WO2022098051A1 - Nouveau peptide ayant des actions anti-inflammatoires et de régénération tissulaire - Google Patents

Nouveau peptide ayant des actions anti-inflammatoires et de régénération tissulaire Download PDF

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Publication number
WO2022098051A1
WO2022098051A1 PCT/KR2021/015692 KR2021015692W WO2022098051A1 WO 2022098051 A1 WO2022098051 A1 WO 2022098051A1 KR 2021015692 W KR2021015692 W KR 2021015692W WO 2022098051 A1 WO2022098051 A1 WO 2022098051A1
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Prior art keywords
peptide
present
absent
composition
group
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PCT/KR2021/015692
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English (en)
Korean (ko)
Inventor
이철호
김용훈
김경심
노정란
이경륜
김병찬
최동희
김재훈
강은정
고준
최영근
이인복
서윤정
최정현
장동호
박혜연
박정호
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한국생명공학연구원
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • 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
    • 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
    • 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
    • C07K5/10—Tetrapeptides

Definitions

  • the present invention relates to novel peptides having anti-inflammatory and tissue regeneration action and uses thereof.
  • Inflammation is a complex biological response of the immune system to clear harmful extrinsic and endogenous signals or pathogens and initiate the healing process.
  • Various infectious factors such as bacteria and viruses, ultraviolet light, heavy metals, cholesterol, asbestos and many nanomaterials, cause inflammation.
  • Inflammatory response is essential for recovery from infection or wound healing process, but uncontrolled inflammatory response or chronic inflammation is not only caused by diseases such as arthritis, metabolic disease, hepatitis, enteritis, gastritis, gastric ulcer, esophagitis, dermatitis, encephalitis, depression, anxiety, etc. It can also cause disability, cognitive impairment, memory impairment, degenerative brain disease, and developmental disability.
  • the inflammatory response is often one of the causes of damage by causing a decrease in the function of cells, tissues, and organs.
  • diseases such as skin aging, loss of muscle strength, and hair loss are diseases caused by tissue damage, and recent attention has been focused on developing therapeutic agents that can effectively inhibit such tissue damage.
  • the present inventors developed the peptide of the present invention after intensive research efforts to develop a therapeutic agent capable of effectively inhibiting the onset and exacerbation of inflammatory diseases and tissue damage-related diseases, which are recently increasing in incidence in modern people, and developed anti-inflammatory and tissue regeneration
  • the present invention was completed by confirming that the effect was excellent.
  • X1 is Ser or absent
  • X2 is Ile or absent
  • X3 is Lys or absent
  • X4 is Gly or absent
  • X5 is Ala or absent
  • X6 is Tyr or absent
  • X2 is Val or absent
  • X3 is Ser or absent
  • X4 is Ser or absent
  • X5 is Ile or absent
  • X6 is Lys or absent.
  • Another object of the present invention is to provide a polynucleotide encoding the peptide and a vector comprising the polynucleotide.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammatory diseases, including the peptide.
  • Another object of the present invention is to provide a composition for tissue regeneration comprising the peptide.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating tissue damage-related diseases, including the peptide.
  • Another object of the present invention is to provide a health functional food composition, feed composition, veterinary medicine, quasi-drug, and cosmetic composition comprising the peptide.
  • Another object of the present invention is to provide a method for preventing or treating an inflammatory disease, comprising administering the peptide to an individual.
  • Another object of the present invention is to provide a method for tissue regeneration, comprising administering the peptide to a subject.
  • the peptide of the present invention has anti-inflammatory and tissue regeneration effects, it can be used for tissue regeneration as well as prevention, improvement and treatment of inflammatory diseases.
  • PEP001 is SEQ ID NO: 1
  • PEP002 is SEQ ID NO: 2
  • PEP003 is SEQ ID NO: 3
  • PEP004 is SEQ ID NO: 4
  • PEP005 is SEQ ID NO: 5
  • Amuc_1409 is a functional fragment except for the leader sequence of SEQ ID NO: 6 refers to SEQ ID NO:7.
  • 1 is a comparison result of knee joint thickness and weight bearing measurement results by administration of Amuc_1409 and PEP001, PEP002, PEP003, PEP004 and PEP005 in an animal model of degenerative arthritis (*p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001 Amuc_1409 vs. vehicle group, ⁇ p ⁇ 0.05, ⁇ p ⁇ 0.01, ⁇ p ⁇ 0.001 PEP001 vs. vehicle group, #p ⁇ 0.05, ##p ⁇ 0.01, ###p ⁇ 0.001 PEP002 vs. vehicle $p ⁇ 0.05, $$$p ⁇ 0.001 PEP003 vs. vehicle, ⁇ p ⁇ 0.05, ⁇ p ⁇ 0.01, ⁇ p ⁇ 0.001 PEP004 vs. vehicle, ⁇ p ⁇ 0.05, ⁇ p ⁇ 0.001 PEP005 vs. vehicle group).
  • Figure 4 is the result of confirming the change in the daily arthritis index (A), ankle joint thickness (B) and edema (C) by Amuc_1409 administration in an animal model of rheumatoid arthritis (p ⁇ 0.05, **p ⁇ 0.01 vs. vehicle group) ).
  • A daily arthritis index change
  • B ankle joint thickness
  • C edema change
  • PEP001, PEP002, PEP003, PEP004 and PEP005 in an animal model of rheumatoid arthritis ( ⁇ p ⁇ 0.01) , ⁇ p ⁇ 0.001 PEP001 vs. vehicle group, ##p ⁇ 0.01, ###p ⁇ 0.001 PEP002 vs. vehicle group, $p ⁇ 0.05, $$p ⁇ 0.01, $$$p ⁇ 0.001 PEP003 vs. vehicle group, ⁇ p ⁇ 0.05, ⁇ p ⁇ 0.01, ⁇ p ⁇ 0.001 PEP004 vs. vehicle group, ⁇ p ⁇ 0.05, ⁇ p ⁇ 0.001 PEP005 vs. vehicle group).
  • 11 is an analysis result of liver damage change by administration of Amuc_1409, PEP001, PEP002, PEP003, PEP004 and PEP005 in an acute hepatitis animal model (*p ⁇ 0.05 vs. vehicle group).
  • 13 is an analysis result of weight change by administration of PEP002, PEP003, PEP004 and PEP005 in an inflammatory bowel disease mouse model ( ⁇ p ⁇ 0.05, ⁇ p ⁇ 0.01 PEP004 vs. vehicle group, ⁇ p ⁇ 0.01 PEP005 vs. vehicle) army).
  • 16 is an analysis result of changes in the expression of inflammatory marker genes in the colon by administration of PEP002, PEP003, PEP004 and PEP005 in an inflammatory bowel disease mouse model (*p ⁇ 0.05, **p ⁇ 0.01 vs. vehicle group).
  • 17 is a result of analysis of gastric mucosal damage by Amuc_1409 administration in an animal model of gastritis/gastric ulcer (*p ⁇ 0.05 vs. vehicle group).
  • 19 is an analysis result of gastric mucosal damage by administration of PEP001, PEP002, PEP003, PEP004 and PEP005 in an animal model of gastritis/gastric ulcer (*p ⁇ 0.05 vs. vehicle group).
  • 20 is an inflammatory marker gene analysis result by administration of PEP001, PEP002, PEP003, PEP004 and PEP005 in an HCl/ethanol-induced gastritis/gastric ulcer model (*p ⁇ 0.05 vs. vehicle group).
  • Figure 21 is a comparison of ear thickness (Figure 21B) and weight change (Figure 21C) per area (Figure 21C) of mouse ear erythema and edema change by Amuc_1409 administration in an animal model of dermatitis ( Figure 21A) (**p ⁇ 0.01) vs. vehicle group).
  • FIG. 22 is a photograph taken of changes in mouse ear erythema and edema by administration of PEP001, PEP002, PEP003, PEP004, and PEP005 in an animal model of dermatitis (FIG. 22A), comparing ear thickness (FIG. 22B) and weight change per area (FIG. 22C) (*p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.05 vs. vehicle group).
  • 25 is a gene analysis result of brain inflammation index by administration of Amuc_1409 in a depression and anxiety model (*p ⁇ 0.05 vs. vehicle group).
  • 26 is an analysis result of FST, TST immobility posture, and EPM open arm time by Amuc_1409 administration in a depression and anxiety model (*p ⁇ 0.05 vs. vehicle group).
  • FIG. 29 is a graph showing the effect of improving cognitive function and memory in a novel object recognition test (NORT) according to administration of Amuc_1409 and PEP002, PEP003, PEP004 and PEP005 in a cognitive dysfunction model (A and C) , new object detection time; B and D, number of new object detections. *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.01)
  • FIG. 30 is a graph showing the effect of improving cognitive function and memory in a novel object recognition test (NORT) for new objects by administration of Amuc_1409 and PEP002, PEP003, PEP004 and PEP005 in a natural aging animal model (A and C, new object detection time; B and D, number of new object detections) (*p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.01).
  • NERT novel object recognition test
  • Figure 31 shows the time of sniffing behavior to determine the degree of social interaction and social curiosity between two mice after administration of Amuc_1409 and PEP001, PEP002, PEP003, PEP004 and PEP005 to developmentally disabled animal model mice. (A and C) and the number of times (B and D) analysis results (*p ⁇ 0.05, ***p ⁇ 0.01).
  • Figure 32 is a photograph and graph showing the comparison of the wound healing effect by day according to the application of Amuc_1409 and PEP001, PEP002, PEP003, PEP004 and PEP005 in the full-thickness skin defect wound-inducing animal model (*p ⁇ 0.05, **p ⁇ 0.01, * **p ⁇ 0.001 Amuc_1409 vs. vehicle group, ⁇ p ⁇ 0.05, ⁇ p ⁇ 0.01 PEP001 vs. vehicle group, #p ⁇ 0.05, ##p ⁇ 0.01, ###p ⁇ 0.001 PEP002 vs. vehicle group, $p ⁇ 0.05, $$p ⁇ 0.01 PEP003 vs. vehicle group, ⁇ p ⁇ 0.01, ⁇ p ⁇ 0.001 PEP004 vs. vehicle group, ⁇ p ⁇ 0.01, ⁇ p ⁇ 0.001 PEP005 vs. vehicle army).
  • Figure 33 confirms the effect of improving muscle strength and muscle mass by administration of Amuc_1409 in an aging animal model (*p ⁇ 0.05 vs. vehicle group).
  • 35 is a result of analysis of muscle strength, muscle mass, and protein synthesis-related gene expression in muscle cells according to PEP001 administration in an aging animal model (*p ⁇ 0.05 vs. vehicle group).
  • Figure 36 is a result of muscle atrophy-related gene analysis by treatment with PEP004 and PEP005 in C2C12 myoblasts (*p ⁇ 0.05 vs. vehicle group).
  • FIG. 37 is a macroscopic photograph (FIG. 37A) and a scoring graph (FIG. 37B) observing the progress of hair growth on the 21st day after application of Amuc_1409 (*p ⁇ 0.05 vs. vehicle group).
  • Fig. 38 shows the results of H&E staining by Amuc_1409 skin application (Fig. 38A), histological number of follicles (Fig. 38B), hair follicle depth (Fig. 38C), dermal thickness (Fig. 38D) and subcutaneous thickness (Fig. 38) after the end of the experimental period in an animal model. 38E) This is a change comparison result (**p ⁇ 0.01, ***p ⁇ 0.001 vs. vehicle group).
  • Fig. 40 shows the results of analysis of gene expression related to collagen degradation and synthesis according to Amuc_1409 treatment in human skin keratinocytes (p ⁇ 0.05).
  • One aspect of the present invention provides a peptide comprising the amino acid sequence of SEQ ID NO: 4 or 5.
  • the peptide of the present invention may include a sequence represented by the following general formula 1:
  • X1 is Ser or absent
  • X2 is Ile or absent
  • X3 is Lys or absent
  • X4 is Gly or absent
  • X5 is Ala or absent
  • X6 is Tyr or absent.
  • X1 may be Ser and X2 may be Ile.
  • X1 to X6 may be absent.
  • X1 may be Ser
  • X2 may be Ile
  • X3 may be Lys
  • X4 may be Gly
  • X5 may be Ala
  • X6 may be Tyr.
  • the peptide of the present invention may include a sequence represented by the following general formula 2:
  • X2 is Val or absent
  • X3 is Ser or absent
  • X4 is Ser or absent
  • X5 is Ile or absent
  • X6 is Lys or absent.
  • X6 may be Lys.
  • X1 to X6 may be absent.
  • X1 may be Ala
  • X2 may be Val
  • X3 may be Ser
  • X4 may be Ser
  • X5 may be Ile
  • X6 may be Lys.
  • absence for example "X5 is Ile or absent" should be understood to mean that amino acid residues directly adjacent to the absent amino acid are directly linked to each other by conventional amide bonds.
  • the peptides provided in the present invention include salt forms thereof.
  • salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • metal salts include alkali metal salts such as sodium salts, potassium salts and the like; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts and the like; aluminum salts and so on
  • the peptide of the present invention comprises, consists essentially of, or consists of the amino acid sequence of any one of SEQ ID NOs: 1-7.
  • the present invention is not limited thereto, and peptides exhibiting the same activity as the sequence are included without limitation.
  • amino acid sequence of SEQ ID NO: 7 of the present invention corresponds to a sequence except for the leader sequence in the amino acid sequence of SEQ ID NO: 6, it contains the amino acid sequence of SEQ ID NO: 7, or consists essentially of SEQ ID NO: 7 (consisting of the amino acid sequence of SEQ ID NO: 7) Peptides essentially of, or consisting of, are also included within the scope of the peptides of the present invention.
  • the peptide of the present invention may consist of 3 to 150 consecutive amino acids among the amino acid sequence of SEQ ID NO: 6 including the amino acid sequence of SEQ ID NO: 4 or 5.
  • the peptide of the present invention may be a peptide derived from Akkermansia muciniphila strain.
  • the peptide of the present invention can be produced according to a method for synthesizing a peptide known in the art. For example, it may be converted into the peptide molecule of the present invention under physiological conditions.
  • the peptide of the present invention may be synthesized according to a solid-phase synthesis process and a liquid-phase synthesis process. That is, the peptide provided in the present invention can be produced by repeatedly condensing a partial peptide or amino acid constituting the peptide molecule, a peptide to be synthesized, and the remaining portion in a desired order.
  • the target peptide can be produced by removing the protecting group.
  • Another aspect of the present invention provides a polynucleotide encoding the peptide.
  • Another aspect of the present invention provides a vector comprising the polynucleotide.
  • the polynucleotide of the present invention is a polymer of nucleotides in which nucleotide monomers are connected in a long chain form by covalent bonds, and is a DNA or RNA strand of a certain length or longer, which means a polynucleotide encoding the peptide according to the present invention. do.
  • a known vector such as a plasmid vector, a cosmid vector, or a bacteriophage vector
  • the vector is any known vector using DNA recombination technology. It can be easily prepared by those skilled in the art according to the method
  • peptide analog having a function corresponding to the peptide provided by the present invention is also included in the scope of the present invention.
  • peptide analog refers to a non-naturally occurring amino acid sequence, or a modified naturally occurring amino acid sequence.
  • the peptide of the present invention may be in a form in which a carrier material is linked.
  • Examples of the carrier material usable in the present invention may be selected from the group consisting of immunoglobulin Fc region, albumin, transferrin, and polyethylene glycol (PEG), but is not limited thereto.
  • PEG non-specifically binds to a specific site or various sites of the target peptide to increase the molecular weight of the peptide, thereby inhibiting loss by kidney and preventing hydrolysis, and does not cause any special side effects.
  • binding of PEG to a foreign peptide can sometimes inhibit recognition of antigenic sites present in the foreign peptide by immune cells. Specifically, by inhibiting phagocytosis and intracellular proteolysis of the peptide by antigen-presenting cells, the possibility of the peptide acting as an antigen can be reduced.
  • the peptide of the present invention may be linked to the carrier material through a linker.
  • the linker may be a peptidic or non-peptidyl polymer.
  • non-peptidyl polymers usable in the present invention include polyethylene glycol, polypropylene glycol, copolymers of ethylene glycol and propylene glycol, polyoxyethylated polyols, polyvinyl alcohol, polysaccharides, dextran, polyvinyl ethyl It may be selected from the group consisting of ethers, biodegradable polymers such as PLA (polylactic acid) and PLGA (polylactic-glycolic acid), lipid polymers, chitins, hyaluronic acid, and combinations thereof.
  • PLA polylactic acid
  • PLGA polylactic-glycolic acid
  • lipid polymers chitins, hyaluronic acid, and combinations thereof.
  • the peptide of the present invention is in addition to a moiety that can be selected from the group consisting of PEG, monosaccharides, fluorophores, chromophores, radioactive compounds and cell-penetrating peptides. can be joined.
  • the peptides of the present invention are phosphorylation, sulfation, acrylation, and glycosylation in some cases to the extent that the activity of the molecule is not entirely altered. ), methylation, farnesylation, acetylation, and amidation may be modified.
  • the peptide of the present invention may be present in glycosylated, PEGylated, amidated, esterified, acylated, acetylated and/or alkylated form.
  • the peptides provided in the present invention may have anti-inflammatory and/or regenerative properties.
  • one aspect of the present invention provides a use for preventing or treating inflammatory diseases of the peptide of the present invention.
  • Another aspect of the present invention provides the use of the peptide of the present invention for tissue regeneration.
  • anti inflammation refers to inhibiting inflammation
  • the inflammation is one of the biological tissue's defense responses to certain stimuli, and is a complex complex that can cause tissue deterioration, circulatory disturbance and exudation, and tissue proliferation. say lesion.
  • Inflammation is part of innate immunity, and as in other animals, human innate immunity recognizes patterns on the surface of cells that are specific to pathogens. Phagocytes recognize cells with such a surface as non-self and attack pathogens. When pathogens break through the body's physical barriers, an inflammatory response can occur. The inflammatory response is a part of the immune defense mechanism, but if it occurs excessively or continuously, acute or chronic inflammatory diseases are induced.
  • Inflammation occurs in various mechanisms in the body, such as hormone secretion, cytokines, and C-reactive protein (CRP), and there are many related substances. Among them, various cytokines secreted from immune cells regulate the immune system, and some promote inflammation. Therefore, the expression level of intracellular cytokines can be an indicator of inflammatory response activation.
  • CRP C-reactive protein
  • inflammatory disease means a disease caused by an inflammatory reaction
  • the inflammatory disease is, for example, increased expression of one or more inflammatory markers selected from the group consisting of Tnf ⁇ , Il-1 ⁇ , Il-6, Cox2, iNos, CCl2, Cd11b, F4/80, Ifn ⁇ ; And/or it may be caused by a decrease in the expression of an anti-inflammatory marker consisting of Il-10 and Il-1rn.
  • one or more inflammatory markers selected from the group consisting of Tnf ⁇ , Il-1 ⁇ , Il-6, Cox2, iNos, CCl2, Cd11b, F4/80, Ifn ⁇
  • an anti-inflammatory marker consisting of Il-10 and Il-1rn.
  • it is not limited thereto.
  • the inflammatory disease of the present invention is a disease selected from the group consisting of arthritis, metabolic disease, hepatitis, enteritis, gastritis, gastric ulcer, esophagitis, dermatitis, encephalitis, depression, anxiety disorder, cognitive impairment, memory disorder, degenerative brain disease and developmental disorder. can but not limited to this
  • Inflammatory diseases of the present invention include both acute and chronic diseases.
  • arthritis of the present invention means an inflammatory disease occurring in the joints.
  • the arthritis includes osteoarthritis, rheumatoid arthritis, chronic rheumatoid arthritis, degenerative arthritis, bruised arthritis, gouty arthritis, atrophic arthritis, chronic inflammatory arthritis, deformable arthritis, infectious arthritis, menopausal arthritis, monoarthritis, hypertrophic arthritis, suppurative arthritis do.
  • the "metabolic disease” of the present invention is a generic term for diseases caused by metabolic disorders in a living body.
  • the metabolic disease is characterized by a change in the function of the intestinal barrier, a change in the concentration of LPS in the blood, an occurrence of intestinal inflammation, a change in intestinal mucus, an increase in insulin resistance, a decrease in insulin sensitivity, an increase in fasting blood sugar, an increase in insulin resistance, an increase in glucose tolerance, and creatinine in the blood.
  • urea nitrogen (BUN), uric acid may indicate one or more of an increase in the concentration of creatine kinase, or may be a disease caused by the above-mentioned phenomenon or a disease having the above-mentioned phenomenon as a prognostic symptom, but is not limited thereto.
  • the metabolic disease may be selected from the group consisting of insulin resistance disease, obesity, diabetes, fatty liver, nonalcoholic fatty liver, hyperlipidemia, kidney damage, arteriosclerosis, dyslipidemia and hypertension, for example, obesity, diabetes, insulin resistance and dyslipidemia, but is not limited thereto.
  • Hepatitis in the present invention means an inflammatory disease occurring in the liver.
  • the hepatitis is acute or chronic hepatitis, cirrhosis, fatty liver, liver failure, liver cancer, alcoholic fatty liver, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis ( Liver fibrosis) and Liver cirrhosis.
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • liver fibrosis Liver fibrosis
  • Liver cirrhosis Liver cirrhosis
  • the hepatitis may be acute hepatitis or non-alcoholic hepatitis, but is not limited thereto.
  • the non-alcoholic hepatitis includes, without limitation, those that occur due to causes other than alcohol, for example, metabolic diseases such as obesity, diabetes, dyslipidemia, metabolic syndrome, or a high-fat diet that is the cause of the metabolic diseases. It may be caused by, but not limited to.
  • enterritis refers to an inflammatory disease occurring in the intestine.
  • the “enteritis” is used in the same sense as “inflammatory bowel disease", and includes ulcerative colitis, Crohn's disease, intestinal Bechet's disease, hemorrhagic rectal ulcer, and ileal capsuleitis. do.
  • stomach in the present invention means an inflammatory disease occurring in the stomach.
  • the gastritis is used in the sense of including stomach diseases such as stomach cramps, gastritis, gastric ulcer, duodenitis, duodenal ulcer.
  • Esophagitis of the present invention means an inflammatory disease occurring in the esophagus.
  • the esophagitis includes all those caused by various causes such as bacterial infection, gastric contents or acid reflux, drugs, and may be, for example, gastroesophageal reflux disease, but is not limited thereto.
  • Dermatitis of the present invention means an inflammatory disease occurring on the skin.
  • the dermatitis is allergic contact dermatitis, urticaria, alopecia dermatitis (dry skin on the lower leg), atopic dermatitis, contact dermatitis such as irritant contact dermatitis and poison ivy-induced contact dermatitis, eczema, gravitational dermatitis, monetary dermatitis , otitis externa, perioral dermatitis and seborrheic dermatitis.
  • Encephalitis in the present invention means an inflammatory disease occurring in the brain.
  • inflammatory cells When inflammatory cells are excessively activated in the brain, the secretion of inflammatory cytokines increases, and brain cell damage can be induced by this overactivation of the brain inflammatory response. Accordingly, the encephalitis is closely related to cognitive impairment, memory impairment, and degenerative brain disease. The encephalitis includes neuroinflammation.
  • “Depression” in the present invention refers to a disease that causes a decrease in daily functioning by causing various cognitive and psychosomatic symptoms with a decrease in motivation and depression as the main symptoms.
  • the "anxiety disorder” of the present invention is a kind of mental disorder, and it is a widespread, very unpleasant, and vaguely anxious feeling, accompanied by related physical symptoms (chest palpitation, sweating, etc.) and behavioral symptoms (irritability, pacing, etc.). When anxious, the entire brain enters an arousal state, and therefore, an anxiety disorder causes disturbances in peripheral behavior, autonomic nervous system, sensation, and perception. Anxiety disorders can also be associated with various combinations of psychological and physical signs of anxiety that are not attributable to real danger but appear as an aggression (panic disorder) or a persistent state (generalized anxiety disorder).
  • Cognitive impairment refers to a disease caused by a decrease in cognitive function (cognitive ability) such as memory ability, temporal and spatial grasping ability, judgment, language ability or calculation ability due to brain damage.
  • the "memory disorder” of the present invention is a pathological condition in which it is difficult or impossible to remember things or recall past experiences, and diseases caused by memory loss, such as forgetfulness, instantaneous memory loss, short-term memory loss, Includes long-term memory loss and transient amnesia. However, it is not limited thereto.
  • the peptide of the present invention may be used to improve memory and/or cognitive ability, but is not limited thereto.
  • degenerative brain disease refers to a disease occurring in the brain among degenerative diseases.
  • the degenerative brain disease includes Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, mild cognitive impairment, stroke, and Huntington's disease. However, it is not limited thereto.
  • Developmental disability of the present invention refers to a state in which mental and physical development is not developed as much as the age, and is 25% behind the normal expectation of the age in the developmental screening test.
  • Common symptoms of developmental disorders are difficulties in understanding and using language, difficulties in overall understanding of social situations and formation of human relationships, and a pattern of clinging to specific objects and repeating certain behavioral procedures.
  • Developmental disorders in the present invention include intellectual disabilities, cerebral palsy, pervasive developmental disorders, developmental speech disorders, functional disorders of special senses including sight or hearing, learning disorders, attention deficit hyperactivity disorder, epilepsy, and combinations thereof. It may be selected from the group consisting of, but is not limited thereto.
  • the pervasive developmental disorder may be selected from the group consisting of autism spectrum disorder, Asperger's syndrome, Childhood Disintegrative Disorder, Rett Syndrome, atypical autism spectrum disorder, and combinations thereof,
  • developmental disorders can include all disorders occurring in developmental areas such as perception, cognition, movement, and language, and include learning disabilities, communication disorders, motor dysfunction, cerebral palsy, genetic disorders, and chromosome disorders.
  • Down Syndrome; Fragile X Syndrome may include all developmental disorders with delay in development or function. However, it is not limited thereto.
  • One aspect of the present invention provides a pharmaceutical composition for preventing or treating inflammatory diseases, including the peptide provided by the present invention.
  • the peptides of the present invention and inflammatory diseases are the same as described above.
  • prevention means any action that inhibits or delays the onset of a disease by administering the peptide according to the present invention.
  • treatment refers to any action in which the symptoms of a suspected disease and onset individual are improved or beneficially changed by administering the peptide according to the present invention.
  • the pharmaceutical composition of the present invention may further include an appropriate carrier, excipient or diluent commonly used in the preparation of the pharmaceutical composition.
  • the pharmaceutical composition is each formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories and sterile injection solutions according to conventional methods to be used.
  • carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the extract and its fractions, for example, starch, calcium carbonate, It is prepared by mixing sucrose or lactose, gelatin, etc.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral use include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to simple diluents such as water and liquid paraffin, which are commonly used for suspensions, solutions, emulsions, and syrups. there is.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
  • Another aspect of the present invention provides a health functional food composition for preventing or improving inflammatory diseases comprising the peptide provided in the present invention.
  • the food composition of the present invention can be ingested on a daily basis, it is very useful because it can be expected to prevent or improve the effect of diseases.
  • the food composition of the present invention includes the form of pills, powder, granules, needles, tablets, capsules or liquids, and the food to which the composition of the present invention can be added, for example, various foods, for example, There are beverages, gum, tea, vitamin complexes, and health supplements.
  • the term “improvement” refers to any action that at least reduces a parameter related to a condition to be treated by administration of the peptide of the present invention, for example, the severity of symptoms.
  • the food composition of the present invention includes the form of pills, powder, granules, needles, tablets, capsules or liquids, and the food to which the composition of the present invention can be added, for example, various foods, for example, There are beverages, gum, tea, vitamin complexes, and health supplements.
  • the food supplement additives include food supplement additives conventional in the art, for example, flavoring agents, flavoring agents, coloring agents, fillers, stabilizers, and the like.
  • Examples of the natural carbohydrate include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents eg, rebaudioside A, glycyrrhizin, etc.
  • synthetic flavoring agents sacharin, aspartame, etc.
  • the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and fillers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts. salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages, and the like.
  • it may contain the pulp for the production of natural fruit juice and fruit juice beverages and vegetable beverages. These components may be used independently or in combination.
  • the health supplement includes health functional food and health food.
  • the functional food is the same term as food for special health use (FoSHU), and in addition to nutritional supply, it is processed to efficiently exhibit bioregulatory functions and has high medical effects.
  • function (sex) means to obtain a useful effect for health purposes such as regulating nutrients or physiological action with respect to the structure and function of the human body.
  • the food of the present invention can be prepared by a method commonly used in the art, and at the time of manufacture, it can be prepared by adding raw materials and components commonly added in the art.
  • the formulation of the food may be prepared without limitation as long as it is a formulation recognized as a food.
  • the food composition of the present invention can be prepared in various forms, and unlike general drugs, it has the advantage of not having side effects that may occur during long-term administration of the drug using food as a raw material, and has excellent portability, Food can be ingested as an adjuvant for enhancing the effect of preventing or improving cognitive dysfunction and neuroinflammation.
  • Another aspect of the present invention provides a feed composition for preventing or improving inflammatory diseases comprising the peptide provided in the present invention.
  • the composition for feed may include a feed additive.
  • the feed additive of the present invention corresponds to an auxiliary feed under the Feed Management Act.
  • feed refers to any natural or artificial diet, one-meal, etc., or a component of the one-meal, which is suitable for or suitable for the animal to eat, ingest, and digest.
  • the type of feed is not particularly limited, and feed commonly used in the art may be used.
  • Non-limiting examples of the feed include plant feeds such as grains, root fruits, food processing by-products, algae, fibers, pharmaceutical by-products, oils and fats, starches, gourds or grain by-products; and animal feeds such as proteins, inorganic materials, oils and fats, minerals, oils and fats, single cell proteins, zooplankton, or food. These may be used alone or in mixture of two or more.
  • Another aspect of the present invention provides a method for preventing or treating an inflammatory disease comprising administering to an individual the peptide provided in the present invention.
  • the "individual" of the present invention means any animal, such as a rat, livestock, or human, that is likely to or has developed a disease.
  • humans may be excluded from the subject of the present invention, but is not limited thereto.
  • the peptide may be administered through any general route as long as it can reach the target tissue.
  • the peptide may be administered in the form of a pharmaceutical composition.
  • the treatment method of the present invention not only a method of administering the peptide provided by the present invention alone, but also a combination therapy may be considered.
  • Other agents used in the combination therapy may be included without limitation as long as they are known to be effective in preventing or treating inflammatory diseases, and may be provided in an amount effective to produce a desired result in the prevention or treatment of inflammatory diseases.
  • the treatment method of the present invention can be achieved by administering a therapeutically effective amount of the first therapeutic agent comprising the peptide provided in the present invention and, optionally, the second therapeutic agent or factor.
  • the pharmaceutical composition of the present invention is not particularly limited thereto, but routes such as intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, intranasal administration, intrapulmonary administration, rectal administration, etc. can be administered through
  • the oral composition may be coated with the active agent or formulated to be protected from degradation in the stomach.
  • the pharmaceutical composition may be an enteric coating to be protected from decomposition from the stomach, but is not limited thereto.
  • the composition may be administered by any device capable of transporting the active agent to a target cell.
  • the peptide of the present invention is useful for preventing or treating inflammatory diseases can be used
  • Another aspect of the present invention provides an animal pharmaceutical composition for preventing or treating inflammatory diseases comprising the peptide provided in the present invention.
  • the peptides and inflammatory diseases are the same as described above.
  • the animal means all animals, such as mice, livestock, and humans, that are likely to develop or have a disease, and may be animals other than humans in one embodiment, but is not limited thereto.
  • composition of the present invention when used as an veterinary pharmaceutical composition, the composition may be used as it is or may be used together with other pharmaceuticals or quasi-drug ingredients, and may be appropriately used according to a conventional method, but is not limited thereto.
  • the mixed amount of the active ingredient may be appropriately determined according to the purpose of use (prevention, health, improvement or therapeutic treatment).
  • Another aspect of the present invention provides a quasi-drug for preventing or improving inflammatory diseases comprising the peptide provided by the present invention.
  • quasi-drug refers to articles with a milder action than pharmaceuticals among articles used for the purpose of diagnosing, treating, improving, alleviating, treating or preventing diseases of humans or animals.
  • quasi-drugs exclude products used for medicinal purposes, and include products used for the treatment or prevention of diseases in humans and animals, and products with minor or no direct action on the human body.
  • the quasi-drug composition of the present invention may be prepared from one or more selected from the group consisting of body cleanser, foam, soap, mask, ointment, cream, lotion, essence and spray, but is not limited thereto.
  • Another aspect of the present invention provides a cosmetic composition for preventing or improving inflammatory diseases comprising the peptide provided in the present invention.
  • the cosmetic composition may be prepared in various forms according to a conventional cosmetic preparation method.
  • the cosmetic composition may be prepared in the form of a cosmetic product, lotion, cream, lotion, etc. containing the peptide of the present invention, which may be used by diluting it with a conventional cleansing solution, astringent solution and moisturizing solution.
  • the cosmetic composition may include conventional adjuvants such as stabilizers, solubilizers, vitamins, pigments, and fragrances commonly used in the field of cosmetic compositions.
  • the peptide content of the present invention may be included in an effective amount to achieve the effect of preventing or improving inflammatory diseases. For example, it may be contained in an amount of 0.001 to 10% by weight based on the total weight of the composition, specifically, it may be contained in an amount of about 0.01 to 1% by weight, but is not limited thereto.
  • the formulation of the cosmetic composition is a solution, an external ointment, a cream, a foam, a nutritional lotion, a flexible lotion, a perfume, a pack, a soft water, an emulsion, a makeup base, an essence, a soap, a liquid detergent, a bath agent, a sunscreen cream, a sun oil, a suspension , emulsion, paste, gel, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, patch or spray.
  • the cosmetic composition may further include one or more cosmetically acceptable carriers to be formulated in general skin cosmetics, and as common ingredients, for example, oil, water, surfactant, humectant, lower alcohol, thickener, chelating agent , inorganic salts, colorants, antioxidants, disinfectants, preservatives, fragrances, etc. may be appropriately mixed, but the present invention is not limited thereto.
  • one or more cosmetically acceptable carriers to be formulated in general skin cosmetics, and as common ingredients, for example, oil, water, surfactant, humectant, lower alcohol, thickener, chelating agent , inorganic salts, colorants, antioxidants, disinfectants, preservatives, fragrances, etc. may be appropriately mixed, but the present invention is not limited thereto.
  • the peptide provided in the present invention is characterized in that it has a regeneration effect.
  • one aspect of the present invention provides the use of the above-described peptide of the present invention for tissue regeneration.
  • the tissue may be selected from skin, muscle, hair, hair follicles and hair roots.
  • the tissue regeneration may be selected from skin regeneration, muscle tissue regeneration, wound healing, muscle strength enhancement, hair loss prevention, wool promotion, hair growth promotion, damaged hair improvement, and hair regeneration.
  • regeneration means suppressing the deterioration of the function of cells, tissues, or organs or restoring the reduced function.
  • Decreased function of cells, tissues, or organs may be due to damage to cells, tissues, or organs. Such damage may be caused by various factors such as radiation therapy, drug treatment, surgery, infection, inflammation, degenerative diseases, autoimmune diseases, and aging. Meanwhile, the “regeneration” may be achieved by promoting cell differentiation, but is not limited thereto.
  • the peptide provided by the present invention may have the ability to regenerate muscle tissue.
  • the regeneration of the muscle tissue may be achieved by myoblast differentiation, but is not limited thereto.
  • myocytes are muscle cells in an undifferentiated state, and when myocytes are differentiated into skeletal muscle cells, muscle tissue is formed, so differentiation of myocytes is also called myogenesis.
  • Factors involved in the differentiation of these myoblasts include Mef2, Serum response factor (SRF), MyoD, Myf5, Myf6, myogenin and myosin heavy chain, and the expression level of these factors By measuring, it is possible to determine whether myoblasts are differentiated.
  • the regeneration of the muscle tissue may be achieved by inhibiting myoblast atrophy.
  • myoblast atrophy For example, by measuring the expression levels of atrogin1 and MuRF1, which are factors involved in muscle atrophy, it can be determined whether or not atrophy of myoblasts is suppressed.
  • composition for tissue regeneration comprising the peptide provided in the present invention.
  • composition for tissue regeneration may be used for the prevention or treatment of tissue damage-related diseases. Therefore, another aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of tissue damage-related diseases comprising the peptide provided in the present invention as an active ingredient.
  • the peptide and pharmaceutical composition are the same as described above.
  • the tissue of the present invention may be a muscle tissue, and the tissue damage-related disease may be a muscle-related disease.
  • the muscle-related disease is muscle dystrophy (muscular dystrophy), muscular atrophy (muscular atropy), sarcopenia (muscular sarcopenia), myositis (Myositis), polymyositis, peripheral vascular disease (peripheral vascular disease) and fibrosis ( fibrosis) may be selected from the group consisting of, but is not limited thereto.
  • the tissue in the present invention may be selected from hair, hair follicles, and hair roots.
  • the composition for tissue regeneration may exhibit effects such as preventing hair loss, promoting hair growth, promoting hair growth, improving damaged hair, and regenerating hair. Therefore, the composition for tissue regeneration of the present invention can be used as a composition for preventing, treating or improving hair loss. However, it is not limited thereto.
  • tissue regeneration in the present invention may be wound healing.
  • the wound healing means treating a wound caused by damage to cells, and the wound is a meaning encompassing all damage to the living body, and is also referred to as a wound.
  • the wound healing may refer to any action of administering the composition of the present invention to a wounded individual to inhibit or delay the deterioration of the wound, or to improve or benefit the symptoms of the wound. Therefore, the composition for tissue regeneration of the present invention can be used as a composition for preventing or treating wounds or wounds.
  • the wound may be, for example, a skin tissue, but is not limited thereto.
  • the peptides provided by the present invention may exhibit an effect of inhibiting and/or improving skin aging. Inhibition and/or improvement of skin aging may also be referred to as “skin regeneration”. Therefore, the composition for tissue regeneration of the present invention can be used as a composition for skin regeneration.
  • Skin aging of the present invention refers to the appearance of symptoms such as reduced elasticity, reduced gloss, wrinkles, weakened regeneration, or severe dryness in the skin, and may be caused by the passage of time or external environment.
  • the skin aging includes both intrinsic aging that appears naturally with the passage of time and photoaging that occurs in the skin due to ultraviolet rays.
  • the synthesis amount of collagen, hyaluronic acid, elastin, proteoglycan, fibronectin and/or its precursors decreases, and the expression of degrading enzymes of the components increases Or a phenomenon such as a decrease in the expression of the synthetase of the component may appear.
  • Skin aging inhibition of the present invention may also be referred to as “skin regeneration”, and may include an increase in the amount of synthesis of collagen or a precursor thereof in skin cells.
  • the skin cells include skin keratinocytes and skin fibroblasts.
  • the inhibition of skin aging of the present invention may include an increase in collagen synthetase activity and/or inhibition of collagenase activity.
  • the collagen synthetase may be Col1a1 and/or Col3a1.
  • the collagen-degrading enzyme may be MMP-1 and/or MMP-3. However, it is not limited thereto.
  • the inhibition of skin aging of the present invention is to increase skin moisture, increase skin elasticity, increase skin thickness, improve skin wrinkles, alleviate skin irritation, recover skin damage and/or improve skin tone may include However, it is not limited thereto.
  • Another aspect of the present invention provides a health functional food composition for tissue regeneration comprising the peptide provided in the present invention as an active ingredient.
  • the peptide, tissue regeneration and health functional food are as described above.
  • Another aspect of the present invention provides a feed composition for tissue regeneration comprising the peptide provided in the present invention as an active ingredient.
  • Another aspect of the present invention provides an veterinary pharmaceutical composition for tissue regeneration comprising the peptide provided in the present invention as an active ingredient.
  • the peptide, tissue regeneration, feed, and veterinary medicine are the same as described above.
  • Another aspect of the present invention provides a method for preventing or treating tissue damage-related diseases comprising administering to an individual the peptide provided by the present invention.
  • Another aspect of the present invention provides a method for tissue regeneration comprising administering to an individual the peptide provided by the present invention.
  • a method of administering the peptide provided by the present invention alone not only a method of administering the peptide provided by the present invention alone, but also a combination therapy may be considered.
  • Other agents used in the combination therapy may be included without limitation as long as they are known to have a tissue regeneration effect, and may be provided in an amount effective to produce a desired result in tissue regeneration.
  • the peptide, subject, administration, tissue damage-related disease and prevention or treatment method are the same as described above.
  • tissue regeneration and differentiation-related genes increased according to the promotion of cell differentiation by administration of the peptide of the present invention, and accordingly, it was confirmed that muscle tissue, skin tissue, hair, and hair root tissue were regenerated,
  • the peptide of the present invention can be usefully used for the prevention and treatment of tissue-related diseases.
  • Another aspect of the present invention provides a quasi-drug composition for tissue regeneration comprising the peptide provided in the present invention as an active ingredient.
  • Another aspect of the present invention provides a cosmetic composition for tissue regeneration comprising the peptide provided in the present invention as an active ingredient.
  • the peptide, tissue regeneration, quasi-drug composition and cosmetic composition are the same as described above.
  • PEP001 is SEQ ID NO: 1
  • PEP002 is SEQ ID NO: 2
  • PEP003 is SEQ ID NO: 3
  • PEP004 is SEQ ID NO: 4
  • PEP005 is SEQ ID NO: 5
  • Amuc_1409 is functional except for the leader sequence of SEQ ID NO: 6 It refers to the fragment SEQ ID NO:7.
  • Example 1 Efficacy verification of novel peptides in arthritis animal models
  • Example 1-1 Efficacy verification of novel peptides in degenerative arthritis animal model
  • the diameter of the knee joint was measured using a caliper to evaluate edema caused by inflammatory changes in the joint.
  • the knee joint tissue of the mouse was fixed with 10% neutral buffered formalin, and the process of removing calcification from the bones with 0.5 M EDTA solution was performed. Then, the joint tissue was embedded in paraffin to prepare a 5 ⁇ m joint section, and the degree of damage to the cartilage tissue was analyzed histopathologically by staining with Safranin O. At this time, the degree of damage to the cartilage tissue was evaluated by checking the degree of safranin O staining of the section, and scoring was performed according to OARSI (Osteoarthritis Research Society International grade) guidelines. The scoring criteria according to the OARSI guidelines are as follows (Table 1).
  • the group administered with Amuc_1409, PEP002, PEP003 and PEP004 compared to the PBS buffer group on the 1st day after MIA injection.
  • the group administered with Amuc_1409 and PEP001, PEP002, PEP003, PEP004 and PEP005 had knee joint compared to the group administered with PBS buffer. was significantly decreased (p ⁇ 0.05, Student's t-test) (Fig. 1).
  • the group administered with Amuc_1409, PEP001, PEP002, PEP003, PEP004 and PEP005 significantly increased the decrease in weight bearing rate by MIA injection compared to the PBS buffer administration group ( p ⁇ 0.05, Student's t-test) (Fig. 1).
  • the PBS buffer administration group showed a marked decrease in safranin O staining and cartilage thickness, but compared with Amuc_1409, PEP001, PEP002, PEP003,
  • the group administered with PEP004 and PEP005 showed only a slight loss of safranin O in the cartilage area, and it was observed that the overall cartilage morphology was maintained.
  • Example 1-2 Efficacy verification of novel peptides in rheumatoid arthritis animal model
  • bovine type 2 collagen (CII) was dissolved in 0.1 M acetic acid solution to 2 mg/ml and then dialyzed with phosphate buffered saline to M. tuberculosis (tuberculosis). ) containing Complete Fred's Adjuvant (CFA, Chondrex) in the same amount and emulsified, and then 100 ⁇ l of the emulsified collagen solution was added to the base of the tail of 8-week-old male DBA/1J mice (i.e., 100 ⁇ g/100 ⁇ l) intradermal injection to induce primary immunity (primary immunity).
  • CFA Complete Fred's Adjuvant
  • the same CII was mixed with an equal amount of CFA and then injected intradermally into the base of the tail of the mouse by 100 ⁇ l (ie, 100 ⁇ g/100 ⁇ l) to induce a secondary immune response (secondary immunization).
  • a boosting reaction was induced by intraperitoneal injection of 40 ⁇ g of lipopolysaccharide (LPS) per animal, and the experiment was terminated on the 35th day after the primary immunization.
  • LPS lipopolysaccharide
  • the severity of joint inflammation was evaluated at 2-day intervals.
  • the arthritis evaluation was used by adding up the scores from the four legs according to the scale below.
  • the score criteria according to the arthritis evaluation are as follows (Table 2).
  • the thickness of the ankle joint was measured with a caliper, pictures for each test group were taken, and the test animals were killed. proceeded. Then, a 5 ⁇ m joint section was prepared by embedding the mouse hind paw tissue in paraffin, stained with hematoxylin and eosin (H&E), and histopathologically, the severity of joint inflammation was evaluated. At this time, the evaluation of arthritis was used by averaging the scores based on the following scale. The score criteria according to the arthritis evaluation are as follows.
  • the group administered with Amuc_1409 compared to the group administered with the PBS buffer decreased close to a significant level.
  • the arthritis index significantly decreased in the group administered with Amuc_1409 (p ⁇ 0.01, Student's t-test).
  • the thickness of the ankle joint was significantly reduced in the group administered with Amuc_1409 compared to the group administered with PBS buffer. It was confirmed that the swelling of the hind paws was overall reduced (p ⁇ 0.05, Student's t-test) (FIG. 4).
  • the arthritis index significantly decreased in the PEP001-administered group from the 30th day after the first CII injection to the end of the experiment compared to the PBS buffer-administered group, and PEP002 And the PEP003 administration group had a significant decrease in the arthritis index from the 26th day after the first CII injection to the end of the experiment, the PEP004 administration group significantly decreased the arthritis index from the 32nd day after the first CII injection to the end of the experiment, and the PEP005 administration group showed a significant decrease in the CII 1 From the 28th day after the primary injection to the end of the experiment, the arthritis index decreased significantly.
  • the thickness of the ankle joint was significantly reduced in the group administered with PEP001, PEP002, PEP003, PEP004 and PEP005 compared to the group administered with the PBS buffer.
  • the edema of the hind paws was overall reduced in the group administered with PEP001, PEP002, PEP003, PEP004 and PEP005 (p ⁇ 0.05, Student's t-test) (FIG. 5).
  • the peptide of the present invention is effective in preventing and treating arthritis.
  • Obesity/diabetes and metabolic disease animal models accompanied by chronic inflammation were induced by free feeding on a high-fat diet for 45 weeks or 8 weeks using 8-week-old SPF male C57BL/6J mice.
  • Amuc_1409 was fed to mice fed a high-fat diet for an additional 3 weeks to mice fed a high-fat diet for 45 weeks, or PEP001, PEP002, and PEP001, PEP002, to mice fed a high-fat diet for an additional 3 weeks to mice fed a high-fat diet for 8 weeks.
  • PEP003, PEP004 and PEP005 in PBS buffer were orally administered to mice once a day at the same time until the end of the test.
  • PBS buffer was orally administered in the same way.
  • fasting blood glucose was measured using ACCU-CHECK in a small amount of blood obtained through a wound at the tip of the tail of a mouse fasted for 16 hours, and blood was collected from the orbital venous plexus using a heparin-treated capillary tube. The collected blood was immediately centrifuged at 10,000 rpm (4°C) for 10 minutes to separate plasma. analyzed.
  • the blood glucose of the group administered with Amuc_1409 decreased compared to the group administered with PBS buffer from 30 minutes to 120 minutes of insulin administration. It showed resistance improvement efficacy, and as a result of converting the graph of the insulin resistance experiment into AUC (area under the curve), it was confirmed that the group administered with Amuc_1409 was reduced close to a significant level compared to the group administered with PBS buffer. In addition, when fasting blood glucose was measured after fasting for 16 hours at the end of the test, it was confirmed that the group administered with Amuc_1409 significantly decreased (p ⁇ 0.05, Student's t-test) ( FIG. 8 ).
  • the initial body weight of the group administered with PEP001, PEP002, PEP003, PEP004 and PEP005 decreased compared to the group administered with PBS buffer, and the group administered with PEP003, PEP004 and PEP005 decreased significantly.
  • the group administered with PEP001, PEP002, PEP003, PEP004 and PEP005 showed an anti-obesity effect as all decreased compared to the group administered with PBS buffer (p ⁇ 0.05, Student's t-test) (FIG. 9) .
  • the blood glucose of the group administered with PEP001, PEP002, PEP003, PEP004 and PEP005 decreased compared to the group administered with PBS buffer at 30 minutes of insulin administration.
  • the effect of improving insulin resistance by a high-fat diet was reduced compared to the group administered with PBS buffer in all groups administered with PEP001, PEP002, PEP003, PEP004 and PEP005 as a result of converting the graph of the insulin resistance experiment into AUC.
  • TC and LDL-C concentrations which are blood lipid indicators, did not show a significant difference between the Amuc_1409 administration group and the PBS buffer administration group, but decreased in the PEP001, PEP002, PEP003, PEP004 and PEP005 administration groups compared to the PBS buffer administration group.
  • TC significantly decreased in the PEP003-administered group, and showed a tendency to decrease in the PEP004 and PEP005-administered groups.
  • the peptide of the present invention has a preventive and therapeutic effect on various metabolic diseases.
  • Example 3 Efficacy verification of novel peptides in hepatitis animal model
  • Example 3-1 Efficacy verification of novel peptides in acute hepatitis animal model
  • ConA Concanavalin A
  • SPF specific pathogen free mice
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • Sections with a thickness of 5 ⁇ m were prepared by embedding in paraffin and stained with hematoxylin and eosin (H&E).
  • ALT was significantly decreased in the group administered with Amuc_1409, PEP002, PEP003, and PEP004 compared to the group administered with the PBS buffer, and was close to a significant level in the group administered with PEP001 and PEP005. was confirmed to be lowered.
  • AST decreased significantly in the group administered with Amuc_1409 compared to the group administered with PBS buffer, and decreased close to a significant level in the group administered with PEP001, and showed a tendency to decrease in the groups administered with PEP002, PEP003, PEP004 and PEP005 (p ⁇ 0.05, Student's t). -test) (Fig. 11).
  • Example 3-2 Efficacy verification of novel peptides in nonalcoholic steatohepatitis animal model
  • the nonalcoholic hepatitis model was induced by free feeding on a high-fat diet for 45 weeks or 8 weeks using 8-week-old SPF male C57BL/6J mice.
  • Amuc_1409 was fed to mice fed a high-fat diet for an additional 3 weeks to mice fed a high-fat diet for 45 weeks, or PEP001, PEP002, and PEP001, PEP002, to mice fed a high-fat diet for an additional 3 weeks to mice fed a high-fat diet for 8 weeks
  • PEP003, PEP004 and PEP005 in PBS buffer to a concentration of 2.4 ⁇ M
  • 150 ⁇ l per animal was orally administered to mice once a day at the same time until the end of the test.
  • PBS buffer was orally administered in the same way.
  • RNA was added to Trizol and homogenized to extract RNA.
  • Reverse transcriptase was added to the obtained RNA and reacted to synthesize cDNA, followed by quantitative real-time PCR (RT-qPCR) by adding SYBR Green and primers, followed by Tnf ⁇ , Il-1 ⁇ , Il-10 and Il-
  • RT-qPCR quantitative real-time PCR
  • Tnf ⁇ was significantly reduced in the PEP003, PEP004 and PEP005 administration groups compared to the PBS buffer administration group, and Il-1 ⁇ was It decreased close to a significant level in the PEP001 and PEP004 administration groups, and significantly decreased in the Amuc_1409, PEP002, PEP003 and PEP005 administration groups.
  • Il-10 an anti-inflammatory index, significantly increased in the groups administered with Amuc_1409 and PEP001, PEP003, PEP004 and PEP005 compared to the group administered with PBS buffer, and showed a tendency to increase close to a significant level in the group administered with PEP002.
  • An additional anti-inflammatory index, Il-1rn was significantly increased in the Amuc_1409 administration group compared to the PBS buffer administration group (p ⁇ 0.05, Student's t-test) (Fig. 12).
  • the peptide of the present invention is effective in preventing and treating hepatitis.
  • PEP002, PEP003, PEP004 and PEP005 were dissolved in PBS buffer at a concentration of 4.3 ⁇ M, and 150 ⁇ l per animal was orally administered at the same time once a day, and the same amount of PBS buffer was orally administered to the control group.
  • the rate of increase in body weight due to the recovery of enteritis was confirmed through oral administration 6 times for 6 days.
  • the test was terminated after oral administration three times for 3 days.
  • the length of the colon is measured, and a part of the distal colon is rapidly cooled in liquid nitrogen, RNA is extracted using Trizol, reverse transcriptase is added and reacted to synthesize cDNA, and SYBR Green and primer are added.
  • RT-qPCR quantitative real-time PCR
  • the Il-6 gene expression level was quantified.
  • a part of the distal colon was fixed in 10% NBF at room temperature for more than 24 hours, then embedded in paraffin to prepare a 5 ⁇ m-thick section and stained with hematoxylin and eosin (H&E). H&E-stained tissue sections were observed under a light microscope to evaluate the degree of histopathological enteritis using a histologic colitis scoring system (Table 4).
  • the group administered with PEP002, PEP004 and PEP005 significantly increased compared to the group administered with the PBS buffer, and showed a tendency to increase in the group administered with PEP003 (p ⁇ 0.05, Student's t-test) (Fig. 14). ).
  • the peptide of the present invention has a preventive and therapeutic effect on inflammatory bowel disease.
  • Example 5 Efficacy verification of novel peptides in gastritis/gastric ulcer animal models
  • Gastritis/gastric ulcer model was performed using 7-week-old male C57BL/6J mice from 3 days before induction so that the concentrations of Amuc_1409 or PEP001, PEP002, PEP003, PEP004 and PEP005 were 6.7 ⁇ M in PBS buffer and then 150 ⁇ l per animal once a day. The mice were orally administered at the same time.
  • 0.2 ml of 0.3 M HCl/60% ethanol was orally administered, and the tissue was excised after 1 hour to take pictures of the inner side of the stomach and compare the degree of gastric damage.
  • the measurement of gastritis/gastric ulcer index was converted by scoring according to the degree of mucosal damage. If there is no damage, there is at least one site of bleeding corrosion corresponding to 0 points, minor circular bleeding erosion less than 5 mm, 1 point for one site, 2 points for a site with a length greater than 5 mm, and 2 points for bleeding corrosion. 3 points, 4 points for bleeding corrosion with a length of 5 mm or more and 2 mm or less, 5 points for 2-3 bleeding corrosion corresponding to 4 points, 6 points for 4-5 pieces, 6 points for 6 points or more A score of 7 and 8 points were given if there was hemorrhagic erosion throughout the gastric mucosa.
  • the peptide of the present invention is effective in preventing and treating gastritis and gastric ulcer.
  • Example 6 Efficacy verification of novel peptides in dermatitis animal model
  • the dermatitis model was performed by applying 2.5 ⁇ g of TPA (12-otetrade-canoyl-phorbol-13-acetate) dissolved in 25 ⁇ l acetone to the right ear of an 8-week-old male C57BL/6J mouse one day before sample application. Skin edema and inflammation were induced, and 25 ⁇ l of acetone, a TPA solvent, was applied to the left ear and used as a negative control.
  • TPA (12-otetrade-canoyl-phorbol-13-acetate) dissolved in 25 ⁇ l acetone
  • the thickness of the ears was measured to check the degree of edema and inflammation relief of the ears, and both ears were photographed for each test group.
  • the weight per area of the ear was measured, and the mouse ear was fixed in 10% neutral buffered formalin at room temperature for at least 24 hours, then embedded in paraffin to prepare a 5 ⁇ m-thick section, and hematoxylin and (H&E) staining with eosin (Eosin).
  • H&E hematoxylin and
  • Eosin hematoxylin and eosin
  • the group administered with PEP001, PEP002, PEP003, PEP004, and PEP005 markedly reduced erythema and edema of the ear compared to the group administered with PBS buffer.
  • the group administered with PEP001, PEP002, PEP003, PEP004 and PEP005 markedly reduced erythema and edema of the ear compared to the group administered with PBS buffer.
  • the group administered with PEP001, PEP002, PEP003, PEP004 and PEP005 significantly decreased compared to the group administered with the PBS buffer (p ⁇ 0.05, Student's t-test) ( FIG. 22 ).
  • the group administered with Amuc_1409, PEP001, PEP002, PEP003, PEP004, and PEP005 showed improvement in ear tissue edema and inflammatory cells by TPA application compared to the PBS buffer administration group. Infiltration was markedly reduced ( FIG. 23 ).
  • the peptide of the present invention is effective in preventing and treating skin inflammatory diseases.
  • Example 7 Efficacy verification of novel peptides in animal models of depression and anxiety disorders
  • LPS lipopolysaccharide
  • TST tail suspension test
  • FST forced swim test
  • Elevated plus-maze was performed to analyze the effect on anxiety level.
  • the EPM device consists of two open arms (50 ⁇ 10 cm) intersected with two closed arms (50 ⁇ 10 cm) at a height of 50 cm from the floor, connected by an area of 10 ⁇ 10 cm in the center.
  • the mice were placed in the center of the maze and using a video camera, the time spent on the open arm was measured for a total of 5 min, and the ratio of time spent on the open arm was calculated as [(time spent in open arm/time spent in open and closed arms) Time spent in) ⁇ 100] was calculated and recorded.
  • the PEP001, PEP002, PEP003, PEP004 and PEP005 administration groups significantly decreased the retention time of immobility due to tail suspension and forced swimming compared to the PBS buffer administration group (p ⁇ 0.05, Student's). t-test)
  • the PEP001, PEP002, PEP003, PEP004 and PEP005 administration groups showed anxiolytic efficacy by increasing the time spent in the open arm compared to the PBS buffer administration group (p ⁇ 0.05, Student's t-test) ) (Fig. 26).
  • Example 8 Efficacy verification of novel peptides in animal models of cognitive/memory disorders
  • Example 8-1 Efficacy verification of novel peptides in Alzheimer's disease animal model
  • Amuc_1409 was orally administered to 5-month-old male APP/PS1 Alzheimer's disease mice with amyloid deposition and cognitive and memory impairments observed in the brain, 5 ⁇ g daily for 5 days a week, and administered for 8 weeks. After dissolving PEP001 in PBS buffer to a concentration of 2.4 ⁇ M, 150 ⁇ l per animal was orally administered 5 days a week for 8 weeks. The control group (vehicle) was orally administered with PBS in the same amount (volume). In addition, normal mice (Non-Tg) not administered with the novel protein fragment were used as a control group.
  • a novel object recognition test was performed to test the cognitive function improvement effect in APP/PS1 Alzheimer's disease mice administered with Amuc_1409 and PEP001. Recognition and memory were tested by measuring the search time and number of searches for the new object when the original object and the new object were provided 24 hours ago.
  • Example 8-2 Efficacy verification of novel peptides in animal models of cognitive/memory impairment
  • Cognitive and memory impairments were induced by intraperitoneal injection of LPS at 250 ⁇ g/kg/day for 7 days in male C57BL/6J mice.
  • Akkermansia muciniphila-derived protein Amuc_1409 was orally administered 5 ⁇ g daily from one week before LPS administration until the cognitive and memory test was performed.
  • PEP002, PEP003, PEP004 and PEP005 were tested for cognition and memory from three days before LPS administration. After dissolving in PBS buffer so that the concentration became 2.4 ⁇ M until completion, 150 ⁇ l per animal was orally administered to the mouse every day at the same time once a day.
  • the control group (vehicle) was orally administered with PBS in the same amount (volume).
  • a novel object recognition test was performed to test the effect of improving cognitive function in cognitive and memory impaired mice administered with Amuc_1409 or PEP002, PEP003, PEP004 and PEP005. Recognition and memory were tested by measuring the search time and number of searches for the new object when the original object and the new object were provided 24 hours ago.
  • Example 8-3 Verification of cognitive/memory efficacy of novel peptides in naturally aging mice
  • a novel object recognition test was performed to test the cognitive function improvement effect in naturally aging mice administered with Amuc_1409 and PEP002, PEP003, PEP004 and PEP005. Recognition and memory were tested by measuring the search time and number of searches for the new object when the original object and the new object were provided 24 hours ago.
  • the peptide of the present invention has the effect of preventing and treating cognition and memory disorders as well as preventing and treating degenerative brain diseases, and improving cognition and memory.
  • BTBR mice (BTBR T + Itpr3 tf /J (BTBR)), a developmental disability model, were used as experimental animals.
  • mice To 3-week-old male BTBR mice, Amuc_1409 was orally administered 5 ⁇ g daily for 5 days a week, and PBS (Phosphate-buffered saline) was administered to the control group. After dissolving PEP001, PEP002, PEP003, PEP004 and PEP005 in PBS buffer to a concentration of 2.4 ⁇ M, 150 ⁇ l per animal was orally administered to mice once a day at the same time for 5 days a week. Behavioral evaluation was performed by observing the social behavior of the mice 4 weeks after administration. The mice were allowed to freely ingest sterilized feed and water in a breeding facility in a specific pathogen-free environment in which the temperature was maintained at 22-24° C., and were bred while maintaining a 12-hour day and night cycle.
  • PBS Phosphate-buffered saline
  • the sniffing time (A) and the number of times (B) were measured by observing the sniffing behavior with other mice for 3 minutes. It was confirmed that the social behavior of the mice orally administered with Amuc_1409, PEP001, PEP002, PEP003, PEP004 and PEP005 was significantly increased compared to the group administered with the vehicle to the BTBR mice (p ⁇ 0.05, Student's t-test) (FIG. 31) ).
  • the full-thickness skin defect wound induction model was designed to show a full-thickness wounding after anesthetizing 9-week-old specific pathogen free (SPF) male C57BL/6J mice, about 1.0 cm from the base of the tail of the mouse.
  • SPF pathogen free
  • a full-thickness wound was made on the back of the tail of the mouse that had fallen off using a 10 ⁇ 3mm sterile dissection mass No. 10.
  • the wound was compressed to stop bleeding, and the wound was covered with a film spray dressing (Cavilon, 3M).
  • the wound area of the animals of each test group was individually photographed using a digital camera at a constant height from the wound for 28 days at intervals of 7 days from the day of wound induction, and the wound area was used using the Image J Soft program. was measured.
  • the peptide of the present invention has an effect on damage and regeneration of body tissues including skin tissues.
  • Example 11 Verification of tissue regeneration promoting efficacy of novel peptides
  • novel peptide of the present invention has the effect of promoting tissue regeneration, it was confirmed whether the regeneration of muscle tissue and muscle strength were improved.
  • Example 11-1 Validation of muscle strength improvement and muscle regeneration efficacy of new peptides in aging animal models
  • the aged mouse was asked to hold the wire mesh connected to the strength probe of the grip strength meter with all four legs, and then carefully pulled the tail backward to measure the maximum grip strength at the moment of holding the wire mesh and holding it. did In the case of muscle weight, after administration, the gastrocnemius (GC), soleus, and tibialis anterior (TA) muscles from both hind paws of each group of aged mice were carefully separated not to be damaged, and then each weight was measured and the weight of the mouse was used. After correction, the muscle weight compared to the body weight was calculated.
  • GC gastrocnemius
  • TA tibialis anterior
  • the TA muscle was fixed in 10% formalin, and a frozen section sample (8 ⁇ m) was prepared to prepare a slide.
  • the prepared slides were washed with PBS buffer, then permeated with 0.5% Triton X-100 and blocked, and treated with a primary antibody (anti-laminin).
  • a fluorescent secondary antibody Alexa Fluor 488 Goat anti-rabbit IgG was applied, and finally, DAPI was treated for nuclear staining.
  • the muscle tissue was photographed using a confocal microscope, and the cross-sectional area of the muscle fibers was measured from at least 500 to 3500 ⁇ m 2 or more using image analysis software (ImageInside). The distribution was calculated for each size.
  • RNA-like growth factor involved in protein synthesis in muscle cells
  • RT-qPCR quantitative real-time PCR
  • Example 11-2 Verification of muscle regeneration efficacy of novel peptides in myoblast model
  • myoblast C2C12 myoblast
  • DMEM medium containing 10% FBS and 1% antibotics
  • C2C12 cells were replaced with a differentiation medium containing 2% horse serum and treated with PEP004 and PEP005 at a concentration of 64 nM for a time to induce differentiation to form myotubes. was observed.
  • Reverse transcriptase was added to the obtained RNA and reacted to synthesize cDNA, and quantitative real-time PCR (RT-qPCR) was performed by adding SYBR Green and primers, and then atrogin-1 and MuRF1, factors involved in muscular atrophy, By measuring the expression level, it was confirmed whether the atrophy of the differentiated myoblasts was inhibited.
  • the peptide of the present invention has the effect of promoting muscle regeneration, strengthening of muscle strength, and improving muscle strength.
  • Example 12 Verification of hair regeneration and hair growth promoting efficacy of novel peptides
  • Criteria for scoring evaluation of gross hair growth Criteria score not growing at all 0 Less than 30% of the hair removal area darkens the skin color Hair does not grow in the epilation area One About 30-70% of the hair removal area darkens the skin color Hair does not grow in the epilation area 2 More than 70% of the hair removal area darkens the skin color Less than 30% growth in the hair removal site 3 More than 70% of the hair removal area darkens the skin color 30-70% growth at the hair removal site 4 More than 70% of the hair removal area darkens the skin color More than 70% growth in the hair removal area 5 More than 90% of the hair removal site grows 6
  • the mouse skin tissue was fixed in 10% NBF at room temperature for more than 24 hours, then embedded in paraffin to prepare a 5 ⁇ m thick section, and then treated with hematoxylin and eosin. (H&E) staining.
  • H&E staining The histological changes of the hair follicle tissue were observed using the H&E-stained tissue sections under an optical microscope.
  • the quantity and depth of hair follicles and the thickness of the dermis and subcutaneous tissue were measured under an optical microscope, and the hair growth cycle was evaluated.
  • the number of hair follicles the number of hair follicles present in the subcutaneous tissue was counted using an optical microscope at 100 magnification.
  • the depth of hair follicles and changes in the dermis and subcutaneous thickness were measured through the Image J program using a scale bar.
  • the group applied with Amuc_1409 significantly increased the number of hair follicles in the subcutaneous fat layer compared to the group applied with Vehicle, and the depth of hair follicles and the thickness of the dermis and subcutaneous tissue were significantly thicker than the group applied with Vehicle. lost (p ⁇ 0.05, Student's t-test) ( FIG. 38 ).
  • the peptide of the present invention has the effect of promoting hair regeneration and hair growth.
  • human skin keratinocytes were used.
  • HaCaT Human dermal keratinocytes
  • FBS Fetal Bovine Serum
  • penicillin-streptomycin under conditions of 37°C and 5% CO2.
  • the cell density reached 80%, the number of 4x105 cells per well was aliquoted in a 6-well plate and cultured for 24 hours.
  • Amuc_1409 was pretreated at a concentration of 30 nM for 1 hour and washed twice with PBS (phosphate buffered saline) after 1 hour, using an ultraviolet (UVB) irradiation device (CL-1000 UV crosslinker; UVP, USA).
  • UVB ultraviolet irradiation device
  • Trizol (Invitrogen, USA) was added to cells in each well to confirm the expression of collagen degrading enzymes MMP-1 and MMP-3 genes and collagen synthesizing enzymes Col1a1 and Col3a1 genes in relation to skin wrinkles caused by skin aging.
  • cDNA was synthesized using 1 ug of each RNA.
  • the peptide of the present invention has the effect of suppressing symptoms related to skin aging and promoting skin regeneration.

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Abstract

La présente invention concerne un nouveau peptide ayant des actions anti-inflammatoires et de régénération tissulaire et son utilisation.
PCT/KR2021/015692 2020-11-05 2021-11-02 Nouveau peptide ayant des actions anti-inflammatoires et de régénération tissulaire WO2022098051A1 (fr)

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KR20100061482A (ko) * 2007-09-11 2010-06-07 몬도바이오테크 래보래토리즈 아게 치료제로서의 라미닌 펩티드의 용도
WO2017060698A1 (fr) * 2015-10-05 2017-04-13 Liam O'mahony Utilisation d'akkermansia muciniphila pour traiter des états inflammatoires
KR20180011130A (ko) * 2015-05-06 2018-01-31 바게닝겐 유니버시테이트 면역 신호전달 초래 및/또는 창자 장벽 기능에 영향 및/또는 대사 상태를 조절하기 위한 폴리펩티드의 용도
KR20200129059A (ko) * 2019-05-07 2020-11-17 한국생명공학연구원 염증성 장질환의 예방 또는 치료용 펩타이드

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WO2014200651A1 (fr) 2013-06-14 2014-12-18 Helix Biomedix Inc. Tétrapeptides dérivés des chimiokines c-x-c humaines pouvant être utilisés en vue du traitement de diverses affections cutanées
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