Peptides for inducing tissue regeneration and uses thereof

文档序号：1651927 发布日期：2019-12-24 浏览：28次中文

阅读说明：本技术 用于诱导组织再生的肽及其应用 (Peptides for inducing tissue regeneration and uses thereof ) 是由二桥阳一郎河内智行山津维子麓昌高山崎尊彦于 2018-04-24 设计创作，主要内容包括：本发明提供可用作下述组合物的有效成分的肽：用于刺激PDGFRα阳性细胞迁移的组合物、用于将骨髓间充质干细胞从骨髄募集到外周血中的组合物、用于使组织再生的组合物、或者用于刺激骨髄来源的基质细胞迁移的组合物。(The present invention provides peptides useful as active ingredients of the following compositions: a composition for stimulating the migration of PDGFR α -positive cells, a composition for recruiting bone marrow mesenchymal stem cells from the bone marrow into the peripheral blood, a composition for regenerating tissue, or a composition for stimulating the migration of bone marrow derived matrix cells.)

1. A peptide, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, selected from the group consisting of:

a peptide having any one of the amino acid sequences shown in SEQ ID Nos. 1 to 399 and 403;

a peptide having an amino acid sequence in which 1 or more amino acids are added to a peptide having any one of the amino acid sequences shown in SEQ ID Nos. 1 to 399 and 403, and having an activity of stimulating cell migration; and

comprises or consists of an amino acid sequence obtained by substituting, deleting or inserting 1 or more amino acids from the 1 st to 42 th amino acids of a peptide having any one of the amino acid sequences shown in SEQ ID Nos. 1 to 399 or the 1 st to 41 th amino acids of a peptide having the amino acid sequence shown in SEQ ID No. 403, and has an activity of stimulating cell migration.

2. A peptide, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, selected from the group consisting of:

a peptide having an amino acid sequence of any one of SEQ ID NOs 1 to 5, 126, 128, 129, 138, 167, 248, 254, 280, 282, 283, 292 and 403;

a peptide having an amino acid sequence in which 1 or more amino acids are added to any one of the peptides having the amino acid sequences shown in SEQ ID Nos. 1 to 5, 126, 128, 129, 138, 167, 248, 254, 280, 282, 283, 292, and 403, and having an activity of stimulating cell migration; and

comprising or consisting of an amino acid sequence obtained by substituting, deleting or inserting 1 or more amino acids at positions 1 to 42 of a peptide having any one of the amino acid sequences shown in SEQ ID Nos. 1 to 5, 126, 128, 129, 138, 167, 248, 254, 280, 282, 283 and 292 or amino acids at positions 1 to 41 of a peptide having the amino acid sequence shown in SEQ ID No. 403, and having an activity of stimulating cell migration.

3. A peptide, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, selected from the group consisting of:

a peptide having an amino acid sequence of any one of SEQ ID NOs 1 to 5, 167 and 403;

a peptide having an amino acid sequence obtained by adding 1 or more amino acids to a peptide having any one of the amino acid sequences shown in SEQ ID Nos. 1 to 5, 167 and 403, and having an activity of stimulating cell migration; and

comprises or consists of an amino acid sequence obtained by substituting, deleting or inserting 1 or more amino acids at the 1 st to 42 th amino acids of a peptide having an amino acid sequence represented by any one of SEQ ID NOs 1 to 5 and 167 or the 1 st to 41 th amino acids of a peptide having an amino acid sequence represented by SEQ ID NO 403, and has an activity of stimulating cell migration.

4. A peptide, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, selected from the group consisting of:

a peptide having an amino acid sequence of any one of SEQ ID NOs 1 to 5 and 403;

a peptide having an amino acid sequence in which 1 or more amino acids are added to a peptide having any one of the amino acid sequences shown in SEQ ID Nos. 1 to 5 and 403, and having an activity of stimulating cell migration; and

comprises or consists of an amino acid sequence obtained by substituting, deleting or inserting 1 or more amino acids at the 1 st to 42 th amino acids of a peptide having any one of the amino acid sequences shown in SEQ ID Nos. 1 to 5 or the 1 st to 41 th amino acids of a peptide having the amino acid sequence shown in SEQ ID No. 403, and has an activity of stimulating cell migration.

5. A composition for stimulating migration of PDGFR α positive cells, the composition comprising: the peptide, derivative thereof, pharmaceutically acceptable salt thereof, or solvate thereof according to any one of claims 1 to 4.

6. A composition for recruiting bone marrow mesenchymal stem cells from the bone marrow into the peripheral blood, the composition comprising: the peptide, derivative thereof, pharmaceutically acceptable salt thereof, or solvate thereof according to any one of claims 1 to 4.

7. A composition for regenerating tissue, the composition comprising: the peptide, derivative thereof, pharmaceutically acceptable salt thereof, or solvate thereof according to any one of claims 1 to 4.

8. The composition for stimulating bone marrow derived stromal cell migration, comprising: the peptide, derivative thereof, pharmaceutically acceptable salt thereof, or solvate thereof according to any one of claims 1 to 4.

Technical Field

The present invention relates to peptides for inducing tissue regeneration and uses thereof.

Background

It has been clarified that tissue stem cells that maintain the homeostasis of their structure and function are present in each organ and tissue in the living body. For example, cardiac muscle stem cells are present in the heart, neural stem cells are present in the brain, epidermal stem cells or hair follicle stem cells are present in the skin, and these stem cells are retrospectively supplied to cardiac muscle cells, neural cells, epidermal cells or hair follicle epithelial cells to maintain the structure/function of the heart, brain, skin. On the other hand, the bone marrow contains hematopoietic stem cells differentiated into blood cells such as red blood cells, white blood cells, and platelets.

These hematopoietic stem cells circulate in all organs and tissues in the body via the blood stream, and play an essential role in maintaining life, such as oxygen supply, immune response, hemostasis, and repair of damaged tissues. That is, the bone marrow hematopoietic stem cell maintains the homeostasis of the bone marrow or bone tissue, which is a tissue locally present therein, not to say, it contributes to the homeostasis of all tissues in the body through the peripheral circulation.

In recent years, the bone marrow has revealed that mesenchymal stem cells capable of differentiating into mesodermal tissues such as osteogenic, cartilage, and fat and further into ectodermal tissues such as nerve and epidermis exist in addition to hematopoietic stem cells, but their existence in vivo has been largely unknown. However, if there are hematopoietic stem cells that supply blood cells through peripheral circulation to maintain the steady state of all tissues and organs, the following possibilities are expected: the mesenchymal stem cells present in the bone marrow also contribute to the maintenance of homeostasis of living tissues by supplying cells differentiated into bone, cartilage, fat, nerve, epithelium, and the like to essential living tissues and organs through the peripheral circulation.

Currently, the following regenerative medicine is being developed vigorously: the bone marrow is collected and proliferated by cell culture, and then transplanted to a refractory tissue injury site or peripheral circulation blood to induce regeneration of an injured tissue. Clinical applications of bone marrow mesenchymal stem cell transplantation have been carried out in regenerative medicine of cerebral infarction (cerebral infarction), myocardial infarction (myocardial infarction), intractable skin ulcer, and the like. Furthermore, it has been revealed that transplanted mesenchymal stem cells locally exhibit an inflammatory/immune response inhibitory action and a fibrous scar formation inhibitory action in vivo, and clinical trials of mesenchymal stem cell transplantation therapy have been started as a new method for treating Graft Versus Host Disease (GVHD), which is a serious side effect after bone marrow transplantation or blood transfusion, or scleroderma, which is an autoimmune disease. However, bone marrow containing mesenchymal stem cells can only be collected by open technique (blood-feeding technique) in which a thick needle is inserted into the ilium several times. In addition, if the bone marrow mesenchymal stem cells are continuously subcultured in vitro, the proliferation ability or the multi-differentiation ability is gradually lost. Furthermore, since the culture of mesenchymal stem cells based on high-quality management for ensuring the safety of in vivo transplantation requires special culture equipment such as CPC (cell processing center), it is currently practiced only in very limited universities or enterprises. That is, in order to provide regenerative medicine using mesenchymal stem cells to many patients worldwide who are afflicted with intractable tissue damage, technical development for mesenchymal stem cell regenerative medicine that can be implemented in all medical facilities is an urgent issue.

HMGB1(High mobility group box 1: High mobility group protein 1) was identified about 30 years ago as a non-histone chromatin protein, which controls the endochromatin structure and thus gene expression or DNA repair. The structure of the HMGB1 protein is mainly composed of two DNA binding domains, the DNA binding domain located on the N-terminal side is called a-box, and the DNA binding domain located on the C-terminal side is called B-box. The following were clarified from previous studies: the domain that binds to TLRs within HMGB1 molecule to trigger the inflammatory response is present within the B-box.

It has been reported that when recombinant HMGB1 protein is administered from the tail vein after a skin ulcer or cerebral infarction is produced in a mouse, PDGFR α positive cells are recruited (called) from the bone marrow to the blood and further accumulate in the skin ulcer or cerebral infarction, thereby strongly inducing regeneration of the skin ulcer or cerebral infarction. The bone marrow PDGFR α -positive cells have been reported to be mesenchymal stem cells that differentiate into bone, cartilage, fat, and also into nerves or epithelium. That is, the bone marrow mesenchymal stem cells are recruited to the peripheral circulation by administering HMGB1, and thus many mesenchymal stem cells can be accumulated in a damaged tissue in a living body without taking out the cells to the outside of the body and performing special culture.

By developing HMGB1 as a damaged tissue regeneration-inducing drug based on recruitment in the blood of mesenchymal stem cells in vivo, regeneration-inducing medicine based on mesenchymal stem cells in bone marrow was made available in all medical institutions. As a result, many problems of the above-described conventional regenerative medicine using mesenchymal stem cells can be solved.

As described above, HMGB1 is an epoch-making therapeutic agent that promotes the recruitment of bone marrow mesenchymal stem cells into the blood, the accumulation in damaged tissues, and the induction of tissue regeneration in vivo. There have been reports on HMGB 1: not only the full-length HMGB1 protein but also fragments of HMGB1 protein have the same effect.

Disclosure of Invention

Problems to be solved by the invention

The problem to be solved by the present invention is: provides a peptide having the migration activity of bone marrow-derived stromal cells, namely, a peptide for inducing tissue regeneration.

Means for solving the problems

The inventors of the present invention have intensively studied and found that: the present inventors have completed the present invention by finding that a peptide having an amino acid substitution at position 43 and/or 44 among peptides consisting of amino acids at positions 1 to 44 of the HMGB1 protein and a peptide having an amino acid substitution at position 43 and/or 44 among peptides consisting of amino acids at positions 2 to 44 of the HMGB1 protein have a migration activity of a stromal cell derived from the mouse bone marrow.

Namely, the present invention relates to:

(1) a peptide, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, selected from the group consisting of:

a peptide having any one of the amino acid sequences shown in SEQ ID Nos. 1 to 399 and 403;

a peptide having an amino acid sequence in which 1 or more (for example, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 5, or 4, 3, or 2) amino acids are added to a peptide having any one of the amino acid sequences shown in SEQ ID Nos. 1 to 399 and 403, and having an activity of stimulating cell migration; and

comprises an amino acid sequence obtained by substituting, deleting or inserting 1 or more (for example, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 5, or 4, 3 or 2) amino acids in the amino acids at the 1 st to 42 th positions of a peptide having any one of the amino acid sequences of SEQ ID NOs 1 to 399 or in the amino acids at the 1 st to 41 th positions of a peptide having the amino acid sequence of SEQ ID NOs 403, or a peptide comprising the amino acid sequence and having an activity of stimulating cell migration.

(2) A peptide, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, selected from the group consisting of:

a peptide having an amino acid sequence of any one of SEQ ID NOs 1 to 5, 126, 128, 129, 138, 167, 248, 254, 280, 282, 283, 292 and 403;

a peptide having an amino acid sequence in which 1 or more (for example, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 5, or 4, 3, or 2) amino acids are added to a peptide having any one of the amino acid sequences shown in SEQ ID NOS 1 to 5, 126, 128, 129, 138, 167, 248, 254, 280, 282, 283, 292, and 403, and having an activity of stimulating cell migration; and

comprises an amino acid sequence obtained by substituting, deleting or inserting 1 or more (for example, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 5, or 4, 3 or 2) amino acids in the amino acid residues 1 to 42 of a peptide having any one of the amino acid sequences shown in SEQ ID Nos. 1 to 5, 126, 128, 129, 138, 167, 248, 254, 280, 282, 283 and 292 or in the amino acid residues 1 to 41 of a peptide having the amino acid sequence shown in SEQ ID No. 403, or a peptide having an activity of stimulating cell migration.

(3) A peptide, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, selected from the group consisting of:

a peptide having an amino acid sequence of any one of SEQ ID NOs 1 to 5, 167 and 403;

a peptide having an amino acid sequence in which 1 or more (for example, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 5, or 4, 3, or 2) amino acids are added to a peptide having any one of the amino acid sequences shown in SEQ ID NOS 1 to 5, 167, and 403, and having an activity of stimulating cell migration; and

comprises an amino acid sequence obtained by substituting, deleting or inserting 1 or more (for example, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 5, or 4, 3 or 2) amino acids in the amino acid residues 1 to 42 of the peptide having any one of the amino acid sequences of SEQ ID NOs 1 to 5 and 167 or the amino acid residues 1 to 41 of the peptide having the amino acid sequence of SEQ ID NO 403, or a peptide comprising the amino acid sequence and having an activity of stimulating cell migration.

(4) A peptide, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, selected from the group consisting of:

a peptide having an amino acid sequence of any one of SEQ ID NOs 1 to 5 and 403;

a peptide having an amino acid sequence in which 1 or more (for example, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 5, or 4, 3, or 2) amino acids are added to a peptide having any one of the amino acid sequences shown in SEQ ID NOS 1 to 5 and 403, and having an activity of stimulating cell migration; and

comprises an amino acid sequence obtained by substituting, deleting or inserting 1 or more (for example, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 5, or 4, 3 or 2) amino acids in the amino acids at the 1 st to 42 th positions of a peptide having any one of the amino acid sequences of SEQ ID NOs 1 to 5 or the amino acids at the 1 st to 41 th positions of a peptide having the amino acid sequence of SEQ ID NOs 403, or a peptide comprising the amino acid sequence and having an activity of stimulating cell migration.

(5) A composition for stimulating migration of PDGFR α positive cells, the composition comprising: the peptide according to any one of the above (1) to (4), a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

(6) A composition for recruiting bone marrow mesenchymal stem cells from the bone marrow into the peripheral blood, the composition comprising: the peptide according to any one of the above (1) to (4), a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

(7) A composition for regenerating tissue, the composition comprising: the peptide according to any one of the above (1) to (4), a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

(8) The composition for stimulating bone marrow derived stromal cell migration, comprising: the peptide according to any one of the above (1) to (4), a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

Effects of the invention

The peptide of the present invention can be used, for example, as an active ingredient of the following composition: a composition for stimulating the migration of PDGFR α -positive cells, a composition for recruiting bone marrow mesenchymal stem cells from the bone marrow into the peripheral blood, a composition for regenerating tissue, or a composition for stimulating the migration of bone marrow derived matrix cells.

Drawings

[ FIG. 1] A]FIG. 1 shows the results of stability tests in plasma of 6 (peptides 2 to 44 (2-44) of human HMGB1 and 5 peptides obtained by modifying amino acids 43 and 44 (peptide-1 to peptide-5)). P1-P5 refer to peptide-1-peptide-5. The vertical axis shows the residual ratio calculated with the peptide immediately after plasma addition as 100, and the horizontal axis shows the time after plasma addition. The peptides 2 to 44 were added to the plasma, and the sample was taken as the lower limit of quantitation 15 minutes after the addition of the plasma (0.5)μg/mL) or less, so the residual ratio cannot be plotted in FIG. 1.

FIG. 2 shows the results of measurement of cell migration activity of 2 kinds of peptides (peptide 2-44 from position 2 to position 44 of human HMGB1 and peptide 6 obtained by modifying amino acids at position 43 and position 44). NC shows negative controls.

FIG. 3 shows the results of stability tests in plasma of 3 kinds of peptides (peptides 2 to 44 of human HMGB1 and 2 kinds of peptides (peptides-3 and 6) obtained by modifying amino acids at positions 43 and 44). The vertical axis shows the residual ratio calculated with the peptide immediately after plasma addition as 100, and the horizontal axis shows the time after plasma addition.

Detailed Description

The present invention provides a peptide according to any one of the following (a) to (c).

(a) A peptide having any one of the amino acid sequences shown in SEQ ID Nos. 1 to 399 and 403;

(b) a peptide having an amino acid sequence in which 1 or more (for example, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 5, or 4, 3, or 2) amino acids are added to a peptide having any one of the amino acid sequences shown in SEQ ID Nos. 1 to 399 and 403, and having an activity of stimulating cell migration; and

(c) comprises an amino acid sequence obtained by substituting, deleting or inserting 1 or more (for example, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 5, or 4, 3 or 2) amino acids in the amino acids at the 1 st to 42 th positions of a peptide having any one of the amino acid sequences of SEQ ID NOs 1 to 399 or in the amino acids at the 1 st to 41 th positions of a peptide having the amino acid sequence of SEQ ID NOs 403, or a peptide comprising the amino acid sequence and having an activity of stimulating cell migration.

The present invention provides a composition for stimulating the migration of a PDGFR alpha-positive cell or bone marrow derived stromal cell, which comprises a peptide according to any one of the following (a) to (c).

(a) A peptide having any one of the amino acid sequences shown in SEQ ID Nos. 1 to 399 and 403;

The composition for stimulating the migration of PDGFR alpha-positive cells or bone marrow derived matrix cells of the present invention includes a reagent composition and a pharmaceutical composition. In this specification, an agent composition is also expressed as an agent, and a pharmaceutical composition is also expressed as a drug, a medicament, or a pharmaceutical composition.

The reagent composition for stimulating the migration of PDGFR α -positive cells or bone marrow-derived matrix cells of the present invention is useful, for example, as a reagent for basic research and clinical research for developing regenerative medicine and regenerative induction medicine. For example, by using the reagent composition, cells can be recruited in the organism tissue of an experimental animal, and the degree of tissue repair and tissue function reconstruction can be studied. In addition, for example, by using the reagent composition, tissue regeneration induction studies based on cell recruitment can be performed in vitro.

The pharmaceutical composition for stimulating the migration of PDGFR α -positive cells or bone marrow-derived matrix cells of the present invention is useful as a drug for regenerative medicine or regenerative induction medicine, for example. For example, by using the pharmaceutical composition, tissue regeneration can be achieved. The pharmaceutical composition can be used, for example, as a so-called prophylactic agent for preventing a decrease in the function of a tissue/organ due to a decrease in tissue stem cells, or as an anti-aging agent (anti-aging agent) for delaying the progress of aging.

In the present specification, the composition for stimulating the migration of PDGFR α -positive cells or bone marrow-derived stromal cells is further expressed as: an agent for stimulating the migration of PDGFR alpha-positive cells or bone marrow-derived stromal cells, a cell migration stimulating agent, a composition for inducing cell migration, an agent for inducing cell migration, a cell migration inducing agent, or a cell inducing agent.

In the present invention, the cell migration stimulating activity means an activity of stimulating cell migration. In the present specification, the cell migration stimulating activity is also expressed as a cell migration inducing activity or a cell inducing activity.

The present invention provides a composition for recruiting a bone marrow mesenchymal stem cell from the bone marrow into the peripheral blood, the composition comprising any one of the following substances (a) to (c).

(a) A peptide having any one of the amino acid sequences shown in SEQ ID Nos. 1 to 399 and 403;

The composition for recruiting a bone marrow mesenchymal stem cell from the bone marrow into the peripheral blood of the present invention includes a reagent composition and a pharmaceutical composition.

The reagent composition for regenerating tissue of the present invention is useful, for example, as a reagent required for basic research and clinical research for developing regenerative medicine, regeneration-inducing medicine. In addition, the pharmaceutical composition for regenerating tissue of the present invention is useful, for example, as a drug in regenerative medicine and regeneration-inducing medicine. For example, bone marrow cells can be recruited to the peripheral circulation to regenerate tissues by using the pharmaceutical composition. In addition, for example, cells recruited to peripheral blood by the pharmaceutical composition can be collected in vitro, concentrated, and administered to a tissue for treatment. The bone marrow is known to be capable of collecting cells from the bone marrow located at a deep portion of the body and therefore invasive to the living body, but if the pharmaceutical composition of the present invention is used, the bone marrow is collected from the peripheral blood with low invasiveness and is used for bone marrow transplantation and the like. In the present specification, the composition for recruiting a bone marrow mesenchymal stem cell from the bone marrow into the peripheral blood is further expressed as: a composition for inducing a bone marrow mesenchymal stem cell from the bone marrow into the peripheral blood.

The present invention provides a composition for regenerating tissue, which contains any one of the following substances (a) to (c).

(a) A peptide having any one of the amino acid sequences shown in SEQ ID Nos. 1 to 399 and 403;

The composition for regenerating tissue of the present invention includes a reagent composition and a pharmaceutical composition.

In the present specification, the composition for regenerating tissue is also expressed as a composition for inducing or promoting tissue regeneration, an agent for inducing or promoting tissue regeneration, a tissue regeneration-inducing agent, or a tissue regeneration-promoting agent. In addition, tissue regeneration also includes tissue repair.

The composition for regenerating tissue of the present invention is not selected for administration/addition site. That is, the composition can exert its effect even when administered to any tissue such as a tissue requiring regeneration, a tissue different from the tissue requiring regeneration, or blood. For example, by administering/adding the composition, cells are recruited to tissue at or near the site of administration/addition, inducing or promoting tissue regeneration. In addition, cells are recruited in the damaged tissue, inducing or promoting tissue regeneration, e.g., by administering/adding the composition to or near the site of the damaged tissue. For example, by administering and adding the composition to a tissue different from the tissue to be regenerated, the bone marrow cell is recruited from the bone marrow through the peripheral circulation to the tissue to be regenerated, thereby inducing or promoting tissue regeneration. Here, "peripheral circulation" is also referred to as "blood circulation" or "peripheral circulation blood flow".

Examples of the tissue to be regenerated include damaged tissue, necrotic tissue, post-operative tissue, tissue with reduced function, fibrotic tissue, aged tissue, diseased tissue, and the like, and examples thereof include living skin tissue, and biopsy (operation) tissue in vivo (brain, lung, heart, liver, stomach, small intestine, large intestine, pancreas, kidney, bladder, spleen, uterus, testis, blood, and the like).

Administration to a tissue different from the tissue to be regenerated means administration to a site other than the site to be regenerated (a site different from the site to be regenerated). Thus, "tissue different from the tissue to be regenerated" can be expressed as: a site different from the tissue requiring regeneration, a site different from the site requiring regeneration, a site free from the tissue requiring regeneration, a site free from the site requiring regeneration, a site distant from the site requiring regeneration, a tissue distant from the tissue requiring regeneration, a distal end portion, a distal end tissue. That is, the composition of the present invention can be effectively used for regenerating tissues (brain, heart, etc.) which are difficult to administer directly from the outside of the body.

The cells recruited in the tissue to be regenerated are differentiated into various cells, which contribute to the regeneration of the function and maintenance and enhancement of the function of the tissue to be regenerated. In the present invention, examples of the tissue to be regenerated include: various pathological conditions caused by ischemia, anemia/hypoxia, and tissues damaged by trauma, scald, inflammation, autoimmunity, genetic abnormality, etc., but the causes are not limited thereto.

The tissue of the present invention is not particularly limited as long as it is a tissue that differentiates bone marrow-derived cells, and examples thereof include: skin tissue, bone tissue, cartilage tissue, muscle tissue, adipose tissue, cardiac muscle tissue, nervous system tissue, lung tissue, digestive tract tissue, liver/gall/pancreas tissue, urinary/genital tissue, and the like. Moreover, by using the above composition, it is possible to induce functional tissue regeneration in tissues requiring regeneration, such as cerebral infarction, myocardial infarction, bone fracture, pulmonary infarction, gastric ulcer, and intestinal inflammation, not to mention skin diseases such as intractable skin ulcer, skin wound, vesicular disease, and alopecia. The species of animals to which the above composition is administered are not particularly limited, and mammals, birds, fishes, and the like can be mentioned. Examples of mammals include human and non-human animals, and examples thereof include: human, mouse, rat, monkey, pig, dog, rabbit, hamster, guinea pig, horse, sheep, whale, etc., but is not limited thereto.

In addition, as a tissue different from the tissue requiring regeneration, there can be exemplified: blood tissue, muscle tissue, subcutaneous tissue, intradermal tissue, abdominal cavity, and the like.

Examples of the nerve tissue include, but are not limited to, central nerve tissue. The composition for regenerating nerve tissue can be used for, for example, treatment of cerebral infarction, cerebral hemorrhage, cerebral contusion, etc., but is not limited thereto. In addition, the composition for regenerating bone tissue is useful for, for example, treatment of bone fracture, but is not limited thereto. The composition for regenerating skin tissue can be used for, for example, treatment of skin ulcer, incomplete suture of surgical wound, scald, incised wound, contusion, skin erosion, abrasion, etc., but is not limited thereto.

In the present invention, the cells stimulating migration or the cells recruited from the bone marrow to the peripheral blood include, but are not limited to, undifferentiated cells and cells at various differentiation stages. In the present invention, the cells stimulating migration or the cells recruited from the bone marrow to the peripheral blood include, but are not limited to, stem cells, non-stem cells, and the like. The stem cells include circulating stem cells or non-circulating stem cells. As the non-circulating stem cells, tissue stem cells generally present in tissues can be exemplified. As the circulating stem cells, circulating stem cells in blood can be exemplified.

The bone marrow-derived cell or hematopoietic stem cell may be used as the cell that stimulates migration or is recruited to the peripheral blood from the bone marrow, but the present invention is not limited thereto. In the present specification, the term "hematopoietic stem cell" refers to a stem cell that can differentiate into leukocytes such as neutrophils, eosinophils, basophils, lymphocytes, monocytes and macrophages, as well as into hematocyte-like cells such as erythrocytes, platelets, mast cells and dendritic cells, and as a marker, CD 34-positive and CD 133-positive are known in humans, and CD 34-negative, c-Kit-positive, Sca-1-positive and Lineagarker-negative are known in mice. In addition, hematopoietic stem cells are characterized by: in the case of culture using a petri dish, it is difficult to culture alone, and co-culture with stromal cells is required.

The "bone marrow cell" as used herein refers to a cell present in the bone marrow, and the "bone marrow derived cell" refers to a bone marrow cell that collects or removes the bone marrow. The "bone marrow cell" includes a cell containing a tissue precursor cell group present in the bone marrow. The "bone marrow-derived cell" may be a cell including Mesoangioblast, or a cell other than Mesoangioblast.

Tissue precursor cells are defined as undifferentiated cells having the ability to differentiate unidirectionally into specific tissue cells other than the blood system, and include undifferentiated cells having the ability to differentiate into the above-mentioned mesenchymal tissue, epithelial tissue, neural tissue, solid organ, vascular endothelium.

The term "bone marrow cell" and "bone marrow derived cell" refer to hematopoietic stem cells, and differentiated cells derived therefrom such as leukocytes, erythrocytes, platelets, osteoblasts and fibroblasts (ファイブロサイト), or stem cells represented by cells known as bone marrow mesenchymal stem cells, bone marrow pluripotent stem cells or bone marrow pluripotent stem cells. The "bone marrow stem cell" in the present specification refers to a stem cell present in the bone marrow, and the "bone marrow stem cell" refers to a bone marrow stem cell that collects or removes the bone marrow. In the present invention, the bone marrow-derived stem cell is exemplified as a cell that stimulates migration or a cell that is recruited from the bone marrow to the peripheral blood, but the invention is not limited thereto. The bone marrow cell and the bone marrow derived cell are isolated by collecting the bone marrow cell or collecting peripheral blood. The hematopoietic stem cell is a non-adherent cell, and a part of the "bone marrow derived cell" is obtained as an adherent cell by culturing a mononuclear cell component in blood obtained by collecting the bone marrow cell and the peripheral blood.

The term "bone marrow cell" or "bone marrow derived cell" includes mesenchymal stem cells, and preferably has the ability to differentiate into osteoblasts (which can be identified by the recognition of calcium precipitates upon differentiation induction), chondrocytes (which can be identified by staining with alcyon blue, staining with safranin-O, or the like), adipocytes (which can be identified by staining with sudan III), mesenchymal cells such as fibroblasts, smooth muscle cells, stromal cells, tendon cells, and the like, and neural cells, epithelial cells (for example, epidermal keratinocytes, intestinal epithelial cell-expressing keratin family cells), and vascular endothelial cells. The differentiated cells are not limited to the above-mentioned cells, but include the ability to differentiate into cells of solid organs such as liver, kidney, pancreas, and the like.

The "bone marrow stromal cell" as used herein refers to a cell other than the hematopoietic stem cell and the blood cell derived therefrom among the cells present in the bone marrow, and refers to a cell which can be collected by the bone marrow and cultured/proliferated as an adherent cell in a culture dish. The bone marrow-derived matrix cell or the bone marrow-derived matrix cell includes a pluripotent cell (bone marrow-derived pluripotent matrix cell) as the bone marrow-derived matrix cell. The bone marrow derived stromal cell may be a cell established as a cell line. Examples of bone marrow-derived stromal cells that form a cell line include ST2 cells (Ogawa et al, EMBO J1988; 7: 1337-43). The ST2 cell is a bone marrow-derived pluripotent stromal cell line having the ability to differentiate into osteoblasts and adipocytes.

In the present specification, the term "bone marrow mesenchymal stem cell" is used interchangeably with the "bone marrow mesenchymal matrix cell", "bone marrow pluripotent matrix cell" and "bone marrow pluripotent stem cell". In the present specification, the "mesenchymal stem cell" refers to a cell present in the bone marrow, and has the following characteristics: the bone marrow is a cell which is directly collected or indirectly collected from other tissues (blood, skin, fat, and other tissues), can be cultured and proliferated as adherent cells in a culture dish (made of plastic or glass), has the ability to differentiate into mesenchymal tissues (mesenchymal stem cells) such as bone, cartilage, and fat, skeletal muscle, cardiac muscle, and further differentiate into nerve tissue and epithelial tissue (pluripotent stem cells), and can be obtained by collecting bone marrow cells.

On the other hand, the "bone marrow-derived mesenchymal stem cell", "bone marrow-derived mesenchymal matrix cell", "bone marrow-derived pluripotent matrix cell", or "bone marrow-derived pluripotent stem cell" that is capable of collecting peripheral blood and further collecting peripheral blood from mesenchymal tissues such as fat, epithelial tissues such as skin, and nerve tissues such as brain, is collected from the bone marrow.

In addition, these cells also have the following characteristics: the cells once attached to a culture dish are administered directly after collection or to a damaged part of an organism, and thus have the ability to differentiate into, for example, epithelial tissues such as keratinocytes constituting the skin and neural tissues constituting the brain.

The bone marrow mesenchymal stem cell, the bone marrow pluripotent stem cell, or the cells recruited from the bone marrow are preferably differentiated into osteoblasts (which are specified by the recognition of calcium precipitates upon induction of differentiation), chondrocytes (which are specified by staining with alcian blue or staining with safranin-O), adipocytes (which are specified by staining with sudan III), mesenchymal cells such as fibroblasts, smooth muscle cells, skeletal muscle cells, stromal cells, tendon cells, etc., neural cells, pigment cells, epidermal cells, hair follicle cells (which express cytokeratin family, hair keratin family, etc.), epithelial cells (which express epidermal keratinocytes, intestinal epithelial cell keratin family, etc.), endothelial cells, liver cells, etc, The ability of cells of solid organs such as kidney and pancreas, but the cells after differentiation are not limited to these cells.

The human bone marrow cell and the human bone marrow derived cell include: the bone marrow is obtained by collecting bone marrow cells, collecting peripheral blood, collecting fat, and culturing cells obtained as adherent cells directly or after separating mononuclear cell components, but the present invention is not limited thereto. The marker of the human bone marrow cell or the human bone marrow derived cell (for example, a mesenchymal stem cell) includes, but is not limited to, all or a part of PDGFR α -positive, PDGFR β -positive, Lin-negative, CD 45-negative, CD 44-positive, CD 90-positive, CD 29-positive, Flk-1-negative, CD 105-positive, CD 73-positive, CD 90-positive, CD 71-positive, Stro-1-positive, CD 106-positive, CD 166-positive, CD 31-negative, CD 271-positive, and CD11 b-negative.

The mouse bone marrow cell and the mouse bone marrow derived cell include: the bone marrow is obtained by collecting bone marrow cells, collecting peripheral blood, collecting fat, and culturing cells obtained as adherent cells directly or after separating mononuclear cell components, but the present invention is not limited thereto. Examples of markers for the mouse bone marrow derived cell or the mouse bone marrow derived cell (for example, the bone marrow mesenchymal stem cell) include, but are not limited to, all or a part of CD 44-positive, PDGFR-positive, CD 45-negative, Lin-negative, Sca-1-positive, c-kit-negative, CD 90-positive, CD 29-positive, Flk-1-negative, CD 271-positive, and CD11 b-negative.

In the present invention, the cells that stimulate migration or cells that are recruited from the bone marrow to the peripheral blood include PDGFR α -positive cells, but the present invention is not limited thereto. Examples of markers other than PDGFR α include, but are not limited to, all or some of CD29 positive, CD44 positive, CD90 positive, CD271 positive, CD11b negative, and Flk-1 negative. As PDGFR α -positive cells, there can be exemplified: the bone marrow derived cell is not limited to, but may be any of a bone marrow derived cell that is positive for PDGFR α, a mesenchymal stem cell derived from PGFR α positive bone marrow, a tissue cell (for example, a fibroblast cell) that is usually present in a PDGFR α positive tissue, a cell that is a bone marrow derived cell that is obtained by collecting a bone marrow (bone marrow cell) and a cell that is obtained as an adherent cell by culturing a mononuclear cell fraction cell in blood obtained by collecting peripheral blood.

The composition of the present invention may further contain another substance in addition to at least one of the peptides described in any one of (a) to (c) above. In the composition of the present invention, the substance other than at least one of the peptides described in (a) to (c) is not particularly limited as long as it does not inhibit cell migration stimulating activity, cell recruitment activity, or tissue regeneration promoting activity. For example, the composition of the present invention may contain, in addition to at least one of the peptides described in the above (a) to (c): a molecule (group) related to the enhancement of the function of the peptide described in the above (a) to (c), a molecule (group) inhibiting an action other than the expected effect of the peptide described in the above (a) to (c), a factor controlling the proliferation or differentiation of cells, and another factor enhancing/maintaining the factor or the function of cells.

The human HMGB1 protein of the present invention is a protein consisting of the amino acid sequence of SEQ ID NO. 401, which is a human HMGB1 protein. The peptide consisting of the amino acid sequences at positions 1 to 44 of the HMGB1 protein is a peptide consisting of the amino acid sequence shown in SEQ ID NO. 402.

The cell migration stimulating activity of the peptide can be confirmed by, for example, the method described in examples, but is not limited to, the method disclosed in WO 2012/147470.

The stability of the peptide in plasma can be confirmed by, for example, the method described in examples, but the invention is not limited thereto.

The peptide of the present invention may be exemplified by a peptide having the following amino acid sequence, but is not limited thereto.

(1) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKP(SEQ ID NO: 1)

(2) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPK(SEQ ID NO: 2)

(3) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPP(SEQ ID NO: 3)

(4) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKA(SEQ ID NO: 4)

(5) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKE(SEQ ID NO: 5)

(6) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAA(SEQ ID NO: 6)

(7) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAC(SEQ ID NO: 7)

(8) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAD(SEQ ID NO: 8)

(9) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAE(SEQ ID NO: 9)

(10) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAF(SEQ ID NO: 10)

(11) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAG(SEQ ID NO: 11)

(12) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAH(SEQ ID NO: 12)

(13) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAI(SEQ ID NO: 13)

(14) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAK(SEQ ID NO: 14)

(15) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAL(SEQ ID NO: 15)

(16) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAM(SEQ ID NO: 16)

(17) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAN(SEQ ID NO: 17)

(18) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAP(SEQ ID NO: 18)

(19) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAQ(SEQ ID NO: 19)

(20) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAR(SEQ ID NO: 20)

(21) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAS(SEQ ID NO: 21)

(22) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAT(SEQ ID NO: 22)

(23) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAV(SEQ ID NO: 23)

(24) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAW(SEQ ID NO: 24)

(25) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSAY(SEQ ID NO: 25)

(26) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCA(SEQ ID NO: 26)

(27) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCC(SEQ ID NO: 27)

(28) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCD(SEQ ID NO: 28)

(29) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCE(SEQ ID NO: 29)

(30) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCF(SEQ ID NO: 30)

(31) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCG(SEQ ID NO: 31)

(32) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCH(SEQ ID NO: 32)

(33) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCI(SEQ ID NO: 33)

(34) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCK(SEQ ID NO: 34)

(35) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCL(SEQ ID NO: 35)

(36) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCM(SEQ ID NO: 36)

(37) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCN(SEQ ID NO: 37)

(38) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCP(SEQ ID NO: 38)

(39) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCQ(SEQ ID NO: 39)

(40) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCR(SEQ ID NO: 40)

(41) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCS(SEQ ID NO: 41)

(42) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCT(SEQ ID NO: 42)

(43) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCV(SEQ ID NO: 43)

(44) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCW(SEQ ID NO: 44)

(45) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSCY(SEQ ID NO: 45)

(46) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDA(SEQ ID NO: 46)

(47) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDC(SEQ ID NO: 47)

(48) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDD(SEQ ID NO: 48)

(49) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDE(SEQ ID NO: 49)

(50) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDF(SEQ ID NO: 50)

(51) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDG(SEQ ID NO: 51)

(52) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDH(SEQ ID NO: 52)

(53) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDI(SEQ ID NO: 53)

(54) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDK(SEQ ID NO: 54)

(55) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDL(SEQ ID NO: 55)

(56) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDM(SEQ ID NO: 56)

(57) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDN(SEQ ID NO: 57)

(58) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDP(SEQ ID NO: 58)

(59) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDQ(SEQ ID NO: 59)

(60) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDR(SEQ ID NO: 60)

(61) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDS(SEQ ID NO: 61)

(62) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDT(SEQ ID NO: 62)

(63) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDV(SEQ ID NO: 63)

(64) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDW(SEQ ID NO: 64)

(65) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSDY(SEQ ID NO: 65)

(66) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSEA(SEQ ID NO: 66)

(67) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSEC(SEQ ID NO: 67)

(68) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSED(SEQ ID NO: 68)

(69) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSEE(SEQ ID NO: 69)

(70) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSEF(SEQ ID NO: 70)

(71) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSEG(SEQ ID NO: 71)

(72) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSEH(SEQ ID NO: 72)

(73) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSEI(SEQ ID NO: 73)

(74) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSEK(SEQ ID NO: 74)

(75) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSEL(SEQ ID NO: 75)

(76) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSEM(SEQ ID NO: 76)

(77) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSEN(SEQ ID NO: 77)

(78) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSEP(SEQ ID NO: 78)

(79) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSEQ(SEQ ID NO: 79)

(80) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSER(SEQ ID NO: 80)

(81) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSES(SEQ ID NO: 81)

(82) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSET(SEQ ID NO: 82)

(83) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSEV(SEQ ID NO: 83)

(84) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSEW(SEQ ID NO: 84)

(85) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSEY(SEQ ID NO: 85)

(86) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFA(SEQ ID NO: 86)

(87) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFC(SEQ ID NO: 87)

(88) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFD(SEQ ID NO: 88)

(89) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFE(SEQ ID NO: 89)

(90) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFF(SEQ ID NO: 90)

(91) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFG(SEQ ID NO: 91)

(92) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFH(SEQ ID NO: 92)

(93) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFI(SEQ ID NO: 93)

(94) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFK(SEQ ID NO: 94)

(95) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFL(SEQ ID NO: 95)

(96) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFM(SEQ ID NO: 96)

(97) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFN(SEQ ID NO: 97)

(98) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFP(SEQ ID NO: 98)

(99) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFQ(SEQ ID NO: 99)

(100) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFR(SEQ ID NO: 100)

(101) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFS(SEQ ID NO: 101)

(102) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFT(SEQ ID NO: 102)

(103) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFV(SEQ ID NO: 103)

(104) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFW(SEQ ID NO: 104)

(105) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSFY(SEQ ID NO: 105)

(106) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGA(SEQ ID NO: 106)

(107) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGC(SEQ ID NO: 107)

(108) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGD(SEQ ID NO: 108)

(109) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGE(SEQ ID NO: 109)

(110) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGF(SEQ ID NO: 110)

(111) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGG(SEQ ID NO: 111)

(112) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGH(SEQ ID NO: 112)

(113) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGI(SEQ ID NO: 113)

(114) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGK(SEQ ID NO: 114)

(115) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGL(SEQ ID NO: 115)

(116) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGM(SEQ ID NO: 116)

(117) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGN(SEQ ID NO: 117)

(118) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGP(SEQ ID NO: 118)

(119) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGQ(SEQ ID NO: 119)

(120) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGR(SEQ ID NO: 120)

(121) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGS(SEQ ID NO: 121)

(122) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGT(SEQ ID NO: 122)

(123) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGV(SEQ ID NO: 123)

(124) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGW(SEQ ID NO: 124)

(125) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSGY(SEQ ID NO: 125)

(126) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHA(SEQ ID NO: 126)

(127) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHC(SEQ ID NO: 127)

(128) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHD(SEQ ID NO: 128)

(129) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHE(SEQ ID NO: 129)

(130) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHF(SEQ ID NO: 130)

(131) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHG(SEQ ID NO: 131)

(132) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHH(SEQ ID NO: 132)

(133) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHI(SEQ ID NO: 133)

(134) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHK(SEQ ID NO: 134)

(135) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHL(SEQ ID NO: 135)

(136) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHM(SEQ ID NO: 136)

(137) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHN(SEQ ID NO: 137)

(138) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHP(SEQ ID NO: 138)

(139) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHQ(SEQ ID NO: 139)

(140) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHR(SEQ ID NO: 140)

(141) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHS(SEQ ID NO: 141)

(142) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHT(SEQ ID NO: 142)

(143) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHV(SEQ ID NO: 143)

(144) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHW(SEQ ID NO: 144)

(145) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSHY(SEQ ID NO: 145)

(146) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSIA(SEQ ID NO: 146)

(147) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSIC(SEQ ID NO: 147)

(148) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSID(SEQ ID NO: 148)

(149) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSIE(SEQ ID NO: 149)

(150) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSIF(SEQ ID NO: 150)

(151) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSIG(SEQ ID NO: 151)

(152) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSIH(SEQ ID NO: 152)

(153) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSII(SEQ ID NO: 153)

(154) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSIK(SEQ ID NO: 154)

(155) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSIL(SEQ ID NO: 155)

(156) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSIM(SEQ ID NO: 156)

(157) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSIN(SEQ ID NO: 157)

(158) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSIP(SEQ ID NO: 158)

(159) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSIQ(SEQ ID NO: 159)

(160) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSIR(SEQ ID NO: 160)

(161) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSIS(SEQ ID NO: 161)

(162) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSIT(SEQ ID NO: 162)

(163) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSIV(SEQ ID NO: 163)

(164) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSIW(SEQ ID NO: 164)

(165) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSIY(SEQ ID NO: 165)

(166) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKC(SEQ ID NO: 166)

(167) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKD(SEQ ID NO: 167)

(168) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKF(SEQ ID NO: 168)

(169) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKG(SEQ ID NO: 169)

(170) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKH(SEQ ID NO: 170)

(171) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKI(SEQ ID NO: 171)

(172) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKL(SEQ ID NO: 172)

(173) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKM(SEQ ID NO: 173)

(174) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKN(SEQ ID NO: 174)

(175) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKQ(SEQ ID NO: 175)

(176) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKR(SEQ ID NO: 176)

(177) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKS(SEQ ID NO: 177)

(178) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKT(SEQ ID NO: 178)

(179) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKV(SEQ ID NO: 179)

(180) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKW(SEQ ID NO: 180)

(181) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKY(SEQ ID NO: 181)

(182) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLA(SEQ ID NO: 182)

(183) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLC(SEQ ID NO: 183)

(184) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLD(SEQ ID NO: 184)

(185) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLE(SEQ ID NO: 185)

(186) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLF(SEQ ID NO: 186)

(187) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLG(SEQ ID NO: 187)

(188) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLH(SEQ ID NO: 188)

(189) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLI(SEQ ID NO: 189)

(190) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLK(SEQ ID NO: 190)

(191) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLL(SEQ ID NO: 191)

(192) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLM(SEQ ID NO: 192)

(193) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLN(SEQ ID NO: 193)

(194) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLP(SEQ ID NO: 194)

(195) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLQ(SEQ ID NO: 195)

(196) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLR(SEQ ID NO: 196)

(197) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLS(SEQ ID NO: 197)

(198) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLT(SEQ ID NO: 198)

(199) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLV(SEQ ID NO: 199)

(200) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLW(SEQ ID NO: 200)

(201) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSLY(SEQ ID NO: 201)

(202) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSMA(SEQ ID NO: 202)

(203) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSMC(SEQ ID NO: 203)

(204) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSMD(SEQ ID NO: 204)

(205) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSME(SEQ ID NO: 205)

(206) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSMF(SEQ ID NO: 206)

(207) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSMG(SEQ ID NO: 207)

(208) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSMH(SEQ ID NO: 208)

(209) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSMI(SEQ ID NO: 209)

(210) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSMK(SEQ ID NO: 210)

(211) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSML(SEQ ID NO: 211)

(212) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSMM(SEQ ID NO: 212)

(213) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSMN(SEQ ID NO: 213)

(214) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSMP(SEQ ID NO: 214)

(215) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSMQ(SEQ ID NO: 215)

(216) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSMR(SEQ ID NO: 216)

(217) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSMS(SEQ ID NO: 217)

(218) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSMT(SEQ ID NO: 218)

(219) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSMV(SEQ ID NO: 219)

(220) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSMW(SEQ ID NO: 220)

(221) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSMY(SEQ ID NO: 221)

(222) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNA(SEQ ID NO: 222)

(223) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNC(SEQ ID NO: 223)

(224) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSND(SEQ ID NO: 224)

(225) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNE(SEQ ID NO: 225)

(226) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNF(SEQ ID NO: 226)

(227) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNG(SEQ ID NO: 227)

(228) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNH(SEQ ID NO: 228)

(229) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNI(SEQ ID NO: 229)

(230) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNK(SEQ ID NO: 230)

(231) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNL(SEQ ID NO: 231)

(232) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNM(SEQ ID NO: 232)

(233) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNN(SEQ ID NO: 233)

(234) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNP(SEQ ID NO: 234)

(235) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNQ(SEQ ID NO: 235)

(236) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNR(SEQ ID NO: 236)

(237) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNS(SEQ ID NO: 237)

(238) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNT(SEQ ID NO: 238)

(239) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNV(SEQ ID NO: 239)

(240) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNW(SEQ ID NO: 240)

(241) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSNY(SEQ ID NO: 241)

(242) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPA(SEQ ID NO: 242)

(243) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPC(SEQ ID NO: 243)

(244) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPD(SEQ ID NO: 244)

(245) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPE(SEQ ID NO: 245)

(246) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPF(SEQ ID NO: 246)

(247) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPG(SEQ ID NO: 247)

(248) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPH(SEQ ID NO: 248)

(249) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPI(SEQ ID NO: 249)

(250) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPL(SEQ ID NO: 250)

(251) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPM(SEQ ID NO: 251)

(252) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPN(SEQ ID NO: 252)

(253) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPQ(SEQ ID NO: 253)

(254) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPR(SEQ ID NO: 254)

(255) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPS(SEQ ID NO: 255)

(256) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPT(SEQ ID NO: 256)

(257) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPV(SEQ ID NO: 257)

(258) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPW(SEQ ID NO: 258)

(259) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPY(SEQ ID NO: 259)

(260) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQA(SEQ ID NO: 260)

(261) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQC(SEQ ID NO: 261)

(262) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQD(SEQ ID NO: 262)

(263) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQE(SEQ ID NO: 263)

(264) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQF(SEQ ID NO: 264)

(265) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQG(SEQ ID NO: 265)

(266) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQH(SEQ ID NO: 266)

(267) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQI(SEQ ID NO: 267)

(268) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQK(SEQ ID NO: 268)

(269) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQL(SEQ ID NO: 269)

(270) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQM(SEQ ID NO: 270)

(271) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQN(SEQ ID NO: 271)

(272) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQP(SEQ ID NO: 272)

(273) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQQ(SEQ ID NO: 273)

(274) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQR(SEQ ID NO: 274)

(275) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQS(SEQ ID NO: 275)

(276) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQT(SEQ ID NO: 276)

(277) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQV(SEQ ID NO: 277)

(278) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQW(SEQ ID NO: 278)

(279) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSQY(SEQ ID NO: 279)

(280) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRA(SEQ ID NO: 280)

(281) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRC(SEQ ID NO: 281)

(282) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRD(SEQ ID NO: 282)

(283) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRE(SEQ ID NO: 283)

(284) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRF(SEQ ID NO: 284)

(285) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRG(SEQ ID NO: 285)

(286) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRH(SEQ ID NO: 286)

(287) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRI(SEQ ID NO: 287)

(288) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRK(SEQ ID NO: 288)

(289) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRL(SEQ ID NO: 289)

(290) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRM(SEQ ID NO: 290)

(291) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRN(SEQ ID NO: 291)

(292) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRP(SEQ ID NO: 292)

(293) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRQ(SEQ ID NO: 293)

(294) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRR(SEQ ID NO: 294)

(295) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRS(SEQ ID NO: 295)

(296) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRT(SEQ ID NO: 296)

(297) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRV(SEQ ID NO: 297)

(298) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRW(SEQ ID NO: 298)

(299) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSRY(SEQ ID NO: 299)

(300) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSA(SEQ ID NO: 300)

(301) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSC(SEQ ID NO: 301)

(302) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSD(SEQ ID NO: 302)

(303) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSE(SEQ ID NO: 303)

(304) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSF(SEQ ID NO: 304)

(305) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSG(SEQ ID NO: 305)

(306) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSH(SEQ ID NO: 306)

(307) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSI(SEQ ID NO: 307)

(308) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSK(SEQ ID NO: 308)

(309) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSL(SEQ ID NO: 309)

(310) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSM(SEQ ID NO: 310)

(311) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSN(SEQ ID NO: 311)

(312) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSP(SEQ ID NO: 312)

(313) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSQ(SEQ ID NO: 313)

(314) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSR(SEQ ID NO: 314)

(315) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSS(SEQ ID NO: 315)

(316) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSST(SEQ ID NO: 316)

(317) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSV(SEQ ID NO: 317)

(318) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSW(SEQ ID NO: 318)

(319) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSSY(SEQ ID NO: 319)

(320) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTA(SEQ ID NO: 320)

(321) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTC(SEQ ID NO: 321)

(322) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTD(SEQ ID NO: 322)

(323) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTE(SEQ ID NO: 323)

(324) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTF(SEQ ID NO: 324)

(325) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTG(SEQ ID NO: 325)

(326) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTH(SEQ ID NO: 326)

(327) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTI(SEQ ID NO: 327)

(328) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTK(SEQ ID NO: 328)

(329) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTL(SEQ ID NO: 329)

(330) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTM(SEQ ID NO: 330)

(331) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTN(SEQ ID NO: 331)

(332) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTP(SEQ ID NO: 332)

(333) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTQ(SEQ ID NO: 333)

(334) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTR(SEQ ID NO: 334)

(335) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTS(SEQ ID NO: 335)

(336) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTT(SEQ ID NO: 336)

(337) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTV(SEQ ID NO: 337)

(338) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTW(SEQ ID NO: 338)

(339) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSTY(SEQ ID NO: 339)

(340) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVA(SEQ ID NO: 340)

(341) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVC(SEQ ID NO: 341)

(342) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVD(SEQ ID NO: 342)

(343) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVE(SEQ ID NO: 343)

(344) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVF(SEQ ID NO: 344)

(345) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVG(SEQ ID NO: 345)

(346) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVH(SEQ ID NO: 346)

(347) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVI(SEQ ID NO: 347)

(348) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVK(SEQ ID NO: 348)

(349) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVL(SEQ ID NO: 349)

(350) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVM(SEQ ID NO: 350)

(351) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVN(SEQ ID NO: 351)

(352) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVP(SEQ ID NO: 352)

(353) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVQ(SEQ ID NO: 353)

(354) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVR(SEQ ID NO: 354)

(355) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVS(SEQ ID NO: 355)

(356) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVT(SEQ ID NO: 356)

(357) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVV(SEQ ID NO: 357)

(358) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVW(SEQ ID NO: 358)

(359) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSVY(SEQ ID NO: 359)

(360) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWA(SEQ ID NO: 360)

(361) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWC(SEQ ID NO: 361)

(362) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWD(SEQ ID NO: 362)

(363) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWE(SEQ ID NO: 363)

(364) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWF(SEQ ID NO: 364)

(365) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWG(SEQ ID NO: 365)

(366) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWH(SEQ ID NO: 366)

(367) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWI(SEQ ID NO: 367)

(368) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWK(SEQ ID NO: 368)

(369) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWL(SEQ ID NO: 369)

(370) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWM(SEQ ID NO: 370)

(371) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWN(SEQ ID NO: 371)

(372) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWP(SEQ ID NO: 372)

(373) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWQ(SEQ ID NO: 373)

(374) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWR(SEQ ID NO: 374)

(375) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWS(SEQ ID NO: 375)

(376) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWT(SEQ ID NO: 376)

(377) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWV(SEQ ID NO: 377)

(378) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWW(SEQ ID NO: 378)

(379) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSWY(SEQ ID NO: 379)

(380) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYA(SEQ ID NO: 380)

(381) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYC(SEQ ID NO: 381)

(382) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYD(SEQ ID NO: 382)

(383) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYE(SEQ ID NO: 383)

(384) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYF(SEQ ID NO: 384)

(385) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYG(SEQ ID NO: 385)

(386) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYH(SEQ ID NO: 386)

(387) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYI(SEQ ID NO: 387)

(388) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYK(SEQ ID NO: 388)

(389) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYL(SEQ ID NO: 389)

(390) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYM(SEQ ID NO: 390)

(391) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYN(SEQ ID NO: 391)

(392) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYP(SEQ ID NO: 392)

(393) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYQ(SEQ ID NO: 393)

(394) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYR(SEQ ID NO: 394)

(395) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYS(SEQ ID NO: 395)

(396) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYT(SEQ ID NO: 396)

(397) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYV(SEQ ID NO: 397)

(398) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYW(SEQ ID NO: 398)

(399) MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSYY(SEQ ID NO: 399)

(400) GKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSPP(SEQ ID NO: 403)

As the peptide of the present invention, there are also included: further, the peptide is obtained by substituting the amino acid at the 43 rd position and/or the 44 th position of the peptide described in SEQ ID NO. 1 to 399 with an unnatural amino acid, or the peptide is obtained by substituting the amino acid at the 42 th position and/or the 43 th position of the peptide described in SEQ ID NO. 403 with an unnatural amino acid.

The peptide of the present invention may be a peptide having a conservative substitution of an amino acid in a peptide having any one of the amino acid sequences shown in SEQ ID Nos. 1 to 5. Conservative substitutions are those substitutions that are substituted with other amino acids that have a structure or properties that are chemically similar to the original amino acid, without substantially altering the function of the peptide. Examples of conservative substitutions are: the mutual substitution between aspartic acid and glutamic acid as acidic amino acids, the mutual substitution between lysine, arginine and histidine as basic amino acids, the mutual substitution between serine, threonine, asparagine and glutamine as hydrophilic amino acids, and the like. For example, the peptide of SEQ ID NO: 167 is a peptide obtained by substituting glutamic acid (E) at position 44 of the peptide of SEQ ID NO: 5 with aspartic acid (D), and is considered to have the same function as the peptide of SEQ ID NO: 5. The peptides represented by SEQ ID Nos. 126, 128, 129, 138, 248, 254, 280, 282, 283 and 292 are peptides having conservative substitutions of amino acids in the peptides having any one of the amino acid sequences represented by SEQ ID Nos. 1 to 5, and are considered to have equivalent functions to any one of the peptides represented by SEQ ID Nos. 1 to 5. In one embodiment, the peptide of the present invention has an amino acid sequence of any one of SEQ ID Nos. 1 to 5, 126, 128, 129, 138, 167, 248, 254, 280, 282, 283, 292, and 403. From the viewpoint of being expected to have the above functions more reliably, in a more preferred embodiment, the peptide of the present invention has any one of the amino acid sequences shown in SEQ ID NOS 1 to 5, 167 and 403, and in a further preferred embodiment, the peptide of the present invention has any one of the amino acid sequences shown in SEQ ID NOS 1 to 5 and 403.

Accordingly, a preferred embodiment of the peptide defined in the above (a) is a peptide having any one of the amino acid sequences shown in SEQ ID NOS 1 to 5, 126, 128, 129, 138, 167, 248, 254, 280, 282, 283, 292 and 403, a more preferred embodiment is a peptide having any one of the amino acid sequences shown in SEQ ID NOS 1 to 5, 167 and 403, and a further preferred embodiment is a peptide having any one of the amino acid sequences shown in SEQ ID NOS 1 to 5 and 403.

Further, a preferable embodiment of the peptide defined in the above (b) is: a peptide having an amino acid sequence in which 1 or more (for example, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 5, or 4, 3, or 2) amino acids are added to a peptide having any one of the amino acid sequences shown in SEQ ID NOs 1 to 5, 126, 128, 129, 138, 167, 248, 254, 280, 282, 283, 292, and 403, and having an activity of stimulating cell migration, and a more preferred embodiment is: a peptide having an amino acid sequence in which 1 or more (for example, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 5, or 4, 3, or 2) amino acids are added to a peptide having any one of the amino acid sequences shown in SEQ ID NOS 1 to 5, 167, and 403, and having an activity of stimulating cell migration, and a more preferred embodiment is: the peptide having any one of the amino acid sequences shown in SEQ ID NOS: 1 to 5 and 403, which is composed of an amino acid sequence obtained by adding 1 or more (for example, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 5, or 4, 3, or 2) amino acids, and has an activity of stimulating cell migration.

Further, a preferable embodiment of the peptide defined in the above (c) is: an amino acid sequence comprising or consisting of 1 or more (for example, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 5, or 4, 3, or 2) amino acids substituted, deleted, or inserted into 1 to 42 amino acids of a peptide having any one of the amino acid sequences shown in SEQ ID Nos. 1 to 5, 126, 128, 129, 138 and 167, 248, 254, 280, 282, 283, and 292 or 1 to 41 amino acids of a peptide having the amino acid sequence shown in SEQ ID No. 403, and having an activity of stimulating cell migration, and more preferably: an amino acid sequence comprising 1 or more (for example, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 5, or 4, 3, or 2) amino acids substituted, deleted, or inserted into the amino acids at positions 1 to 42 of a peptide having any one of the amino acid sequences shown in SEQ ID NOs.1 to 5 and 167 or the amino acids at positions 1 to 41 of a peptide having the amino acid sequence shown in SEQ ID NOs.403, or a peptide comprising the amino acid sequence and having an activity of stimulating cell migration, and more preferably: comprises an amino acid sequence obtained by substituting, deleting or inserting 1 or more (for example, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 5, or 4, 3 or 2) amino acids in the amino acids at the 1 st to 42 th positions of a peptide having any one of the amino acid sequences of SEQ ID NOs 1 to 5 or in the amino acids at the 1 st to 41 th positions of a peptide having the amino acid sequence of SEQ ID NOs 403, or a peptide comprising the amino acid sequence and having an activity of stimulating cell migration.

The "derivative" of the peptide of the present invention means a peptide having substantially the same biological function or activity as the peptide of the present invention, that is, an activity of stimulating cell migration. The C-terminal of the peptide derivative may be any of a carboxyl group, a carboxylate (カルボキシレート), an amide, or an ester. Examples thereof include: modified peptides obtained by adding a modifying group, mutant peptides obtained by modifying an amino acid residue, and the like.

Examples of the modifying group include: fluorescent functional groups, functional groups that do not participate in the formation of the steric structure of the peptide, and the like. Furthermore, the peptide of the present invention may be derived from an amino acid other than the amino acid residues constituting the peptide of the present invention (for example, natural amino acid residuesβ-alanine, etc.). Examples of the fluorescent functional group include eosin and Fluorescein Isothiocyanate (FITC). As steric junctions not participating in peptidesThe functional groups formed in the form of a structure may be enumerated byβA spacer represented by an alanine residue or the like, and the like. The functional group is preferably present at the end. Also, "derivatives" include peptides modified with polyethylene glycol (PEG).

As "pharmaceutically acceptable salts" of the peptides of the present invention, physiologically acceptable salts with acids or bases can be cited, and acid addition salts are particularly preferred. As such salts, for example, there can be used: salts with inorganic acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.; or salts with organic acids such as acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, and the like.

The "solvate" of the peptide of the present invention or the salt includes a solvate in which an arbitrary number of solvent molecules are coordinated to the peptide of the present invention, and is preferably a hydrate.

The present invention provides the above-mentioned peptide. In the synthesis of the peptide of the present invention, the chemical synthesis of the peptide may be carried out by either a peptide liquid phase synthesis method or a peptide solid phase synthesis method. In the present invention, a peptide synthesized by a peptide solid phase synthesis method is preferred. The solid-phase peptide synthesis method is one of the methods generally used for chemical synthesis of peptides, and can be carried out, for example, as follows: beads of polystyrene polymer gel having a diameter of about 0.1mm, the surfaces of which have been modified with amino groups, or the like are used as a solid phase, and from here, amino acid chains are extended one by a dehydration reaction. Once the sequence of the target peptide is completed, it is cleaved from the solid phase surface to obtain the target substance.

It is also possible to carry out, by solid-phase synthesis: the synthesis of ribosomal peptides, which are difficult to synthesize in bacteria, the introduction of unnatural amino acids such as D-type or heavy atom substitutions, and the modification of peptide and protein backbones. When 70 to more than 100 long peptide chains are synthesized by the solid phase method, the synthesis can be performed by binding 2 peptide chains by a native chemical ligation method.

The administration method of the composition of the present invention includes oral administration or parenteral administration, and specific examples of the parenteral administration include injection administration, nasal administration, pulmonary administration, transdermal administration, and the like, but the present invention is not limited thereto. Examples of the injection administration include systemic or local administration (for example, subcutaneous, intradermal, skin surface, eyeball or eyelid conjunctiva, nasal mucosa, oral and digestive tract mucosa, vaginal/intrauterine mucosa, or lesion site) of the composition of the present invention by intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, or the like.

Examples of administration methods of the composition of the present invention include, but are not limited to, intravascular administration (e.g., intra-arterial administration, intravenous administration), intravascular administration, intramuscular administration, subcutaneous administration, intradermal administration, and intraperitoneal administration.

The administration site is not limited, and examples thereof include: a tissue in or near a site in need of regeneration, a site different from a tissue in need of regeneration, or a site remote and different from a tissue in need of regeneration. Examples thereof include: blood (intra-arterial, intravenous, etc.), muscle, subcutaneous, intradermal, intraperitoneal, but not limited to these.

In addition, an appropriate administration method can be selected according to the age and symptoms of the patient. In the case of administering the peptide of the present invention, the amount of administration can be selected, for example, in the range of 0.0000001mg to 1000mg/kg body weight per administration. Alternatively, for example, the administration amount may be selected in the range of 0.00001 to 100000mg per patient. When cells secreting the peptide of the present invention or a vector for gene therapy into which a DNA encoding the peptide is inserted are administered, the administration is performed so that the amount of the peptide falls within the above range. However, the pharmaceutical composition of the present invention is not limited by these administration amounts.

The Pharmaceutical composition of the present invention can be prepared into preparations according to conventional methods (e.g., Remington's Pharmaceutical Science, latest edition, Mark Publishing Company, Easton, U.S. A), and may contain pharmaceutically acceptable carriers or additives. Examples thereof include: surfactants, excipients, colorants, flavors, preservatives, stabilizers, buffers, suspending agents, isotonic agents, binders, disintegrating agents, lubricants, fluidity enhancers, flavoring agents, and the like, but are not limited thereto, and other conventional carriers may be suitably used. Specifically, there may be mentioned: light silicic anhydride, lactose, crystalline cellulose, mannitol, starch, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, gelatin, medium-chain fatty acid triglyceride, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethylcellulose, corn starch, inorganic salts, and the like.

All prior art documents cited in the present specification are incorporated herein by reference.

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Peptides for inducing tissue regeneration and uses thereof

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