Novel peptides having growth promoting activity and uses thereof

Abstract

The peptide of the present application has an activity of promoting growth hormone (GH) production and promoting growth plate growth. Therefore, the peptide of the present application can be used for promoting growth, and can be effectively used as an active ingredient for treating, preventing or alleviating a growth retardation disorder such as dwarfism.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to Korean Patent Application No. 10-2024-0047911, filed on April 9, 2024, the entire disclosure of which is incorporated herein by reference. Technical Field

[0003] This invention relates to a peptide with growth-promoting activity and its uses. Background Technology

[0004] Bone development is regulated by numerous growth factors and growth hormones. Growth hormone is a peptide hormone secreted by the pituitary gland that promotes bone growth by inducing calcium deposition in chondrocytes located in the growth plates of the epiphysis, where longitudinal bone growth occurs. The growth plate is a region of bone responsible for longitudinal growth near joints or in the arms and legs. It is primarily located at the ends of long bones and consists of cartilaginous plates between the bones. During fetal development, although all bones are composed of cartilage, bone growth occurs through calcium deposition as this cartilage develops. It is known that after the cartilage transforms into bone, the remaining cartilage becomes the growth plate.

[0005] Growth retardation or growth disorders can cause age- or sex-inappropriate growth delays, resulting in short stature. Short stature can be caused by: chronic systemic diseases, such as chronic renal failure; hormonal abnormalities, such as growth hormone deficiency, hypothyroidism, and diabetes; or congenital abnormalities, such as Turner syndrome. Growth hormone deficiency can be caused by: anencephaly or micropituitarism due to abnormal development; central nervous system abnormalities, such as brain tumors, congenital brain malformations, and hydrocephalus; pituitary damage due to trauma, encephalitis, brain tumors, tuberculous meningitis, or central nervous system radiography; or pituitary or hypothalamic damage due to insufficient oxygen supply to the neonatal brain during difficult delivery. In addition, chromosomal abnormalities or environmental factors (such as nutrition, exercise, sleep, and stress) may also be causes of abnormal or deficient growth hormone secretion.

[0006] It has been reported that prescriptions for growth hormone medications used to treat stunted growth or short stature can lead to a reduction in the normal production of growth hormone or a decrease in the ability to produce growth hormone endogenously, accompanied by side effects such as inducing diabetes, causing hypothyroidism, neurological symptoms such as headaches or dizziness, gastrointestinal symptoms, and skin diseases such as hives or itching.

[0007] International application PCT / EP2014 / 050800 (WO2014 / 111467) discloses a soluble fibroblast growth factor receptor 3 (FGFR3) peptide for the prevention or treatment of bone growth retardation, and international application PCT / US2013 / 068009 (WO2014 / 071158) discloses an activator ACTRII antagonist for the treatment of bone diseases.

[0008] [Existing Technical Documents]

[0009] [Patent Literature]

[0010] International application PCT / EP2014 / 050800 (WO2014 / 111467)

[0011] International application PCT / US2013 / 068009 (WO2014 / 071158) Summary of the Invention

[0012] [Technical Issues]

[0013] The inventors conducted intensive research to develop an active substance with growth-promoting activity for treating growth retardation or dwarfism. As a result, the inventors experimentally confirmed that the peptide developed by the inventors has the activity of promoting the production of growth hormone by the pituitary gland and promoting the growth plate. Based on this, the inventors confirmed that the peptide described in this invention can be used as a therapeutic agent for diseases related to growth retardation, thus completing this invention.

[0014] Therefore, the object of the present invention is to provide a composition for promoting growth.

[0015] Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of growth retardation.

[0016] Another object of the present invention is to provide a food composition for improving or preventing growth retardation.

[0017] [Technical Solution]

[0018] One aspect of the present invention provides a composition for promoting growth, comprising a peptide containing the amino acid sequence of SEQ ID NO: 1 as an active ingredient.

[0019] Another aspect of the present invention provides a pharmaceutical composition for treating or preventing growth retardation, comprising a peptide containing the amino acid sequence of SEQ ID NO: 1 as an active ingredient.

[0020] Another aspect of the present invention provides a food composition for improving or preventing growth retardation, comprising a peptide containing the amino acid sequence of SEQ ID NO: 1 as an active ingredient.

[0021] The present invention will be described in detail below.

[0022] According to one aspect of the present invention, a peptide containing the amino acid sequence described in SEQ ID NO: 1 is provided.

[0023] [Amino acid sequence of SEQ ID NO: 1]

[0024] RERMS (Arg-Glu-Arg-Met-Ser)

[0025] As used in this article, the term "peptide" refers to a linear molecule formed by amino acid residues linked together by peptide bonds.

[0026] The peptide containing the amino acid sequence of SEQ ID NO:1 of the present invention can be used as is; however, variants or fragments of peptides with different amino acid sequences generated by deletion, insertion, substitution or combination thereof of amino acid residues can also be used, as long as the inherent activity of the peptide (e.g., growth-promoting activity) is not affected.

[0027] The peptides of the present invention can be modified by phosphorylation, sulfation, acrylation, glycosylation, methylation, farnesylation, etc., without changing their activity.

[0028] The peptides of the present invention include peptides, variants thereof, or active fragments thereof containing an amino acid sequence substantially identical to that of SEQ ID NO: 1. A substantially identical amino acid sequence is defined as an amino acid sequence having at least 75%, for example, at least 80%, at least 85%, at least 90%, at least 95%, or at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 1. Furthermore, the peptide may also contain a targeting sequence, a tag, labeled residues, or an amino acid sequence prepared for a specific purpose to increase half-life or peptide stability.

[0029] In the peptides of the present invention, their activity can be enhanced by introducing N-terminal and / or C-terminal modifications into specific regions of the amino acid sequence. Such N-terminal and / or C-terminal modifications can significantly improve the stability of the peptides of the present invention, for example, by extending the half-life of the peptide after in vivo administration. The term "stability" includes not only in vivo stability that protects the peptides of the present invention from proteolytic enzyme attack, but also storage stability (e.g., room temperature storage stability).

[0030] N-terminal modification can be a protecting group attached to the N-terminus of the peptide, selected from the group consisting of acetyl group, fluorenylmethoxycarbonyl group, formyl group, palmitoyl group, myristyl group, stearyl group, and polyethylene glycol (PEG). C-terminal modification can be, but is not limited to, the formation of hydroxyl group (-OH), amino group (-NH2), hydrazino group (-NHNH2), etc., attached to the C-terminus of the peptide.

[0031] The peptides of the present invention can be prepared by various methods widely known in the art to which this invention pertains. For example, the peptides of the present invention can be prepared according to chemical synthesis methods known in the art, particularly solid-phase synthesis techniques (see Merrifield, etc.). J. Amer. Chem. Soc. 85:2149-54 (1963); Stewart, et al., Solid Phase Peptide Synthesis, 2nd. ed., Pierce Chem.Co.: Rockford, III, (1984)) or liquid phase synthesis (US Patent No. 5,516,891) to prepare it.

[0032] The peptides of this invention have growth-promoting activity.

[0033] The peptides of this invention have the activity of promoting the production of growth hormone (GH).

[0034] In one specific embodiment of the present invention, the peptide of the present invention has the activity of promoting the expression of growth hormone in pituitary or anterior pituitary cells.

[0035] As used herein, the term "growth plate" refers to the bony region responsible for longitudinal growth near joints or in the arms and legs. The growth plate is primarily located at the ends of long bones and is composed of cartilaginous plates interspersed between the bones. The growth plate forms a structure in which multiple layers of cartilage cells (chondrocytes) stack, undergoing cell division on one side while on the other side, the chondrocytes mature and form bone tissue. As the chondrocytes of the growth plate divide, the bone grows longitudinally.

[0036] The peptides of this invention have the activity of promoting growth plate growth.

[0037] Growth of a growth plate refers to an increase in the length, size, or area of ​​the growth plate.

[0038] In one specific embodiment of the present invention, the peptide of the present invention has the activities of increasing the size of proliferative chondrocytes in the growth plate, increasing the expression of IGF-1 (insulin-like growth factor 1), and increasing the expression of IGFBP3 (insulin-like growth factor binding protein 3).

[0039] As described above, the peptides of the present invention have bone growth-promoting activity and therefore can exhibit therapeutic efficacy against diseases associated with growth retardation.

[0040] In another aspect of the invention, a composition for promoting growth is provided, comprising a peptide containing the amino acid sequence of SEQ ID NO: 1 as an active ingredient.

[0041] In one embodiment, the peptide has the activity of promoting growth hormone (GH) production or promoting growth plate growth.

[0042] In one embodiment, the composition for promoting growth may be a food composition, a functional food composition, or a health-functional food composition.

[0043] In another aspect of the invention, a pharmaceutical composition for treating or preventing growth retardation is provided, comprising a peptide containing the amino acid sequence of SEQ ID NO: 1 as an active ingredient.

[0044] As used in this article, the term "growth retardation disorder" refers to a condition in which growth is delayed due to a growth rate lower than the normal growth rate.

[0045] In one implementation, growth retardation can be caused by growth hormone deficiency or insufficient growth hormone secretion.

[0046] In one implementation, growth retardation can be caused by a condition of the growth plate, and the condition of the growth plate can be a growth plate condition caused by growth plate damage, growth plate infection, or genetic factors.

[0047] In one implementation, the growth retardation condition may be termed short stature disorder.

[0048] As used in this article, the term "dwarfism" refers to a condition in which a person's height is below the standard value for their age and sex.

[0049] In one implementation scheme, short stature can be familial short stature, idiopathic short stature, intrauterine growth retardation (IUGR), short stature due to growth plate damage, short stature due to osteochondral dysplasia, short stature due to kidney disease, short stature due to chronic disease, short stature due to growth hormone deficiency, short stature due to thyroid hormone deficiency, short stature due to sex hormone deficiency, short stature due to adrenocortical hormone deficiency, short stature due to Turner syndrome, or short stature due to Down syndrome.

[0050] Growth hormone deficiency can be (i) biologically inactive GH, (ii) genetic GH deficiency, or (iii) growth hormone deficiency caused by brain injury, brain tumor, brain radiation therapy, pituitary infarction, brain inflammation, or granulomatous disease.

[0051] In one implementation, short stature due to kidney disease may be short stature caused by uremia, short stature caused by renal tubular acidosis, or short stature caused by chronic renal failure.

[0052] In one implementation, short stature caused by chronic disease may be short stature caused by congenital heart disease, short stature caused by chronic lung disease, or short stature caused by liver disease.

[0053] In one embodiment, the peptide, as the active ingredient of the pharmaceutical composition, has the activity of promoting growth hormone (GH) production or promoting growth plate growth.

[0054] In a specific embodiment of the present invention, the peptide of the present invention has the activity of promoting the expression of growth hormone in pituitary or anterior pituitary cells.

[0055] The peptides of this invention have activity that promotes the growth of growth plates. Growth of the growth plate refers to an increase in the length, size, or area of ​​the growth plate.

[0056] In a specific embodiment of the present invention, the peptide of the present invention has the activities of increasing the size of proliferating chondrocytes in the growth plate, increasing the expression of IGF-1 (insulin-like growth factor 1), and increasing the expression of IGFBP3 (insulin-like growth factor binding protein 3).

[0057] The pharmaceutical compositions of the present invention may comprise a therapeutically effective amount of the peptide of the present invention containing the amino acid sequence of SEQ ID NO: 1.

[0058] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to achieve the activity or efficacy of a peptide (which is the active ingredient of the pharmaceutical composition of the present invention), for example, an amount sufficient to achieve the efficacy of treating or preventing the aforementioned growth retardation condition.

[0059] As used herein, the term “prevention” means reducing the risk of developing a disease or condition, and includes any behavior that inhibits or delays the onset of a disease by preventing the progression of the disease or one or more of its clinical signs.

[0060] As used herein, the term “treatment” means to alleviate a disease or symptom, and includes all actions that improve or beneficially alter the symptoms of a disease by preventing or reducing the progression of the disease or one or more of its clinical signs.

[0061] The pharmaceutical compositions of the present invention may contain a pharmaceutically acceptable carrier.

[0062] Pharmaceutically acceptable carriers are those commonly used in formulations, including but not limited to lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil.

[0063] The pharmaceutical composition of the present invention may be a composition comprising a therapeutically effective amount of a peptide containing the amino acid sequence of SEQ ID NO: 1; and a pharmaceutically acceptable carrier.

[0064] In addition to the components described above, the pharmaceutical compositions of the present invention may also contain, but are not limited to, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, and preservatives.

[0065] Suitable pharmaceutically acceptable carriers and formulations Remington: The Science and Practice of PharmacyIt is described in detail in (21st ed., 2005, Lippincott Williams & Wilkins).

[0066] The pharmaceutical compositions of the present invention can be administered to treat growth retardation by any suitable route, such as oral or parenteral administration. In the case of parenteral administration, they can be administered via intravenous infusion, subcutaneous infusion, intramuscular infusion, intraperitoneal infusion, local application, transdermal application, etc.

[0067] The dosage of the pharmaceutical composition may be from 0.0001 μg / day to 1000 mg / day, 0.001 μg / day to 1000 mg / day, 0.01 μg / day to 1000 mg / day, 0.1 μg / day to 1000 mg / day, 0.1 μg / day to 500 mg / day, or 1.0 μg / day to 1000 mg / day, but is not limited thereto, and may be prescribed in various ways based on factors such as preparation method, administration method, patient age, weight, sex and pathological condition, food, administration time, route of administration, excretion rate and responsiveness.

[0068] The pharmaceutical compositions of the present invention can be formulated into unit dosage forms or contained in multi-dose containers using pharmaceutically acceptable carriers and / or excipients, according to methods readily practiced by those skilled in the art. In this regard, the formulations may be in the form of solutions, suspensions, or emulsions in oily or aqueous media, or in the form of extracts, powders, granules, tablets, or capsules, and may additionally contain dispersants or stabilizers.

[0069] The pharmaceutical compositions of the present invention may comprise the peptides of the present invention at a concentration of 0.01 μM to 1000 μM, and specifically, the concentrations of the peptides may be 0.01 μM to 900 mM, 0.01 μM to 500 mM, 0.01 μM to 300 mM, 0.01 μM to 100 mM, 0.01 μM to 50 mM, 0.01 μM to 30 mM, 0.01 μM to 10 mM, 0.01 μM to 1 mM, 0.01 μM to 0.1 mM, 0.01 μM to 0.01 mM, 1.01 μM to 1000 μM, 0.05 μM to 800 μM, 0.05 μM to 700 μM, 0.05 μM to 600 μM, 0.05 μM to 500 μM, 0.05 μM to 300 μM, 0.05 μM to 10 ... μM to 200 μM, 0.1 μM to 800 μM, 0.1 μM to 700 μM, 0.1 μM to 600 μM, 0.1 μM to 500 μM, 0.1 μM to 300 μM, 0.1 μM to 200 μM; 1 μM to 800 μM, 1 μM to 700 μM, 1 μM to 600 μM, 1 μM to 500 μM, 1 μM to 300 μM, 1 μM to 200 μM, 5 μM to 800 μM, 5 μM to 700 μM, 5 μM to 600 μM, 5 μM to 500 μM, 5 μM to 300 μM, or 5 μM to 200 μM, but not limited to these.

[0070] Another aspect of the present invention provides a food composition for improving or preventing growth retardation, comprising a peptide containing the amino acid sequence of SEQ ID NO: 1 as an active ingredient.

[0071] As used in this article, the term “improvement” can refer to any behavior that at least reduces parameters (such as symptom severity) related to the relief or treatment of the condition.

[0072] The activity of the peptides of the present invention in the food composition which are related to improving or preventing growth retardation is the same as that described in the above-mentioned pharmaceutical compositions, and therefore is cited herein without further elaboration.

[0073] As used in this article, the term “growth retardation” refers to a symptom or condition that results in a slower-than-normal growth rate.

[0074] In one implementation, growth retardation may be caused by growth hormone deficiency or insufficient growth hormone secretion.

[0075] In one implementation, growth retardation may be caused by growth plate disease, which may be caused by growth plate damage, growth plate infection, or genetic factors.

[0076] In one implementation scheme, growth retardation may be termed short stature disorder.

[0077] As used in this article, the term "dwarfism" refers to a condition in which a person's height is below the standard value for their age and sex.

[0078] In one implementation scheme, short stature can be familial short stature, idiopathic short stature, intrauterine growth retardation (IUGR), short stature due to growth plate damage, short stature due to osteochondrodysplasia, short stature due to kidney disease, short stature due to chronic disease, short stature due to growth hormone deficiency, short stature due to thyroid hormone deficiency, short stature due to sex hormone deficiency, short stature due to adrenocortical hormone deficiency, short stature due to Turner syndrome, or short stature due to Down syndrome.

[0079] In one implementation, short stature due to kidney disease may be short stature caused by uremia, short stature caused by renal tubular acidosis, or short stature caused by chronic renal failure.

[0080] In one implementation, short stature caused by chronic disease may be short stature caused by congenital heart disease, short stature caused by chronic lung disease, or short stature caused by liver disease.

[0081] In one embodiment, the peptide, as an active ingredient in the food composition, has the activity of promoting growth hormone (GH) production or promoting growth plate growth.

[0082] In one specific embodiment of the present invention, the peptide of the present invention has the activity of promoting the expression of growth hormone in pituitary or anterior pituitary cells.

[0083] The peptides of this invention have activity that promotes the growth of growth plates. Growth of the growth plate refers to an increase in the length, size, or area of ​​the growth plate.

[0084] In one specific embodiment of the present invention, the peptide of the present invention has the activities of increasing the size of proliferating chondrocytes in the growth plate, increasing the expression of IGF-1 (insulin-like growth factor 1), and increasing the expression of IGFBP3 (insulin-like growth factor binding protein 3).

[0085] In one embodiment, the appropriate amount of the peptide included as an active ingredient in the food composition of the present invention may be selected from less than 10% by weight of the total weight of the composition, specifically from 0.000001% by weight to 10% by weight.

[0086] The food composition of the present invention may contain a food-effective amount of the peptide and a food-acceptable carrier.

[0087] The food composition of the present invention not only contains the peptides of the present invention as active ingredients, but also contains ingredients commonly added during food manufacturing, and may include, for example, proteins, carbohydrates, fats, nutrients, flavoring agents, and taste agents. Examples of carbohydrates include monosaccharides (e.g., glucose, fructose, etc.); disaccharides (e.g., maltose, sucrose, oligosaccharides, etc.); and polysaccharides, such as conventional sugars (e.g., dextrin, cyclodextrin, etc.) and sugar alcohols (e.g., xylitol, sorbitol, erythritol, etc.). As taste agents, natural taste agents (e.g., sematrandrine, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic taste agents (e.g., saccharin, aspartame, etc.) can be used.

[0088] In addition to the above-mentioned components, the food composition of the present invention may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents (such as synthetic and natural flavoring agents), coloring agents and fillers (e.g., cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, and carbonating agents used in carbonated beverages. Furthermore, the food composition of the present invention may contain fruit pulp used in the preparation of natural fruit juices, fruit juice beverages, and vegetable beverages. For example, when the food composition of the present invention is made into a beverage, in addition to peptides as active ingredients of the present invention, it may also additionally contain citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, Eucommia ulmoides extract, jujube extract, licorice extract, etc.

[0089] There are no particular restrictions on the type of food composition. Examples of food or food compositions include meat, sausage, bread, chocolate, confectionery, snacks, pastries, pizza, ramen, other noodles, chewing gum, dairy products including ice cream, various soups, beverages, tea beverages, alcoholic beverages, vitamin complexes, dairy products and fermented milk, and may include all functional foods or foods in the conventional sense.

[0090] Furthermore, food compositions may include health functional foods. As used herein, the term "health functional food" refers to a food manufactured and processed using raw materials or ingredients that have functional properties beneficial to the human body, in the form of tablets, capsules, powders, granules, liquid preparations, pills, etc. Here, "functional" means, for example, achieving a beneficial effect on health through the regulation of nutrients or physiological functions related to the structure and function of the human body. Health functional foods can be manufactured using methods commonly used in the art, and can be manufactured by adding raw materials and ingredients conventionally added in the art. Moreover, the dosage form of health functional foods can be prepared without restriction, as long as it is considered to be in the form of a health functional food. Food compositions can be manufactured in various dosage forms, and unlike conventional pharmaceuticals, the advantage of food compositions is that they use food as raw materials, thus avoiding the side effects that may occur with long-term use of pharmaceuticals.

[0091] In another aspect of the invention, a method for treating, preventing or improving growth retardation is provided, comprising administering a therapeutically effective amount of the peptide described above containing the amino acid sequence of SEQ ID NO: 1 to a subject in need of it (e.g., a subject in need of treatment for growth retardation).

[0092] Subjects can be humans or non-human animals.

[0093] In another aspect of the invention, the above-mentioned peptide containing the amino acid sequence of SEQ ID NO: 1 is provided for use in treating, preventing or improving growth retardation.

[0094] In another aspect of the invention, the use of the above-described peptide containing the amino acid sequence SEQ ID NO: 1 for preparing a composition for treating, preventing, or improving growth retardation is provided. This composition may be a pharmaceutical composition or a food composition.

[0095] In the methods for treating, preventing or improving growth retardation, the uses for treating, preventing or improving growth retardation, or the uses for preparing compositions for treating, preventing or improving growth retardation, other technical details, including the peptides and the compositions, as described in the present invention for compositions for promoting growth, pharmaceutical compositions for treating or preventing growth retardation, and food compositions for improving or preventing growth retardation, are therefore omitted and will not be repeated.

[0096] [Beneficial Effects]

[0097] The peptides of the present invention have the activity of promoting growth hormone (GH) production and promoting growth plate growth. Therefore, the peptides of the present invention can be used to promote growth and can be effectively developed and used as active ingredients for treating, preventing or improving growth retardation conditions (e.g., dwarfism).

[0098] However, the effects of the present invention are not limited to those described above, and those skilled in the art will clearly understand from the following description other effects not specifically mentioned. Attached Figure Description

[0099] Figure 1 The results of measuring the expression levels of the growth hormone (GH) gene and Pit-1 gene in GH3 cells treated with the peptide of Preparation Example 1 are shown. (Con: control group, peptide: peptide of SEQ ID NO: 1 of the present invention, hGH: recombinant human growth hormone).

[0100] Figure 2a and Figure 2bThe measurements of the nose-to-tail tip length of SD rats are shown in the experimental group (peptide administration group of Preparation Example 1), control group (PBS administration group), and positive control group (hGH administration group). (Con: control group, SEQ 1: peptide of SEQ ID NO: 1 of the present invention, hGH: recombinant human growth hormone).

[0101] Figure 3 This is a graph showing the measurement results of the nose-to-tail tip length of SD rats in the experimental group (peptide administration group of Preparation Example 1), control group (PBS administration group), and positive control group (hGH administration group) at different measurement time points. (Con: control group, SEQ 1: peptide of SEQ ID NO: 1 of the present invention, hGH: recombinant human growth hormone).

[0102] Figure 4a and Figure 4b The body weight measurements of SD rats in the experimental group (peptide administration group of Preparation Example 1), control group (PBS administration group), and positive control group (hGH administration group) are shown. (Con: control group, SEQ 1: peptide of SEQ ID NO: 1 of the present invention, hGH: recombinant human growth hormone).

[0103] Figure 5 This is a graph showing the body weight measurements of SD rats in the experimental group (peptide administration group of Preparation Example 1), control group (PBS administration group), and positive control group (hGH administration group) at different measurement time points. (Con: control group, SEQ 1: peptide of SEQ ID NO: 1 of the present invention, hGH: recombinant human growth hormone).

[0104] Figure 6 The measurements of tibia longitudinal bone length in SD rats from the experimental group (peptide administration group of Preparation Example 1), control group (PBS administration group), and positive control group (hGH administration group) are shown. Figure A shows a representative photograph of the tibia longitudinal bone, and Figure B shows the length measurements obtained using a digital caliper. (Con: control group, SEQ 1: peptide of SEQ ID NO: 1 of the present invention, hGH: recombinant human growth hormone).

[0105] Figure 7aThe tibial growth plate length of SD rats in the experimental group (peptide application group of Preparation Example 1), control group (PBS application group), and positive control group (hGH application group) obtained by H&E staining is shown. Figure A is the control group, Figure B is the experimental group, and Figure C is the positive control group. (RZ: resting zone, PZ: proliferative zone, HZ: hypertrophic zone. Control: control group, peptide: peptide of SEQ ID NO: 1 of this invention, hGH: recombinant human growth hormone).

[0106] Figure 7b Figure 1 shows the measurement results of tibial growth plate length in SD rats in the experimental group (peptide application group of Preparation Example 1), control group (PBS application group), and positive control group (hGH application group) obtained by H&E staining. Figure A shows the tibial growth plate length measured in the resting area, proliferative area, and hypertrophic area, and Figure B shows the length of the entire growth plate. (Con: control group, SEQ 1: peptide of SEQ ID NO: 1 of the present invention, hGH: recombinant human growth hormone).

[0107] Figure 7c The results of IHC staining with Ki67 (a proliferation marker) to confirm proliferating chondrocytes in the tibial growth plate of SD rats in the experimental group (peptide administration group of Preparation Example 1), control group (PBS administration group), and positive control group (hGH administration group) are shown. (Control: control group (PBS), SEQ 1: peptide of SEQ ID NO: 1 of the present invention, hGH: recombinant human growth hormone).

[0108] Figure 8a The expression levels of IGF-1 in the tibial growth plate of SD rats were shown using DAB staining in the experimental group (peptide application group of Preparation Example 1), control group (PBS application group), and positive control group (hGH application group). (Control: control group, peptide: peptide of SEQ ID NO: 1 of this invention, hGH: recombinant human growth hormone).

[0109] Figure 8b The expression levels of IGFBP3 in the tibial growth plate region of SD rats were shown using DAB staining in the experimental group (peptide application group of Preparation Example 1), control group (PBS application group), and positive control group (hGH application group). (Control: control group; peptide: peptide of SEQ ID NO: 1 of this invention; hGH: recombinant human growth hormone).

[0110] Figure 9a and Figure 9bThese are photographs and figures showing the expression levels of GH (growth hormone) in the pituitary gland of SD rats in the experimental group (peptide administration group of Preparation Example 1) and the control group (PBS administration group) using IHC staining. (Control: control group; peptide: peptide of SEQ ID NO: 1 of this invention).

[0111] Figure 10 Photographs are shown of liver tissues from SD rats in the experimental group (peptide administration group of Preparation Example 1) and the control group (PBS administration group) confirmed by H&E staining. (Control: control group; peptide: peptide of SEQ ID NO: 1 of this invention). Detailed Implementation

[0112] The present invention will now be described in detail through embodiments. However, the following embodiments are intended to specifically illustrate the present invention, and the scope of the present invention is not limited to these embodiments.

[0113] Preparation Example 1: Preparation of Peptides

[0114] Peptides with the amino acid sequence SEQ ID NO:1 listed in Table 1 below were synthesized using an automated peptide synthesizer (Milligen 9050, Millipore, USA) and purified using C18 reversed-phase high-performance liquid chromatography (HPLC) (Waters Associates, USA). An ACQUITY UPLC BEH300 C18 column (2.1 mm × 100 mm, 1.7 μm, Waters Co., USA) was used.

[0115] [Table 1]

[0116] The efficacy of the peptide prepared in SEQ ID NO:1 was evaluated through the following experiments.

[0117] Experimental Example 1: Determination of the expression of growth hormone gene and transcription factor Pit-1

[0118] The effects of the peptide prepared in Preparation Example 1 (the peptide of SEQ ID NO: 1) on the expression of growth hormone (GH) gene and transcription factor Pit-1 (pituitary-specific transcription factor) gene in rat anterior pituitary cells were evaluated.

[0119] GH3 cells (rat pituitary-derived cells, ATCC cat. CCL-82.1) were used at a rate of 3 × 10⁻⁶. 5Cells were seeded at a density of 100 cells / well in 12-well cell culture plates and cultured for 24 hours in F12-K medium (ATCC, cat. 30-2004) containing 10% FBS (fetal bovine serum, Gibco). The medium was then replaced with serum-free F12-K medium, and the cells were starved for 6 hours. Cells were treated with the peptides from Preparation Example 1 (100 μM, 200 μM) or as a positive control, hGH (Caregen, recombinant human growth hormone, CG-hGH; 6.8 μg / ml), and cultured for 24 hours before harvesting. After removing the medium from the collected cells and washing them twice with PBS, total RNA was isolated using easy-Blue (iNtRON, Cat. No.: 17061, Korea). The isolated RNA was quantified, and then 2,000 ng of RNA was aliquoted into each tube, and cDNA was synthesized using a cDNA synthesis kit (Enzynomics, Cat. No. RT200, Korea). PCR was performed using primers targeting the GH (growth hormone) gene and the Pit-1 gene (Table 2) and a PCR kit (Enzynomics, Cat. No. P581T, Korea). Subsequently, the PCR products were electrophoresed on a 1.2% agarose gel, and the bands were detected and analyzed using the Bio-Rad gel imaging system.

[0120] PCR primer sequence list

[0121] [Table 2]

[0122] Experimental results are as follows Figure 1 As shown, the peptide prepared in Example 1 confirmed that it increased the expression of the growth hormone (GH) gene and the GH transcription factor Pit-1 gene in GH3 cells to a level comparable to that of hGH (positive control).

[0123] Experimental Example 2: Measurement of height and long bone growth

[0124] To assess whether the peptide prepared in Preparation Example 1 promotes body length growth and long bone growth.

[0125] Three-week-old Sprague-Dawley rats (hereinafter referred to as SD rats) (n=15) were acclimatized for one week, and then administered the peptide of Preparation 1 at four weeks of age. Specifically, the control group (Con) (n=5) was orally administered PBS (1 ml) once daily; the peptide administration group (experimental group) (n=5) was orally administered PBS (1 ml) solution of the peptide of Preparation 1 at a dose of 100 mg / 250 g once daily; and the positive control group (P / C) (n=5) was subcutaneously injected with PBS (0.5 ml) solution of 50 μg / 250 g once daily. Administration was once daily from week 4 to week 9 for a total of four weeks. Body weight and nose-to-tail length were measured using a precision balance and ruler at weeks 5 (1 week), 6 (2 weeks), 8 (3 weeks), and 9 (4 weeks). At week 9 (4 weeks), SD rats were sacrificed, and the tibia of each rat's hind limb was dissected and its length was measured using a digital caliper.

[0126] Compared with the control group and positive control (hGH), SD rats administered the peptide of Example 1 once daily showed a greater increase in the length from the nose to the tip of the tail. Figure 2a and Figure 2b ).

[0127] In SD rats that were administered the peptide of Example 1 once daily for 4 weeks, an increase in the length from the nose to the tip of the tail was observed at 2 weeks and 4 weeks. Figure 3 ).exist Figure 3 In the figure, Figure A shows the length increment from 0W to 1W, Figure B shows the length increment from 1W to 2W, Figure C shows the length increment from 2W to 3W, and Figure D shows the length increment from 3W to 4W.

[0128] It was confirmed that SD rats administered the peptide of Example 1 once daily showed greater weight gain compared to the control group and positive control (hGH). Figure 4a and Figure 4b ).

[0129] In SD rats that received once-daily administration of the peptide from Example 1 for 4 weeks, weight gain was observed at 1, 2, and 4 weeks. Figure 5 ). Figure 5 Figure A shows the weight gain from 0 to 1 week. Figure 5 Figure B shows the weight gain from 1 week to 2 weeks. Figure 5 Figure C shows the weight gain from 2 weeks to 3 weeks, and Figure 5 Figure D shows the weight gain from 3 weeks to 4 weeks.

[0130] Compared with the control group and the positive control group (hGH), SD rats administered the peptide of Example 1 once daily for 4 weeks showed greater longitudinal bone gain in the tibia. Figure 6 ).exist Figure 6 In the figure, Figure A shows a representative photograph of the longitudinal bone of the tibia, and Figure B shows the length measurement results obtained using a digital caliper.

[0131] Experiment 3: Growth plate length measurement experiment, H&E staining and IHC staining

[0132] The purpose of this study was to evaluate whether the peptide prepared in Preparation Example 1 promotes bone growth and has therapeutic activity against growth retardation.

[0133] Preparation of tissue samples

[0134] Three-week-old Sprague-Dawley rats (hereinafter referred to as SD rats) (n=15) were acclimatized for one week, and then administered the peptide prepared in Example 1 at four weeks of age. Specifically, the control group (Con) (n=5) was orally administered PBS (1 ml) once daily; the peptide administration group (experimental group) (n=5) was orally administered PBS (1 ml) solution of the peptide prepared in Example 1 at a dose of 100 mg / 250 g once daily; and the positive control group (P / C) (n=5) was subcutaneously injected with PBS (0.5 ml) solution of hGH at a dose of 50 μg / 250 g once daily. Treatment continued once daily from week 4 to week 9 for a total of four weeks. After four weeks of treatment, the SD rats were sacrificed at week 9, and the tibia of each rat was isolated. The isolated tibia was fixed in 3.7% formaldehyde for 24 hours. After fixation, the tissue was washed in PBS and decalcified in 5% nitric acid for 3 days. After immersing the tissue in PBS and washing it without shaking for at least 3 hours, transfer it to a container and dehydrate it using a tissue processor (in the following order: 70% ethanol, 80% ethanol, 90% ethanol, 100% ethanol I, 100% ethanol II, and xylene I, xylene II). Embed the dehydrated tissue in a paraffin block, cut it into 4 μm thicknesses, place it on a slide glass, and allow it to dry completely for at least 24 hours.

[0135] H&E (hematoxylin and eosin) staining

[0136] Hematoxylin and eosin (H&E) staining was performed as follows. Tissue sections were dewaxed and rehydrated (treated with xylene I and xylene II for 5 minutes each, then for 3 minutes in each of the following steps: 1:1 xylene: 100% ethanol, 100% ethanol I, 100% ethanol II, 90% ethanol, 80% ethanol, and 70% ethanol). The tissues were washed under running water for 5 minutes with intermittent dipping. The samples were stained with hematoxylin (Dako, S3309) for 5 minutes and washed under running water for 5 minutes with intermittent dipping until the dye was completely removed. The samples were then stained with eosin Y (Eosin Y, Shandon, 6766007) for 5 minutes and washed under running water for 5 minutes. Subsequently, the samples were dehydrated (treated for 2 minutes each in 95% ethanol I, 95% ethanol II, 100% ethanol I, 100% ethanol II, and xylene III, then for 3 minutes in xylene IV). After mounting the sample onto the microscope, it was dried for at least 24 hours, and the growth plate was observed under the microscope to measure its length.

[0137] Immunohistochemistry (IHC) staining

[0138] Place the slides in a slide holder and immerse them in xylene (I, II, III) solution for 5 minutes, repeating three times. Then, immerse the slides in 100% ethanol (EtOH) solution for 3 minutes, repeating twice. Next, immerse the slides in 90% ethanol solution for 3 minutes, then in 80% ethanol solution for 3 minutes, and finally in 70% ethanol solution for 3 minutes. Afterward, wash the tissue under running water for 5 minutes, and then mark the tissue periphery with a Dako pen. Treat the tissue with 3% H2O2 for 10 minutes, then wash with DPBS for 10 minutes. Apply pepsin (100 μl / sample) to the tissue and incubate at 37°C for 30 minutes, then wash with DPBS for 10 minutes. Block with Ultravision protein blocking agent (Epredia, cat no. TA-125-PBQ, diluted to 1X in DPBS) at room temperature for 1 hour. The samples were incubated with primary antibody (anti-Ki67 Ab, Invitrogen, MA514520, 1:25) at room temperature (RT) for 2 hours, followed by washing three times with DPBS for 10 minutes each time. Next, the samples were incubated with secondary antibody (goat pAb anti-Rb IgG / Alexa Fluor 488, Abcam, catno. AB150077) at room temperature (RT) for 2 hours, followed by washing three times with DPBS for 10 minutes each time. After treatment with DAPI (2 drops + 2 ml substrate) for 5 minutes, the samples were washed with DPBS for 5 minutes. The samples were then mounted on a confocal microscopy microscope, images were taken, and the length of the growth plate was measured.

[0139] Results Analysis

[0140] Based on H&E staining results ( Figure 7a The study confirmed that the tibial growth plate length increased more in SD rats (experimental group, Figure B) after once-daily administration of the peptide from Preparation 1 for 4 weeks compared to the control group (Figure A) and the positive control group (hGH) (Figure C). Specifically, for the proliferative zone (PZ), the PZ measured in the experimental group was 173.00 μm (Figure B), in the control group it was 146.07 μm (Figure A), and in the positive control group (hGH) it was 146.63 μm (Figure C), confirming that the growth of the growth plate in rats treated with the peptide from Preparation 1 was promoted. Figure 7a ).

[0141] Figure 7b A graph showing the results of tibial growth plate length measurements obtained by H&E staining is presented. Figure 7bThe results show that the growth of the tibial growth plate in rats treated with the peptides of the present invention is promoted.

[0142] Figure 7c The results show the status of proliferative chondrocytes in the tibial growth plate as confirmed by IHC (immunohistochemistry) staining using the proliferation marker Ki67. It was confirmed that the proliferative chondrocyte region in the PZ region of rats treated with the peptide of Preparation Example 1 (experimental group) was longer than that in the control group (PBS treatment).

[0143] Experiment 4: Growth Plate Length Measurement Experiment - DAB Staining

[0144] The DAB staining experiment was used to evaluate whether the peptide prepared in Preparation Example 1 could promote the growth of the growth plate.

[0145] Preparation of tissue samples

[0146] Three-week-old Sprague-Dawley rats (hereinafter referred to as SD rats) (n=15) were acclimatized for one week, and then administered the peptide of Preparation Example 1 at four weeks of age. Specifically, the control group (Con) (n=5) was orally administered PBS (1 ml) once daily; the peptide administration group (experimental group) (n=5) was orally administered PBS (1 ml) solution of the peptide of Preparation Example 1 at a dose of 100 mg / 250 g once daily; and the positive control group (P / C) (n=5) was subcutaneously injected with PBS (0.5 ml) solution of hGH at a dose of 50 μg / 250 g once daily. From week 4 to week 9, the administration was carried out orally or subcutaneously once daily for a total of 4 weeks. After 4 weeks of treatment, the SD rats were sacrificed at week 9, and the tibias of the rats were isolated. The isolated tibias were fixed in 3.7% formaldehyde for 24 hours. After fixation, the tissue was washed in PBS and decalcified in 5% nitric acid for 3 days. After immersing the tissue in PBS and washing it without shaking for at least 3 hours, it was transferred to a cassette and dehydrated using a tissue processor (in the following order: 70% ethanol, 80% ethanol, 90% ethanol, 100% ethanol I, 100% ethanol II, and xylene I, xylene II). The dehydrated tissue was embedded and made into paraffin blocks, then cut into 4 μm thick sections, attached to glass slides, and completely dried for at least 24 hours.

[0147] DAB (3,3'-diaminobenzidine) staining

[0148] Place the slides in a slide holder and immerse them in xylene (I, II, III) solution for 5 minutes, repeating three times. Then, immerse the slides in 100% ethanol (EtOH) solution for 3 minutes, repeating twice. Next, immerse the slides in 90% ethanol solution for 3 minutes, then in 80% ethanol solution for 3 minutes, and finally in 70% ethanol solution for 3 minutes. Afterward, wash the tissue under running water for 5 minutes, and then mark the tissue periphery with a Dako pen. Treat the tissue with 3% H2O2 for 10 minutes, then wash with DPBS for 10 minutes. Apply pepsin (100 μl / sample) to the tissue and incubate at 37°C for 30 minutes, then wash with DPBS for 10 minutes. Block with Ultravision protein blocking agent (Epredia, cat no. TA-125-PBQ, diluted to 1X in DPBS) at room temperature for 1 hour. Apply anti-IGF-1 antibody (Invitrogen, MA518035, 1:100 dilution) or anti-IGFBP3 antibody (Santa Cruz, SC-365936, 1:100 dilution) as the primary antibody and incubate overnight at 4°C. Then wash three times with DPBS for 10 minutes each time. Apply anti-mouse IgG antibody (Jackson, 115-035-003) as the secondary antibody at room temperature (RT) and incubate for 2 hours. Then wash three times with DPBS for 10 minutes each time. Add DAB solution (Epredia, TA-125-QHDX; 2 drops + 2 ml substrate); when it turns brown, immediately add distilled water to stop the reaction. Stop the reaction, mount the plate on a confocal microscopy microscope, take images, and measure the length of the growth plate.

[0149] Results Analysis

[0150] Increased IGF-1 expression was observed in the growth plate region of the tibia of SD rats after once-daily administration of the peptide from Example 1 for 4 weeks. Compared to the control group (Figure A), the experimental group (Figure B) showed a greater increase in IGF-1 (insulin-like growth factor 1) expression. Figure 8a ).

[0151] Increased expression of IGFBP3 (insulin-like growth factor binding protein 3) in the growth plate region of the tibia of SD rats was observed after 4 weeks of once-daily administration of the peptide from Example 1. The experimental group (Figure B) showed a greater increase in IGFBP3 expression compared to the control group (Figure A). Figure 8b ).

[0152] Experiment 5: Determination of GH (growth hormone) expression in the pituitary gland

[0153] To assess whether the peptide prepared in Preparation Example 1 increases the expression of GH (growth hormone) in the pituitary gland.

[0154] Preparation of tissue samples

[0155] Three-week-old Sprague-Dawley rats (hereinafter referred to as SD rats) (n=15) were acclimatized for one week, and then administered the peptide of Preparation Example 1 at four weeks of age. Specifically, the control group (Con) (n=5) was orally administered PBS (1 ml) once daily; the peptide administration group (experimental group) (n=5) was orally administered PBS (1 ml) solution of the peptide of Preparation Example 1 at a dose of 100 mg / 250 g once daily; and the positive control group (P / C) (n=5) was subcutaneously injected with PBS (0.5 ml) solution of 50 μg / 250 g hGH once daily. From week 4 to week 9, the administration was carried out orally or subcutaneously once daily for a total of 4 weeks. After 4 weeks of treatment, the SD rats were sacrificed at week 9, and the pituitary glands of the rats were isolated. The isolated pituitary tissue was fixed in 3.7% formaldehyde for 24 hours. The fixed tissues underwent paraffin processing (sequentially: 70% EtOH for 1 hour, 80% EtOH for 1 hour, 90% EtOH for 1 hour, 95% EtOH for 1 hour, 100% EtOH for 1 hour, 100% EtOH for 1 hour, xylene for 1 hour 30 minutes, xylene for 1 hour 30 minutes, paraffin for 2 hours, and paraffin for 2 hours). The tissues were then paraffin-embedded, sectioned into 5 μm thick sections, attached to glass slides, and completely dried for at least 24 hours. Subsequently, IHC (immunohistochemical) staining was performed.

[0156] Immunohistochemical (IHC) staining and results

[0157] Place the slides in a slide holder and immerse them in xylene (I, II, III) solution for 5 minutes, repeating three times. Then, immerse the slides in 100% ethanol (EtOH) solution for 3 minutes, repeating twice. Next, immerse the slides in 90% ethanol solution for 3 minutes, then in 80% ethanol solution for 3 minutes, and finally in 70% ethanol solution for 3 minutes. Afterward, wash the tissue under running water for 5 minutes, and then mark the tissue periphery with a Dako pen. Treat the tissue with 3% H2O2 for 10 minutes, then wash with DPBS for 10 minutes. Apply pepsin (100 μl / sample) to the tissue and incubate at 37°C for 30 minutes, then wash with DPBS for 10 minutes. Block the tissue at room temperature for 1 hour using Ultravision protein blocking agent (Epredia, cat no. TA-125-PBQ, diluted to 1X in DPBS). The samples were incubated overnight at 4°C with primary antibody (anti-GH Ab, Abcam, cat no. AB126882, 1:1000), followed by washing three times with DPBS for 10 minutes each time. Next, the samples were incubated with secondary antibody (goat pAb anti-Rb IgG / Alexa Fluor 488, Abcam, cat no. AB150077) at room temperature (RT) for 2 hours, followed by washing three times with DPBS for 10 minutes each time. After treatment with DAPI (2 drops + 2 ml substrate) for 5 minutes, the samples were washed with DPBS for 10 minutes. The samples were then mounted on a confocal microscope and images were taken.

[0158] It was confirmed that, compared with the control group, SD rats (experimental group) administered the peptide of Preparation 1 once daily for 4 weeks showed increased GH expression in the pituitary gland. Figure 9a and Figure 9b ).exist Figure 9a In the experimental group, GH fluorescence was enhanced, and... Figure 9b The measured fluorescence intensity is plotted as a graph.

[0159] Test Example 6: Toxicity Test

[0160] The toxicity of the peptide prepared in Preparation Example 1 was assessed upon application.

[0161] Three-week-old Sprague-Dawley rats (hereinafter referred to as SD rats) were acclimatized for one week, and then administered the peptide of Preparation Example 1 at four weeks of age. Specifically, the control group (Con) (n=5) was orally administered PBS (1 ml) once daily; and the peptide administration group (experimental group) (n=5) was orally administered a PBS (1 ml) solution of the peptide of Preparation Example 1 at 100 mg / 250 g once daily. After four weeks of treatment, the SD rats were sacrificed at week 9. Cardiac perfusion was performed twice through the left ventricle of the heart using a syringe filled with PBS (40 ml to 50 ml). Liver tissue was harvested using surgical scissors. The harvested tissue was fixed in 3.7% formaldehyde for 24 hours. After washing with PBS (without shaking), the liver tissue was transferred to a cassette and dehydrated using a tissue processor (in the following order: 70% ethanol, 80% ethanol, 90% ethanol, 100% ethanol I, 100% ethanol II, and xylene I, xylene II). Tissue was embedded and made into paraffin blocks, then cut into 4 μm thick sections, placed on glass slides, and completely dried for at least 24 hours. Subsequently, H&E (hematoxylin and eosin) staining was performed. The paraffin in the tissue was removed, and the tissue was hydrated. (After treatment with xylene I and xylene II for 5 minutes each, the tissue was sequentially treated with a 1:1 xylene:100% ethanol, 100% ethanol I, 100% ethanol II, 90% ethanol, 80% ethanol, and 70% ethanol, for 3 minutes each step). The tissue was washed under running water for 5 minutes, with intermittent immersion. The sample was stained with hematoxylin (Dako, S3309) for 5 minutes and washed under running water for 5 minutes, with intermittent immersion, until the dye was completely removed. The sample was then stained with eosin Y (Shandon, 6766007) for 5 minutes and washed under running water for 5 minutes. The samples were then dehydrated (treated for 2 minutes each in 95% ethanol I, 95% ethanol II, 100% ethanol I, 100% ethanol II, and xylene III, followed by 3 minutes in xylene IV). After mounting the samples on a microscope, they were dried for at least 24 hours and observed under a microscope. No hepatotoxicity was detected in the liver tissue of SD rats after 4 weeks of once-daily administration of the peptide from Preparation 1. Figure 10 ).

[0162] Although representative embodiments of this application have been described above by way of example, the scope of this application is not limited to these specific embodiments, and those skilled in the art will be able to make appropriate modifications within the scope described in the claims of this application.

Claims

1. A composition for promoting growth, comprising a peptide comprising an amino acid sequence of SEQ ID NO: 1 as an active ingredient.

2. The composition according to claim 1, wherein the peptide has an activity of promoting growth hormone production or an activity of promoting growth plate growth.

3. A pharmaceutical composition for treating or preventing a growth retardation disorder, comprising a peptide comprising an amino acid sequence of SEQ ID NO: 1 as an active ingredient.

4. The pharmaceutical composition according to claim 3, wherein the growth retardation disorder is dwarfism.

5. The pharmaceutical composition according to claim 4, wherein the dwarfism is familial short stature, idiopathic short stature, intrauterine growth retardation (IUGR), short stature due to growth plate injury, short stature due to osteochondrodysplasia, short stature due to renal disease, short stature due to chronic illness, short stature due to growth hormone deficiency, short stature due to thyroid hormone deficiency, short stature due to sex hormone deficiency, short stature due to adrenocortical hormone deficiency, short stature due to Turner syndrome, or short stature due to Down syndrome.

6. The pharmaceutical composition according to claim 5, wherein the short stature due to renal disease is short stature due to uremia, short stature due to renal tubular acidosis, or short stature due to chronic renal failure.

7. The pharmaceutical composition according to claim 6, wherein the short stature due to chronic illness is short stature due to congenital heart disease, short stature due to chronic pulmonary disease, or short stature due to liver disease.

8. The pharmaceutical composition according to claim 3, wherein the peptide has an activity of promoting growth hormone (GH) production or an activity of promoting growth plate growth.

9. A food composition for improving or preventing growth retardation, comprising a peptide comprising an amino acid sequence of SEQ ID NO: 1 as an active ingredient.

10. The food composition according to claim 9, wherein the growth retardation is dwarfism.

11. The food composition according to claim 9, wherein the peptide has an activity of promoting growth hormone (GH) production or an activity of promoting growth plate growth.

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