp, Pro-Ala, Hyp-Gly and Pro-Hyp have a synergistic myoblast differentiation promoting effect.
• the mixture of Hyp-Gly and Pro-Hyp in Example 9 exhibited a significant myoblast differentiation promoting effect.
• the mixtures of only amino acids in Comparative Examples 2 and 3 did not exhibit the similar effect, revealing that the myoblast differentiation promoting effect first arises with the mixture of Pro-Hyp and Hyp-Gly as peptide molecules.
• a clinical test was conducted using the collagen peptides of Example 22 and Comparative Example 4 as test collagen peptides.
• Subjects were 34 healthy women who were not athletes, aged 24 to 61. They were randomly assigned to a group taking in the collagen peptide of Example 22 (17 persons) and a group taking in the collagen peptide of Comparative Example 4 (17 persons), and a double blind test was conducted. They continuously took in 5 g per day of respective collagen peptides for 10 weeks.
• the muscle weight (kg: containing water content) of each subject was measured using TANITA body composition monitor right and left regional inner scan 50V BC-622-BK. Also, the water content (kg) measured at the same time was taken away, and a rate of muscle weight (%) per body weight was calculated and evaluated. The result is shown in Table 2 by mean value ⁇ standard deviation.
• the mark ** in the table means significance with P ⁇ 0.001 with respect to Comparative Example 4 in Two-way-ANOVA.
• the present invention is able to provide a myoblast differentiation promoter comprising peptide(s) derived from natural collagen, that is superior to conventional arts.

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