Fibroblast growth factor mimetic peptides and uses thereof

Abstract

The present invention relates to a peptide specifically activating signal transduction by targeting fibroblast growth factor receptor (FGFR), an FGFR agonist comprising the peptide, a pharmaceutical composition for preventing or treating diseases associated with decreased FGFR activity, and a cosmetic composition. An FAP1 peptide according to the present invention is a potent FGFR-activating peptide, which exhibited an effective concentration similar to that of bFGF protein, and showed the ability to promote wound healing and support tissue remodeling in vivo. Considering specificity to FGFR and the ability to promote wound healing , FAP1 can be used as a cost-effective alternative to the bFGF protein in therapeutic fields.

Description

Fibroblast growth factor-like peptide and uses thereof

[0001] The present invention relates to a peptide that induces cell proliferation of fibroblasts and activates FGFR and its downstream signaling pathways, and more specifically, to a peptide that specifically activates signaling by targeting FGFR (fibroblast growth factor receptor), an FGFR agonist comprising said peptide, and pharmaceutical and cosmetic compositions for the prevention or treatment of diseases related to reduced FGFR activity.

[0002]

[0003] Fibroblast growth factor (FGF) plays a central role as a pluripotent mitogen that regulates various cellular processes, such as migration, proliferation, differentiation, and survival, as well as developmental processes, metabolic regulation, and the maintenance of tissue homeostasis (KD Sluzalska, et al., Cytokine Growth Factor Rev 57 (2021) 93-111). Within the FGF family, 22 members transmit signals through four types of FGF receptors (FGFRs) (N. Su, et al., Bone Research 2014 2:1 2 (2014) 1-24). In particular, FGF2, also known as basic FGF (bFGF), exhibits binding affinity for all four FGFRs, but its affinity for each receptor varies (L. Pellegrini, et al., Nature 2000 407:6807 407 (2000) 1029-1034). In the absence of ligands, the inactive form of FGFR kinase is allosterically inhibited by hinge domains and activation loops. However, upon exposure to extracellular ligands, FGFRs undergo autophosphorylation and dimerization, initiating several signaling pathways, including the phospholipase C-γ (PLCγ), PI3K-AKT, and RAS-MAPK cascades (M. Katoh, Nature Reviews Clinical Oncology 2018 16:2 16 (2018) 105-122).

[0004] FGF plays a key role in the complex processes of wound healing and tissue regeneration. When bFGF was applied to a mouse wound healing model, the epithelial-mesenchymal transition was activated, leading to rapid improvement in wound closure. Furthermore, FGF promotes the migration of keratinocytes to the center of the wound, thereby facilitating the development of thick, multilayered epithelium (Y. Koike, et al., Scientific Reports 2020 10:1 10 (2020) 1-13). In an excision wound healing model, the application of bFGF and FGF-7, facilitated by the collagen membrane, resulted in increased angiogenesis and improved epithelial regeneration. Moreover, in a mouse model of bleomycin-induced lung injury, FGF was found to be an important factor in promoting epithelial healing and maintaining its structural integrity.

[0005] FGF has shown potential therapeutic benefits in diabetic foot ulcers, which are chronic wounds that often fail to heal properly due to impaired healing mechanisms (Y. Liu, et al., Front Endocrinol (Lausanne) 12 (2021)). Studies have shown that FGF can induce angiogenesis, a process essential for supplying necessary nutrients and oxygen to the wound site. Furthermore, FGF plays a crucial role in tissue healing by promoting the proliferation and migration of fibroblasts, which produce collagen and other extracellular matrix components. The potential healing mechanisms of FGF in diabetic foot ulcers are summarized as enhanced angiogenesis, improved fibroblast activity, and reduced inflammation (FA Voza, et al., International Journal of Molecular Sciences 2024, Vol. 25, Page 2172 25 (2024) 2172).

[0006] In one embodiment of the present invention, a novel peptide FAP1 (FGFR-agonistic peptide 1) having FGFR agonistic properties was identified and its biological effects were analyzed. Among the three peptides screened, FAP1 was selected as the optimal candidate because it exhibited superior activity. In vitro tests showed that FAP1 specifically activates FGFR and its downstream signaling pathways. Furthermore, its efficacy was demonstrated through in vivo diabetic wound healing experiments. Overall, this suggests that FAP1 is an FGFR-specific peptide and can be a cost-effective alternative to bFGF.

[0007]

[0008] The information described above in the background section is intended solely to enhance understanding of the background of the present invention and may not include information that constitutes prior art already known to those skilled in the art to which the present invention belongs.

[0009]

[0010] Summary of the Invention

[0011] The objective of the present invention is to provide a peptide having the function of activating the FGFR signaling pathway.

[0012] Another objective of the present invention is to provide an FGFR agonist comprising the above peptide.

[0013] Another objective of the present invention is to provide a pharmaceutical composition for the prevention or treatment of diseases related to reduced FGFR activity comprising the above peptide.

[0014] Another objective of the present invention is to provide a method for preventing or treating diseases related to reduced FGFR activity using the peptide, the use of the peptide for preventing or treating diseases related to reduced FGFR activity, and the use of the peptide for manufacturing a drug for preventing or treating diseases related to reduced FGFR activity.

[0015] Another objective of the present invention is to provide a functional cosmetic composition for improving diseases related to reduced FGFR activity, comprising the above peptide.

[0016]

[0017] To achieve the above objective, the present invention provides a peptide represented by the amino acid sequence of SEQ ID NO. 1 or SEQ ID NO. 2.

[0018] The present invention also provides an FGFR agonist comprising the above peptide.

[0019] The present invention also provides a pharmaceutical composition for the prevention or treatment of diseases related to reduced FGFR activity, comprising the peptide.

[0020] The present invention also provides a method for preventing or treating diseases related to reduced FGFR activity, comprising the step of administering the peptide.

[0021] The present invention also provides a use of the peptide for the prevention or treatment of diseases related to reduced FGFR activity.

[0022] The present invention also provides the use of the peptide for the manufacture of a drug for the prevention or treatment of diseases related to reduced FGFR activity.

[0023] The present invention also provides a functional cosmetic composition for improving diseases related to reduced FGFR activity, comprising the above peptide.

[0024]

[0025] Figure 1 illustrates the computer-based design and molecular interactions of FGF-functional peptides. (A) Crystal structure of the FGFR-ligand complex highlighting the targeted region for peptide design. (B) Molecular interaction diagram between the FAP1 peptide and the receptor. (C) Structural representation of the canofin 1 peptide bound to FGFR, highlighting key interacting residues. (D) Molecular interaction diagram between the modified canofin peptide and FGFR.

[0026] Figure 2 illustrates the selection of the optimal FGFR-activating peptide. (A) Cell viability analysis (MTT assay) of mouse fibroblasts treated with candidate peptides at the listed concentrations. (B) SPR analysis for each peptide at a concentration of 100 μg / ml. Sensorgram data represent binding interactions between different peptides and FGFR1 protein. (C) Wound healing effect of the peptides on mouse fibroblasts. (D) Calculation of wound area attributable to the healing effect of the peptides. (E) LD10 calculated by evaluating FAP1-induced apoptosis. 50 (F) Effects of FAP1 on FGFR1 activation in MCF7 cells and EC using GraphPad Prism 50 Calculation. Each experiment was repeated at least 3 times (N = 3), and results are expressed as mean ± SD. *p < 0.033, **p < 0.01, ***p < 0.001.

[0027] Figure 3 illustrates the effects of the FAP1 peptide on cell proliferation and downstream signaling. The cell proliferation effects of FAP1 on NIH-3T3 cells and HDF cells were evaluated by MTT assay (A, B) and trypan blue assay (C, D; live / dead staining). (E) Effects of the FAP1 peptide on p-AKT and p-GSK3β in NIH-3T3 cells. (F) Western blot analysis results on the effects of FAP1 on MAP kinase and p-AKT in HDF cells, with a bFGF concentration of 10 ng / ml. (G) Effects of FAP1 on FGFR activation in the presence of bFGF. (H) SPR analysis on the dose-dependent effects of the FAP1 peptide. Each experiment was repeated at least three times (N = 3), and results are expressed as mean ± SD. *p < 0.033, **p < 0.01, ***p < 0.001.

[0028] Figure 4 illustrates the inhibition of erdafitinib of FAP1-induced agonistic effects. (A) Effect of FAP1 on cell signaling pathways in the presence of erdafitinib (ERD, 50 nM). (BE) Quantification was performed using ImageJ. Each experiment was repeated at least three times (N = 3), and results are expressed as mean ± SD. *p < 0.033, **p < 0.01, ***p < 0.001.

[0029] Figure 5 illustrates the cell migration effect of the FAP1 peptide. (A) Analysis of scratch wounds using NIH-3T3 cells and (C) HDF cells. Images were captured at 0 and 24 hours, analyzed using ImageJ software, and used to calculate the wound closure rate. (B) Wound closure rate in NIH-3T3 cells. (D) Wound closure rate in HDF cells. (E) Cell migration effect of FAP1 in the presence of erdafitinib (50 nM). (F) Wound area calculation using ImageJ software. Each experiment was repeated at least 3 times (N = 3), and results are expressed as mean ± SD. *p < 0.033, **p < 0.01, ***p < 0.001.

[0030] Fig. 6. (A) Experimental plan for wound healing in diabetic mice (N = 5 / group). (B) Camera image. (C) Wound area percentage profile. The graphs are expressed as mean ± SD, and “*” indicates p < 0.05. (D) H&E staining of the wound site. The first row shows the H&E slide image. Next are magnified images of the newly formed granulation tissue and angiogenesis sites, and the last row is a magnified image of collagen deposition.

[0031]

[0032] Detailed Description of the Invention and Preferred Embodiments

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a skilled expert in the art to which this invention pertains. In general, the nomenclature used herein is well known and commonly used in the art.

[0034]

[0035] Fibroblast growth factor (FGF) is a broad class of secreted compounds that act through the fibroblast growth factor receptor (FGFR). The present invention aimed to identify the role of a novel peptide, FAP1 (FGFR-agonistic peptide 1), in tissue regeneration and recovery, and investigated whether FAP1 promotes wound healing in vitro and in vivo by mimicking basic fibroblast growth factor (bFGF).

[0036] In one embodiment of the present invention, the ability to mimic bFGF was evaluated through various in vitro experiments using a designed novel peptide, including its effects on cell signaling such as cell proliferation, wound healing, FGFR1 phosphorylation, and mitogen-activated protein kinase (MAPK) activation. Specificity was confirmed through surface plasmon resonance (SPR) analysis and combination treatment with the FGFR inhibitor erdafitinib. In an in vivo study, the effects of FAP1 on diabetic wound healing were evaluated in a mouse model, and collagen production and the migration and proliferation of keratinocytes and fibroblasts were analyzed.

[0037] As a result, FAP1 specifically phosphorylated FGFR and activated MAPK, similar to bFGF. In vitro, it induced cell proliferation and promoted wound healing, while in vivo, it improved diabetic wound healing by increasing collagen production and promoting the migration and proliferation of keratinocytes and fibroblasts. The specificity of FAP1 was confirmed through SPR.

[0038]

[0039] FGF is a member of the mitogen family that acts as a broad-spectrum signaling molecule, influencing organ development, tissue regeneration, and wound healing by regulating various cellular processes including survival, proliferation, migration, angiogenesis, and differentiation (Y. Xie, et al., Signal Transduct Target Ther 5 (2020)). Downregulated levels of growth factors, including bFGF, contribute to delayed wound healing. FGF promotes the wound healing process by facilitating epithelial-mesenchymal transition in keratinocytes, increasing angiogenesis, and shortening cell doubling time (A. Gragnani, et al., Burns 48 (2022) 104-110). In this application, the potential of a novel FGFR-activating peptide was identified. Through a comprehensive series of in vitro and in vivo experiments, the efficacy and mechanism of action of the FAP1 peptide were elucidated, providing an important basis for the development of therapeutic agents for diabetic wound management.

[0040] The initial screening process included protein binding and in vitro analysis, through which the most promising and potent FGFR-activating peptides were identified for further study. Subsequent experiments showed that the selected peptides exhibited specific binding to FGFR via SPR analysis and phosphorylated FGFR in cell-based experiments.

[0041] FGF activates several intracellular signaling pathways, including mitogen-activated protein kinase (MAPK), PLCγ, and PI3K pathways. Western blot analysis was performed to determine the effects of FAP1 on downstream signaling pathways, and the results showed that the peptide activated all MAPKs in a dose-dependent manner. Additionally, AKT was also activated in a dose-dependent manner. Phosphorylation of AKT inhibited GSK3β, which remains persistently active from the basal state upon FAP1 treatment. These results support the potential of this peptide as a targeted therapeutic agent for regulating FGFR signaling.

[0042] Various members of the FGF family induce proliferation and migration of various cell types (X. Chen, et al., Front Mol Neurosci 12 (2020)). To evaluate the effects of the peptide on cell proliferation, human and mouse fibroblasts were treated with various concentrations of the peptide. As a result, it was confirmed that the peptide induced fibroblast proliferation in a dose-dependent manner. In addition, the effect of the peptide on cell migration was evaluated through a scratch wound assay. Cells were first treated with mitomycin C, which is known to not only reduce cell proliferative capacity but also have a negative effect on wound healing (N. Chen, et al., Respiration 85 (2013) 500-504). The peptide induced fibroblast migration similarly to bFGF. The dose-dependent induction of cell proliferation and migration highlights the ability of this peptide to promote key cellular processes essential for wound healing. Importantly, the specificity of the peptide for FGFR activation was experimentally confirmed using an FGFR-specific inhibitor. The FGFR-dependent mechanism of action of FAP1 was evaluated using the pan-FGFR inhibitor erdafitinib (X. Zheng, et al., Front Oncol 12 (2023) 907377). Pretreatment with erdafitinib inhibited the effects of FAP1, such as migration and cell signaling, demonstrating that these actions are specifically mediated through FGFR signaling. This inhibition by erdafitinib confirms the specificity of FAP1 for FGFR and enhances its role as an FGFR agonist in the observed biological processes by excluding off-target effects.

[0043] Wound healing is a complex process composed of four major stages: hemostasis, inflammation, proliferation, and remodeling. In diabetic patients, wound healing is impaired or delayed primarily due to hyperglycemia, chronic inflammation, vascular dysfunction, hypoxia, nerve damage regulating autonomic and sensory functions, and impaired neuropeptide signaling (G. Theocharidis, A. Veves, Auton Neurosci 223 (2020)). Various growth factors, including FGF, have long been used for diabetic wound healing (MM Rahman, et al., Acta Biomater 136 (2021) 199-209). Therefore, the peptide according to the present invention was evaluated in vivo in a diabetic wound healing model. By reproducing promising in vitro results in an in vivo environment, the potential clinical significance of this peptide is further enhanced. The FAP1 peptide promoted the wound healing process in diabetic mice. In the absence of the peptide (PBS control group), immature granulation tissue and wound cavities were observed in the H&E staining data, but no artificial deformation of the tissue structure was observed at any of the tested peptide doses (Fig. 6D). This demonstrates that the peptide according to the present invention ensured smooth and proper healing in diabetic mice.

[0044] Angiogenesis is the process by which new capillaries are formed from existing blood vessels and is an important process for embryonic development and wound healing. FGF induces angiogenesis by acting on FGFRs present in endothelial cells and stromal cells (T. Jia, et al., BMC Biol 19 (2021) 1-26). It has been reported that one of the reasons for delayed wound healing in diabetic mice is the reduced pro-angiogenicity of wound healing (UA Okonkwo, et al., PLoS One 15 (2020)). Several studies have also discussed the role of FGF in accelerating diabetic wounds (Y. Zhao, et al., Biomedicine & Pharmacotherapy 132 (2020) 110933). FAP1 peptide increased new blood vessel formation at the wound site (Fig. 5D). FGF stimulates fibroblasts involved in collagen synthesis (M. Abdelhakim, et al., Dermatol Ther (Heidelb) 10 (2020)). Collagen increases the tensile strength of the skin (RB Diller, AJ Tabor, Biomimetics 2022, Vol. 7, Page 87 (2022) 87). FAP1 peptide showed a positive effect on collagen deposition (Fig. 6D), which is consistent with the expected role of bFGF (T. Kushibiki, et al., Sci Rep 11 (2021)).

[0045] To date, only a small number of FGFR-activating peptides have been reported, most of which are partial agonists (S. Li, et al., Int J Mol Sci 11 (2010) 2291-2305). The present invention relates to a novel peptide that is specific to FGFR, functions as a full agonist, and can act similarly to bFGF protein. This peptide is less expensive than natural proteins and can be utilized as a substitute for bFGF protein considering its therapeutic implications. Furthermore, because it has a small molecular weight, it generally has a higher absorption rate than proteins, so FAP1 may have additional advantages.

[0046]

[0047] Accordingly, in one aspect, the present invention relates to a peptide represented by the amino acid sequence of SEQ ID NO. 1 or SEQ ID NO. 2.

[0048] In the present invention, the term “peptide” refers to a linear molecule formed by amino acid residues being joined together by peptide bonds. The peptide may be prepared according to chemical synthesis methods known in the art.

[0049] In the present invention, the peptide is a novel peptide having FGFR-agonistic properties that induce cell proliferation of fibroblasts and specifically activate FGFR (fibroblast growth factor receptor) and its downstream signaling pathways, defined herein as FAP (FGFR-agonistic peptide), and the amino acid sequences of FAP1 to FAP3 are as follows:

[0050] FAP1: RERNEVNHYRTY (Sequence No. 1)

[0051] FAP2: HFRDPKRLYCKD (Sequence No. 2)

[0052] FAP3: GERLDENNYNTY (Sequence No. 3)

[0053] In the present invention, the peptide may preferably be characterized as an FAP1 peptide represented by the amino acid sequence of SEQ ID NO. 1, but is not limited thereto.

[0054] The peptide according to the present invention is interpreted to include variants or fragments thereof in which an amino acid residue is conservatively substituted at a specific amino acid residue position.

[0055] In this specification, “conservative substitution” means a modification comprising substituting one or more amino acids with amino acids having similar biochemical properties that do not cause a loss of the biological or biochemical function of the peptide.

[0056] “Conservative amino acid substitution” is a substitution that replaces an amino acid residue with an amino acid residue having a similar side chain. Classes of amino acid residues having similar side chains are defined in the art and are well known. These classes include amino acids having basic side chains (e.g., lysine, arginine, histidine), amino acids having acidic side chains (e.g., aspartic acid, glutamic acid), amino acids having uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), amino acids having non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), amino acids having beta-branched side chains (e.g., threonine, valine, isoleucine), and amino acids having aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0057] It is expected that the FAP1 to FAP3 peptides of the present invention can still retain activity even if they have conservative amino acid substitutions.

[0058] The peptide according to the present invention may be interpreted to include, but is not limited to, a peptide having substantially the same function and / or effect as the peptide and having 80% or 85% or more, preferably 90% or more, more preferably 95% or more, and most preferably 99% or more of amino acid sequence homology with the amino acid sequence of SEQ ID NO. 1 or SEQ ID NO. 2.

[0059] In the present invention, the peptide may be characterized by specifically binding to FGFR and activating its downstream signaling.

[0060] In the present invention, the activation of the downstream signaling pathway may be characterized as p-AKT activation, reduced GSK3β phosphorylation, MAPK activation, or AKT activation.

[0061]

[0062] In one embodiment of the present invention, a peptide represented by the amino acid sequence of SEQ ID NO. 1 or SEQ ID NO. 2 specifically binds to FGFR and exhibits the effect of activating its signal transduction.

[0063] Accordingly, the present invention relates, in another aspect, to an FGFR (fibroblast growth factor receptor) agonist comprising the above peptide.

[0064] In the present invention, “FGFR agonist” may refer to a molecule that imparts activity to FGFR, such as FGF. The FGFR agonist may be characterized as being an FGFR1, FGFR2, FGFR3, or FGFR4 agonist.

[0065] In the present invention, the agent may be characterized as being a full agonist, but is not limited thereto.

[0066]

[0067] According to one embodiment of the present invention, the peptide specifically binds to FGFR and activates it, and induces cell proliferation of fibroblasts associated with its signaling, activates p-AKT and MAPK, etc., and exhibits wound closure and in vivo diabetic wound healing effects, so it can be usefully utilized as a composition for the prevention or treatment of diseases related to reduced FGFR activity.

[0068] Accordingly, in another aspect, the present invention relates to a pharmaceutical composition for the prevention or treatment of diseases related to reduced FGFR (fibroblast growth factor receptor) activity comprising the peptide.

[0069] In another aspect, the present invention relates to a method for preventing or treating diseases related to reduced FGFR activity, comprising the step of administering the peptide.

[0070] In another aspect, the present invention relates to the use of the peptide for the prevention or treatment of diseases related to reduced FGFR activity.

[0071] In another aspect, the present invention relates to the use of the peptide for the manufacture of a drug for the prevention or treatment of diseases related to reduced FGFR activity.

[0072]

[0073] In the present invention, the FGFR activity-related disease is a disease caused by the inactivation of FGFR (low activity, reduced expression, reduced signal transduction), preferably characterized as delayed wound healing, diabetic wound healing impairment, ischemic wound healing impairment, impaired tissue regeneration, postoperative wound healing impairment, post-burn impaired skin regeneration, chronic ulcer (e.g., venous ulcer, pressure ulcer, or diabetic foot ulcer), epidermal or dermal regeneration impairment, skin barrier dysfunction leading to medical complication, or tissue repair impairment due to fibroblast dysfunction, but is not limited thereto.

[0074] The term “prevention” used in the present invention refers to any act of suppressing or delaying diseases related to reduced FGFR activity by administering a pharmaceutical composition containing the peptide. Additionally, the term “treatment” used in the present invention refers to any act of improving or curing the symptoms of diseases related to reduced FGFR activity by administering a pharmaceutical composition containing the peptide.

[0075] A pharmaceutical composition for the prevention or treatment of diseases related to reduced FGFR activity according to the present invention may comprise the above-mentioned peptide alone in a pharmaceutically effective amount, or may comprise one or more pharmaceutically acceptable carriers, excipients, or diluents. In the above, a pharmaceutically effective amount refers to an amount sufficient to prevent, improve, and treat the symptoms of diseases related to reduced FGFR activity.

[0076] The term “pharmaceuticalally acceptable” above refers to a composition that is physiologically acceptable and, when administered to humans, does not typically cause allergic reactions such as gastrointestinal disorders or dizziness, or similar reactions. Examples of the carrier, excipient, and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Additionally, fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, and preservatives may be further included.

[0077] The term “carrier” refers to a substance that facilitates the addition of a compound into a cell or tissue.

[0078] The term “diluent” is defined as a substance that not only stabilizes the biologically active form of a target compound but also dilutes the compound in water to dissolve it.

[0079] In addition, the composition of the present invention may include one or more known active ingredients having a therapeutic effect on diseases related to reduced FGFR activity together with the peptide.

[0080] The composition of the present invention may be formulated using methods known in the art to provide rapid, sustained, or delayed release of the active ingredient after administration to mammals, including humans. The formulation may be in the form of powder, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, sterile powders, patches (nano patches, hydrogel patches), or microneedles.

[0081] The composition of the present invention may be administered via various routes including oral, transdermal, subcutaneous, intravenous, or intramuscular, and the dosage of the active ingredient may be appropriately selected according to various factors such as the route of administration, the patient's age, gender, weight, and severity of the patient, and the composition according to the present invention may be administered in combination with a known compound having the effect of preventing, improving, or treating symptoms of diseases related to reduced FGFR activity.

[0082]

[0083] In another aspect, the present invention relates to a functional cosmetic composition for the prevention or improvement of diseases related to reduced FGFR activity, comprising the peptide.

[0084] The description regarding peptides in the cosmetic composition of the present invention may be based on the description above.

[0085] In the cosmetic composition of the present invention, the diseases related to reduced FGFR activity are not limited thereto but may be characterized as delayed wound healing, impaired skin barrier function, damaged skin, impaired epidermal regenerative capacity, reduced skin elasticity, and wrinkles. Accordingly, the functional cosmetic composition may be characterized as a composition for promoting natural wound closure, improving damaged skin, enhancing epidermal regeneration, improving skin barrier function, increasing skin hydration, improving skin elasticity, reducing or soothing wrinkles, improving skin tone and texture, promoting collagen synthesis, improving skin anti-aging, soothing irritated skin, and promoting skin repair.

[0086] The term "improvement" in the present invention refers to any act of using the peptide according to the present invention to improve or benefit the condition of diseases related to reduced FGFR activity.

[0087] When the composition of the present invention is prepared as a cosmetic composition, it may include the peptide or, in addition to the peptide, ingredients commonly used in cosmetic compositions as active ingredients, and may include, for example, conventional auxiliary agents such as antioxidants, stabilizers, solubilizers, vitamins, pigments, and fragrances, and a carrier.

[0088] In the present invention, the cosmetic composition may be prepared in any formulation conventionally manufactured in the art, for example, as a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, and spray, but is not limited thereto. More specifically, it may be prepared in the form of a nourishing cream, astringent lotion, softening lotion, lotion, essence, nourishing gel, or massage cream.

[0089] In the case where the formulation of the above cosmetic composition is a paste, cream, or gel, animal oil, vegetable oil, wax, paraffin, starch, tragacanth gum, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, or zinc oxide may be used as a carrier component.

[0090] In the case where the formulation of the above cosmetic composition is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder may be used as a carrier component, and in particular, in the case of a spray, it may additionally include a propellant such as chlorofluorohydrocarbon, propane / butane, or dimethyl ether.

[0091] When the formulation of the above cosmetic composition is a solution or an emulsion, a solvent, a solubilizing agent, or an emulsifying agent is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol, or fatty acid ester of sorbitan.

[0092] In the case where the formulation of the above cosmetic composition is a suspension, liquid diluents such as water, ethanol, or propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, or tragacanth may be used as carrier components.

[0093] In the case where the formulation of the above cosmetic composition is a cleansing product containing a surfactant, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, fatty acid amide ether sulfate, alkylamidobetaine, aliphatic alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative, or ethoxylated glycerol fatty acid ester, etc., may be used as a carrier component. In the present invention, the above cosmetic composition may be formulated by stabilizing the above peptide by containing it inside a nanoliposome. When the above peptide is contained inside a nanoliposome, the peptide component is stabilized, which can solve problems such as precipitation formation and deformation during formulation, and can increase the solubility and transdermal absorption rate of the component, thereby maximizing the expression of the expected efficacy from the above peptide.

[0094] The cosmetic composition of the present invention may also be in the form of a polymer gel or microneedles made of a polymer, and the polymer is starch, cellulose ether, cellulose carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, ethylhydroxyethyl cellulose, alginate, carrageenan, hyaluronic acid and its derivatives, polyacrylic acid, polysulfonate, etc.

[0095]

[0096] The present invention will be described in more detail below through examples. These examples are intended solely to illustrate the present invention, and it will be obvious to those skilled in the art that the scope of the present invention is not to be interpreted as being limited by these examples.

[0097]

[0098] Example 1: Materials and Method

[0099] Example 1-1: Compounds (Chemicals)

[0100] bFGF and erdafitinib were purchased from MedChem Express (Monmouth Junction, New Jersey, USA). FGFR1 protein for surface plasmon resonance (SPR) analysis was purchased from ACROBiosystems (Newark, DE 19711, USA). Mitomycin C (MMC) solution was purchased from Sigma-Aldrich (St. Louis, MO, USA). Antibodies against pFGFR1, β-actin, and p-ERK were provided by Santa Cruz Biotechnology Inc. (Dallas, TX, USA), and antibodies against phospho-(p-) p38, p38, ERK, and JNK were purchased from Cell Signaling Technology, Inc. (Danvers, MA, USA).

[0101]

[0102] Example 1-2: Peptide designing and synthesis

[0103] The crystal structure of the bFGF-FGFR2 complex was retrieved from the Protein Data Bank (PDB ID: 1EV2), and energy was minimized using the AMBER10:ETH force field. By analyzing the resulting structure, key interactions between bFGF and FGFR2, which are essential for receptor activation, were identified. In particular, it was confirmed that arginine at position 251 of FGFR is essential for receptor activation because it forms two hydrogen bonds with asparagine at position 104 of bFGF.

[0104] To further investigate the role of this bFGF region in receptor activation, a series of agonistic peptides specifically targeting this region were designed. The peptide sequences were carefully modified to enhance stability and strengthen interactions with the receptor while maintaining the structural phase and binding properties of the original bFGF-FGFR2 complex. To achieve this, specific amino acid substitutions known to increase peptide stability and binding affinity were introduced using the protein building functions of MOE2020.9 (Chemical Computing Group (CCG) | Research, (accessed January 6, 2025)). For example, in the case of FAP1, specific amino acids were modified to other residues with similar properties or to residues capable of forming strong interactions at positions close to the receptor. In contrast, FAP3 was designed based on a common sequence derived from six FGF ligands. The design of FAP3 was confirmed through a thorough analysis of key residue interactions with the receptor. To enhance the stability and binding affinity of the peptide, specific residues were carefully selected and modified based on their potential to improve these properties using the powerful Protein Design tools of MOE software. FAP2 was designed based on canofin, a previously known agonist peptide. These peptides were designed with a focus on optimizing binding affinity to the receptor while maintaining structural integrity and stability. The peptide sequences are presented in Table 1 below. All peptides were purchased from Peptron.

[0105]

[0106]

[0107] Examples 1-3: Cell culture

[0108] Mouse embryonic fibroblasts (NIH-3T3) and human dermal fibroblasts (HDF) were purchased from ATCC (Manassas, VA, USA) and cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin. Cells were cultured in a humidified incubator at 37°C with 5% CO₂. Subculturing was performed using trypsin-EDTA solution when confluency reached approximately 80%.

[0109]

[0110] Examples 1-4: Cell viability and cell proliferation assay

[0111] NIH-3T3 cells were seeded at a density of 2 × 10^5 per well in 96-well plates (BD Biosciences, San Jose, CA, USA) and cultured overnight. Cells were treated with different concentrations of peptides for 24 hours. Cell viability was measured using a colorimetric 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan [MTT] assay (Sigma-Aldrich). After 24 hours of peptide treatment, the medium was replaced with MTT solution and cultured for 3 hours; the solution was then removed and replaced with DMSO, and absorbance was measured at 570 nm.

[0112] To analyze the effect of peptides on cell proliferation, NIH-3T3 and HDF cells were seeded into 96-well plates at a density of 3 × 10^3 cells per well and cultured overnight in DMEM containing 10% FBS and antibiotics, followed by treatment with 5 μg / mL MMC for 2 hours (H. Shi, et al., Int J Biol Sci 11 (2015) 845). After washing with PBS, cells were treated with various concentrations of peptides in serum-free medium and cultured for 48 hours, followed by MTT analysis as described above.

[0113]

[0114] Examples 1-5: Trypan Blue assay

[0115] NIH-3T3 and HDF cells were seeded into 6-well plates (BD Biosciences, San Jose, CA, USA) at a density of 1 × 10^5 per well and cultured overnight. Cells were treated with 5 μg / mL MMC for 2 hours, followed by treatment with different concentrations of peptides for 48 hours. Trypan blue analysis was performed according to standard protocols. Briefly, cells were detached using trypsin to obtain a single-cell suspension and subsequently stained with a 0.4% (w / v) trypan blue solution prepared in phosphate-buffered saline (PBS). The trypan blue solution and cell suspension were mixed in equal volumes (e.g., 100 μL each) and gently stirred to ensure uniform staining. The stained cells were analyzed immediately using a hemocytometer, and live and dead cells were counted separately based on the presence or absence of blue staining. The percentage of surviving cells was calculated using the following formula:

[0116] % Cell viability = [(Total number of cells - Number of dead cells) / Total number of cells] × 100

[0117]

[0118] Examples 1-6: Scratch wound assay

[0119] NIH-3T3 cells were seeded into 6-well plates at a density of 1 × 10^6 cells per well and cultured overnight in high-glucose DMEM. Once the cells reached 80–90% confluency, they were incubated with 5 μg / mL MMC for 2 hours, washed with PBS, and wounds were formed using a micropipette tip (CC Liang, et al., Nature Protocols 2007 2:2 2 (2007) 329-333). After washing once more with PBS to remove suspended cells, the cells were treated with serum-free medium containing bFGF or the peptide of interest for 24 hours. The same protocol was applied to HDF cells. Wound closure was measured by analyzing the intercellular gaps at various time points using ImageJ software and expressed as a percentage of the initial area using the following formula:

[0120] Wound Suture Rate % = [(Area 0-h - area 24-h ) / area 0-h ] × 100

[0121]

[0122] Examples 1-7: Western blot

[0123] Serum starvation was performed for 24 hours prior to treating cells with each concentration of peptide and bFGF. Proteins were extracted using the M-PER reagent (Catalog No. 78505), and concentrations were measured using the BCA assay kit (Catalog No. 23228). Western blots were performed using the Mini-PROTEAN and Mini Trans-Blot systems. 20 μg of total lysate was loaded for all proteins. After gel electrophoresis was completed, proteins were transferred from the gel to a nitrocellulose membrane. Subsequently, blocking was performed using 5% skim milk to prevent non-specific binding.

[0124] Membranes were immunoblotted overnight at 4°C with primary antibodies diluted to 1:500–1:1000 against ThermoFisher Scientific’s p-FGFR1 (catalog number PFGFR1-140AP), Cell Signaling Technology’s p-AKT (catalog number 4060), AKT (catalog number 9272), T-ERK (catalog number 9107), p-p38 (catalog number 4511), p38 (catalog number 9212), p-GSK3β (catalog number 9336), and Santa Cruz Biotechnology’s p-ERK (catalog number sc-81492) and β-actin (catalog number sc-47778). After washing with PBST, the membranes were incubated with peroxidase-conjugated secondary antibodies for 2 hours. Proteins were detected using SuperSignal West Pico ECL (catalog number 34580) and visualized using the ChemiDoc™ Touch Imaging System.

[0125]

[0126] Examples 1-8: Surface plasmon resonance analysis

[0127] Surface plasmon resonance (SPR) analysis was performed using an iMSPR-mini-instrument (iCLUEBiO, Korea). 50 μg / mL of FGFR1 protein was immobilized on the surface of a 3D Carboxylate Linear Polymer sensor chip (HC1000, iCLUEBiO) using a 5 mM sodium acetate solution (pH 5.0). PBS and PBS containing 0.6% DMSO were used as running buffers depending on the peptide dilution. Peptides of different concentrations were injected into the chip to compare their binding affinities to FGFR. Subsequently, the running buffer was injected into the reference channel. The data were analyzed using TraceDrawer software.

[0128]

[0129] Examples 1-9: In vivo experiments

[0130] 1) Mouse

[0131] Seven-week-old female C57BL / 6J mice were purchased from Orient Bio Inc. (Seongnam, South Korea) and reared at the Animal Research Center of Ajou University. Mice were allowed to freely consume standard feed and water in a standard environment. All experiments were performed in accordance with standard guidelines and regulations under the approval of the Institutional Animal Care and Use Committee (IACUC no. 2023-0032).

[0132]

[0133] 2) Induction of diabetes

[0134] To induce diabetes, 150 mg / kg of freshly prepared streptozotocin was injected intraperitoneally into each mouse (Jose Luis Vique-Sanchez, et al., Nutricion Clinica y Dietetica Hospitalaria 40 (2020) 153-161). Fasting blood glucose levels were measured three times by cutting off the mice's tails, and the onset of diabetic symptoms, including frequent urination, was recorded. Mice with fasting blood glucose levels exceeding 250 mg / dl were considered diabetic, and mice with low blood glucose levels were excluded from the experiment.

[0135]

[0136] 3) Wound infliction and treatment

[0137] C57BL / 6J mice were divided into four distinct treatment groups (n = 5 per group): Group A (untreated), Group B (FAP1 1 mg / kg), Group C (FAP1 5 mg / kg), and Group D (FAP1 10 mg / kg). After anesthesia, full-thickness wounds with a diameter of 6 mm were created on the shaved and disinfected dorsal area of ​​each mouse. Each concentration of the peptide was applied to the wound site and covered with Tegaderm. Wound area was measured by taking images every other day from Day 0 to Day 14. On Day 14, the mice were sacrificed, and skin tissues were collected for further analysis. Figure 6A shows a schematic diagram of this procedure.

[0138]

[0139] 4) H&E staining (Hematoxylin and eosin staining)

[0140] After collecting skin tissue samples, they were fixed in 10% neutral-buffered formalin for 24 hours. The fixed samples were processed, embedded in paraffin, and sectioned to a thickness of 4 μm. The sections were stained with hematoxylin and eosin (H&E) according to the manufacturer's instructions (GS Tech Korea Co., Ltd., South Korea). Images were acquired at 20× magnification using an optical microscope (Olympus IX73, Olympus U-TB190, Tokyo, Japan) (H. Iqbal, et al., Microorganisms 2022, Vol. 10, Page 1871 10 (2022) 1871).

[0141]

[0142] Example 1-10: Statistical analysis

[0143] All experiments were blinded and randomized. Each experiment was repeated at least three times, and the results were analyzed using GraphPad Prism 7 (GraphPad Software, Inc., San Diego, CA, USA) with a two-tailed t-test (in vitro experiments), two-way analysis of variance (ANOVA), and post hoc Dunnett's test (in vivo experiments). Data were expressed as mean ± standard deviation, and differences between groups were considered significant at ***p < 0.001, **p < 0.01, and *p < 0.033.

[0144]

[0145] Example 2: Design of FGFR-activating peptide

[0146] The initiation of transmembrane signaling by receptors with tyrosine kinase activity largely depends on ligand-induced dimerization (Y. Liu, et al., Front Endocrinol (Lausanne) 12 (2021)). Unlike dimeric growth factors such as platelet-derived growth factor (PDGF), FGF exists as a monomer and does not self-activate FGFR. The activation of FGFR requires the presence of soluble or cell-surface bound heparan sulfate proteoglycans (HSPG), which promote FGFR dimerization and the initiation of the subsequent biological response. Based on these insights into the essential roles of FGF and HSPG in ligand-induced dimerization and FGFR activation, the inventors investigated peptide design strategies that mimic these interactions and effectively promote receptor dimerization. The peptide design was based on the ligand-receptor interaction observed in the FGF ligand, as shown in Fig. 1.

[0147] Specifically, FIG. 1B illustrates the molecular interactions of FGF-active peptides and details the binding patterns and interactions with target molecules. Furthermore, FIG. 1C and FIG. 1D illustrate the molecular interactions of canopin-derived peptides and explain specific binding interactions between the peptides and receptors.

[0148]

[0149] Example 3: Selection of FAP1 as a peptide with optimal agonistic effect

[0150] Two approaches were used to select the optimal FGF-activating peptide. The first was a cell-based assay (wound healing assay), and the other was a method utilizing protein-protein interactions (SPR). First, cytotoxicity was tested for all peptides. To evaluate the cytotoxicity of the peptides, NIH-3T3 cells were treated with various concentrations of the peptides for 24 hours. Cytotoxicity was assessed using the MTT assay, which is widely used to evaluate cell viability. As a result, all concentrations of FAP1 and FAP2 did not show clear cytotoxic effects in NIH-3T3 cells, suggesting they are safe for use in subsequent experiments. However, mild toxicity was observed in the case of FAP3 (Fig. 2A). SPR analysis revealed that FAP2 exhibited the best binding efficacy, whereas FAP1 showed lower binding affinity to FGFR than FAP2 (Fig. 2B).

[0151] Next, to evaluate the effects of peptides on cell migration, one of the most important functions of FGF, an in vitro scratch wound assay was performed. For the scratch wound assay, cells were seeded onto culture plates and cultured overnight to induce attachment, then treated with MMC. After replacing the medium, scratches were created in the cell monolayer using a yellow tip. Each peptide was treated to the cells at a concentration of 100 ng / ml and left for 24 hours. As a result, FAP1 exhibited the most superior wound healing effect (Figs. 2C and 2D). However, the effect of FAP2 on cell migration was weaker than that of FAP1. Considering that agonists possess both affinity and intrinsic efficacy (KA Berg, WP Clarke, International Journal of Neuropsychopharmacology 21 (2018)), FAP1 was determined to be the optimal candidate and was therefore selected for subsequent experiments. In addition, the lethal dose of FAP1 (LC 50 The calculated result was 3.3 mg / ml (Fig. 2E). The effective concentration of FAP1 (EC 50 ) was calculated via Western blot based on receptor activation induced by FAP1. To this end, MCF-7 cells were seeded, cultured, and serum-deprived for 24 hours, followed by treatment with various concentrations of FAP1. As a result, FAP1 activated FGFR1 in a concentration-dependent manner, confirming FGFR1 activity, and EC 50 It was calculated to be 0.7223 ng / ml (Fig. 2F).

[0152]

[0153] Example 4: FAP1 inducing cell proliferation in human and mouse fibroblasts

[0154] bFGF plays a crucial role in cell proliferation. bFGF ligands bind to FGFR to induce receptor dimerization, which leads to the initiation of downstream signaling cascades that drive cell proliferation. To evaluate the cell proliferation-promoting efficacy of FAP1, mouse fibroblast growth was first inhibited using MMC. Subsequently, the cells were exposed to various concentrations of FAP1 for 48 hours. MTT analysis revealed that FAP1 stimulated fibroblast proliferation in a dose-dependent manner. FAP1 significantly induced proliferation in both human and mouse fibroblasts (Figs. 3A and 3B). For further confirmation, trypan blue analysis was performed, yielding similar results. FAP1 significantly increased the proportion of viable cells and clearly demonstrated increased cell proliferation in both NIH-3T3 and HDF cells (Figs. 3C and 3D).

[0155]

[0156] Example 5: FAP1 activating FGFR1 and downstream signaling pathways

[0157] As the receptor-activating effect of FAP1 was confirmed and its cell proliferation effect was verified through proliferation analysis, the effects of FAP1 on downstream signaling pathways were investigated. FAP1 activated p-AKT and reduced the phosphorylation of GSK3β in NIH-3T3 cells (Fig. 3E). In addition, it induced dose-dependent activation of MAP kinase in HDF cells (Fig. 3F).

[0158] Full agonists exhibit the maximum possible response, whereas partial agonists act as antagonists in the presence of a full agonist (KA Berg, WP Clarke, International Journal of Neuropsychopharmacology 21 (2018) 962). To confirm whether FAP1 is a full agonist, an experiment was conducted to evaluate FGFR activation in the presence of bFGF. If FGFR activation by FAP1 were reduced in the presence of bFGF, it would indicate partial agonism. However, bFGF enhanced FGFR activation by FAP1, thereby confirming that FAP1 is a full agonist of FGFR (Fig. 3G). The dose-dependent binding of FAP1 and FGFR1 was further confirmed through SPR analysis (Fig. 3H).

[0159] To further confirm the FGFR-dependent effects of FAP1, cells were pretreated with an FGFR inhibitor prior to FAP1 treatment. The FGFR-dependent mechanism of the FAP1 peptide was verified by blocking the FGFR signaling pathway using the pan-FGFR inhibitor erdafitinib. Pretreatment of cells with erdafitinib demonstrated that the observed effects of FAP1 are directly linked to FGFR activation. When FAP1 was treated in the presence of erdafitinib (50 nM), Western blot analysis revealed that MAPK and AKT activation were completely inhibited. This further demonstrates the specificity of FAP1 (Fig. 4A). By excluding off-target effects, this approach strengthened confidence in the mechanism of action of FAP1 and established its therapeutic potential.

[0160]

[0161] Example 6: FAP1 promoting wound healing effects in mouse and human fibroblasts

[0162] bFGF is involved in cell proliferation and migration. A scratch wound assay was performed to determine the effects of FAP1 on cell proliferation and migration. NIH-3T3 cells were seeded and cultured overnight. Before inducing scratches, cells were treated with 5 μg / ml of MMC to inhibit cell proliferation. After scratching the cell monolayer, the cells were treated with various concentrations of the peptide. bFGF was added at a concentration of 10 ng / ml. FAP1 peptides were used at three concentrations of 1, 10, and 100 ng / ml, and wound closure rates significantly increased at all concentrations (Figs. 5A and 5B). The acceleration of wound closure rates by FAP1 peptides demonstrates that FAP1 peptides mimic the effects of bFGF protein at the cellular level. Similar effects were observed in human fibroblasts as well (Figs. 5C and 5D). To further confirm the FGFR-dependent effects of the peptide, cells were treated with erdafitinib. The proliferation and migration ability of FAP1-induced fibroblasts was reversed in the presence of erdafitinib, suggesting that the migration and proliferation of FAP1-induced mouse fibroblasts are absolutely FGFR-dependent (Figs. 5E and 5F).

[0163]

[0164] Example 7: FAP1 promoting wound healing in diabetic mice

[0165] Impaired wound healing is a characteristic phenomenon of type 1 diabetes mellitus, characterized by significant loss of beta cells and insulin deficiency. This deficiency leads to complete dependence on exogenous insulin to maintain normal physiological functions (SF Spampinato, et al., Pharmaceuticals 13 (2020)). The inventors evaluated the effects of FAP1 in a mouse model of type 1 diabetes induced by streptozotocin (STZ). Mice were sacrificed on day 14. Animals treated with FAP1 showed improved wound healing ability on days 3, 5, and 7 compared to the vehicle (PBS) treatment group (Figs. 6B and 6C). Wounds healed on day 14 in all FAP1 treatment groups.

[0166] H&E staining was performed on D14 to confirm the wound healing-promoting ability of FAP1 and to investigate its effects at the tissue level. Microscopic analysis revealed that FAP1 enhanced the proliferation of keratinocytes and fibroblasts at the wound site. Angiogenesis is one of the most critical steps in the wound healing process, and bFGF is involved in inducing it. H&E staining results showed a dense capillary network in mice treated with FAP1. Interestingly, no wound cavities were observed in the wound sites of FAP1-treated mice, whereas empty spaces appeared in the PBS-treated group. Collagen deposition is a crucial factor in the wound healing process. In the case of FAP1 peptide treatment, it was confirmed that FAP1 induced collagen deposition in a dose-dependent manner (Fig. 6D).

[0167]

[0168] The FAP1 peptide according to the present invention has been proven by in vitro and in vivo data to be a potent FGFR-activating peptide. FAP1 exhibited effective concentrations similar to those of bFGF protein, and in in vivo diabetic wound healing experiments, the efficacy of FAP1 demonstrated the ability to promote wound healing and support tissue remodeling, suggesting it is a promising candidate in the field of regenerative medicine. The FAP1 peptide demonstrates potential as a novel pharmacological alternative to natural bFGF for skin tissue regeneration and recovery. Considering its ability to promote wound healing and its specificity for FGFR, FAP1 can be utilized as a cost-effective substitute for bFGF protein in the therapeutic field.

[0169]

[0170] Foregoing, specific parts of the present invention have been described in detail. It will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the invention. Accordingly, the actual scope of the invention is defined by the appended claims and their equivalents.

[0171]

[0172] I have attached the electronic file.

Claims

1. A peptide represented by the amino acid sequence of Sequence No. 1 or Sequence No.

2.

2. The peptide according to claim 1, characterized in that the peptide induces cell proliferation of fibroblasts and activates FGFR (fibroblast growth factor receptor) and its downstream signaling pathways.

3. A peptide according to claim 2, characterized in that the activation of the downstream signaling pathway is p-AKT activation, reduction of GSK3β phosphorylation, MAPK activation, or AKT activation.

4. An FGFR (fibroblast growth factor receptor) agonist comprising the peptide of claim 1.

5. A pharmaceutical composition for the prevention or treatment of diseases related to reduced FGFR (fibroblast growth factor receptor) activity, comprising the peptide of claim 1.

6. A pharmaceutical composition according to claim 5, characterized in that the disease related to reduced FGFR activity is delayed wound healing, diabetic wound healing impairment, ischemic wound healing impairment, impaired tissue regeneration, postoperative wound healing impairment, post-burn impaired skin regeneration, chronic ulcer, epidermal or dermal regeneration impairment, skin barrier dysfunction leading to medical complication, or tissue repair impairment due to fibroblast dysfunction.

7. A functional cosmetic composition comprising the peptide of claim 1 for the promotion of natural wound closure, improvement of damaged skin, enhancement of epidermal regeneration, improvement of skin barrier function, increased skin hydration, improvement of skin elasticity, wrinkle improvement or soothing, improvement of skin tone and texture, promotion of collagen synthesis, skin anti-aging improvement, soothing of irritated skin, and promotion of skin repair.

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