Novel peptide having therapeutic effect on inflammatory diseases, and use thereof

Abstract

The present invention relates to a structurally-novel peptide and an anti-inflammatory composition comprising same as an active ingredient. Specifically, the structurally-novel peptide of the present invention exhibits an excellent effect with respect to the prevention or treatment of inflammatory diseases by effectively inhibiting inflammatory mediators, and thus can be used as an anti-inflammatory composition.

Description

Novel peptides with therapeutic effects on inflammatory diseases and their uses

[0001] The present invention relates to a novel peptide structure and an anti-inflammatory composition comprising the peptide as an active ingredient. Specifically, the novel peptide structure of the present invention exhibits excellent effects in the prevention or treatment of inflammatory diseases by effectively suppressing inflammatory mediators, and thus can be used as an anti-inflammatory composition.

[0002]

[0003] Due to industrialization and the resulting changes in lifestyle, the incidence of inflammatory diseases is steadily increasing. Inflammatory diseases are caused by a disruption in the immune system's balance, and various factors are known to be associated with the onset and progression of inflammatory diseases.

[0004] Inflammation is the body's defense mechanism against microbial infection or physical damage, and is typically accompanied by fever, pain, swelling, decreased function, and redness. Inflammation is directly and indirectly linked to a variety of diseases. Infectious diseases often involve an inflammatory response, and other conditions, such as atherosclerosis, dermatitis, inflammatory colitis, arthritis, and psoriasis, are also classified as inflammatory diseases. Furthermore, with the growing recognition that inflammation is involved in diseases such as cancer, the need for the development of new mechanisms or substances that can modulate inflammation is increasing.

[0005] Prostaglandins (PGs), cytokines, histamine, and complement have been reported as substances that mediate inflammation, and among these, cytokines that mediate inflammation are called proinflammatory cytokines. Proinflammatory cytokines are mainly produced by immune cells at the site of inflammation, and representative examples include interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). They are directly or indirectly related to a wide range of inflammatory diseases, and it has been reported several times that the inflammatory response can be controlled by regulating their expression.

[0006] While researching novel peptides, the present inventors discovered that a series of novel peptides could modulate inflammatory responses, suppressing the expression of proinflammatory cytokines even at the animal level. Thus, the present inventors discovered novel peptides with anti-inflammatory effects and elucidated their mechanisms, thereby completing the present invention.

[0007]

[0008] The present invention aims to provide a peptide having a novel structure exhibiting an anti-inflammatory effect.

[0009] The purpose of the present invention is to provide a composition for preventing or treating inflammatory diseases, which comprises a novel peptide as an active ingredient.

[0010] The present invention aims to provide a method for preventing or treating inflammatory diseases using the above composition.

[0011]

[0012] The present invention provides a novel peptide comprising an amino acid sequence of pGZX1X2 or a pharmaceutically acceptable salt thereof, wherein p is L-trans-4-hydroxyproline, G is glycine, Z is Q or N, and X1 and X2 are each A, L, V, or 2-aminoisobutyric acid (Aib).

[0013] In one embodiment, the novel peptide may have a linear structure or a cyclic structure.

[0014] In one embodiment, when the novel peptide has a linear structure, the N-terminus may be a free amine or acetylated, and the C-terminus may be an amide.

[0015] In one embodiment, if the novel peptide has a cyclic structure, it may comprise the amino acid sequence caa-pGZX1X2C', wherein caa is an α-covalently linked acetyl and C' is a cysteine ​​linked to caa via a thiol group.

[0016] In one embodiment, the novel peptide comprises the amino acid sequence of pGZX1X2, wherein p is L-trans-4-hydroxyproline, Z is Q, X1 is A, L, V, or Aib, and X2 can be A, L, V, or Aib.

[0017] In one embodiment, the novel peptide comprises the amino acid sequence of pGZX1X2, wherein p is L-trans-4-hydroxyproline, Z is Q, X1 is A, V, or Aib, and X2 can be L or V.

[0018] In one embodiment, the novel peptide comprises the amino acid sequence of pGZX1X2, wherein p is L-trans-4-hydroxyproline, Z is Q, X1 is A or L, and X2 can be A, L, V, or Aib.

[0019] In one embodiment, the novel peptide comprises the amino acid sequence of pGZX1X2, wherein p is L-trans-4-hydroxyproline, Z is N, X1 is A, and X2 can be A, L, V, or Aib.

[0020] In one embodiment, the novel peptide comprises an amino acid sequence of pGZX1X2, wherein p is L-trans-4-hydroxyproline, Z is N, X1 is A, and X2 can be V.

[0021] In one embodiment, the novel peptide may have a length of 5 to 10 amino acids.

[0022] In one embodiment, the novel peptide may have a length of 5 or 6 amino acids.

[0023] In one embodiment, the novel peptide may be any one selected from the group consisting of amino acid sequences of SEQ ID NOs: 1 to 21.

[0024]

[0025] In one embodiment, the novel peptide may be any one selected from the group consisting of amino acid sequences of SEQ ID NOs: 4, 7, 16, 18, 20 and 21.

[0026] In one embodiment, the novel peptide may be a monomer, a dimer, a trimer, or a tetramer.

[0027] The present invention provides a peptide selected from the group consisting of compounds having the following chemical structural formula or a pharmaceutically acceptable salt thereof.

[0028]

[0029]

[0030]

[0031]

[0032]

[0033] The present invention provides an anti-inflammatory composition comprising a novel peptide or a pharmaceutically acceptable salt thereof.

[0034] The present invention provides a pharmaceutical composition for preventing or treating inflammatory diseases, comprising a novel peptide or a pharmaceutically acceptable salt thereof.

[0035]

[0036] The novel peptide of the present invention can be used to prevent and treat various inflammatory diseases by efficiently suppressing various factors involved in inflammatory responses at the mRNA level in cell models and also suppressing factors involved in inflammatory responses in actual animal models.

[0037]

[0038] Figure 1 shows the HPLC chromatogram and MALDI-TOFMS results of the P-1 peptide (SEQ ID NO: 1) (MALDI-TOF MS [M+Na] + (calcd.)= 651.25 [M+Na] + (obsd.)= 651.62).

[0039] Figure 2 shows the HPLC chromatogram and MALDI-TOFMS results of the P-3 peptide (SEQ ID NO: 2) (MALDI-TOF MS [M+Na] + (calcd.)= 637.24 [M+Na] + (obsd.)= 637.41).

[0040] Figure 3 shows the HPLC chromatogram and MALDI-TOFMS results of the P-6 peptide (SEQ ID NO: 3) (MALDI-TOF MS [M+Na] + (calcd.)= 1307.55 [M+Na] + (obsd.)= 1307.03).

[0041] Figure 4 shows the HPLC chromatogram and MALDI-TOFMS results of the P-7 peptide (SEQ ID NO: 4) (MALDI-TOF MS [M+Na] +(calcd.)= 707.32 [M+Na] + (obsd.)= 707.58).

[0042] Figure 5 shows the HPLC chromatogram and MALDI-TOFMS results of the P-8 peptide (SEQ ID NO: 5) (MALDI-TOF MS [M+Na] + (calcd.)= 679.28 [M+Na] + (obsd.)= 679.59).

[0043] Figure 6 shows the HPLC chromatogram and MALDI-TOFMS results of the P-10 peptide (SEQ ID NO: 6) (MALDI-TOF MS [M+Na] + (calcd.)= 578.29 [M+Na] + (obsd.)= 578.54).

[0044] Figure 7 shows the HPLC chromatogram and MALDI-TOFMS results of the P-11 peptide (SEQ ID NO: 7) (MALDI-TOF MS [M+Na] + (calcd.)= 536.28 [M+Na] + (obsd.)= 536.57).

[0045] Figure 8 shows the HPLC chromatogram and MALDI-TOFMS results of the P-12 peptide (SEQ ID NO: 8) (MALDI-TOF MS [M+Na] + (calcd.)= 564.28 [M+Na] + (obsd.)= 564.64).

[0046] Figure 9 shows the HPLC chromatogram and MALDI-TOFMS results of the P-13 peptide (SEQ ID NO: 9) (MALDI-TOF MS [M+Na] + (calcd.)= 522.26 [M+Na] + (obsd.)= 522.67).

[0047] Figure 10 shows the HPLC chromatogram and MALDI-TOFMS results of the P-16 peptide (SEQ ID NO: 10) (MALDI-TOF MS [M+Na] +(calcd.)= 564.28 [M+Na] + (obsd.)= 564.49).

[0048] Figure 11 shows the HPLC chromatogram and MALDI-TOFMS results of the P-17 peptide (SEQ ID NO: 11) (MALDI-TOF MS [M+Na] + (calcd.)= 522.26 [M+Na] + (obsd.)= 522.52).

[0049] Figure 12 shows the HPLC chromatogram and MALDI-TOFMS results of the P-18 peptide (SEQ ID NO: 12) (MALDI-TOF MS [M+Na] + (calcd.)= 578.29 [M+Na] + (obsd.)= 578.52).

[0050] Figure 13 shows the HPLC chromatogram and MALDI-TOFMS results of the P-20 peptide (SEQ ID NO: 13) (MALDI-TOF MS [M+Na] + (calcd.)= 665.27 [M+Na] + (obsd.)= 665.63).

[0051] Figure 14 shows the HPLC chromatogram and MALDI-TOFMS results of the P-21 peptide (SEQ ID NO: 14) (MALDI-TOF MS [M+Na] + (calcd.)= 1307.55 [M+Na] + (obsd.)= 1308.45).

[0052] Figure 15 shows the HPLC chromatogram and MALDI-TOFMS results of the P-22 peptide (SEQ ID NO: 15) (MALDI-TOF MS [M+Na] + (calcd.)= 1949.83 [M+Na] + (obsd.)= 1950.89).

[0053] Figure 16 shows the HPLC chromatogram and MALDI-TOFMS results of the P-23 peptide (SEQ ID NO: 16) (MALDI-TOF MS [M+K]+ (calcd.)= 510.21 [M+K] + (obsd.)= 510.39).

[0054] Figure 17 shows the HPLC chromatogram and MALDI-TOFMS results of the P-24 peptide (SEQ ID NO: 17) (MALDI-TOF MS [M+Na] + (calcd.)= 536.24 [M+Na] + (obsd.)= 536.41).

[0055] Figure 18 shows the HPLC chromatogram and MALDI-TOFMS results of the P-25 peptide (SEQ ID NO: 18) (MALDI-TOF MS [M+Na] + (calcd.)= 592.31 [M+Na] + (obsd.)= 592.46).

[0056] Figure 19 shows the HPLC chromatogram and MALDI-TOFMS results of the P-26 peptide (SEQ ID NO: 19) (MALDI-TOF MS [M+Na] + (calcd.)= 550.30 [M+Na] + (obsd.)= 550.45).

[0057] Figure 20 is the HPLC chromatogram and MALDI-TOFMS results of the P-27 peptide (SEQ ID NO: 20) (MALDI-TOF MS [M+Na] + (calcd.)= 550.26 [M+Na] + (obsd.)= 550.39).

[0058] Figure 21 shows the HPLC chromatogram and MALDI-TOFMS results of the P-28 peptide (SEQ ID NO: 21) (MALDI-TOF MS [M+Na] + (calcd.)= 536.28 [M+Na] + (obsd.)= 536.40).

[0059] Figure 22 is a graph of qPCR results showing changes in the expression of IL-1β mRNA after treating mouse macrophages with the peptides of the present invention (P-1 and P-3).

[0060] Figure 23 is a qPCR result graph showing changes in the expression of IL-1β mRNA after treating mouse macrophages with the peptides of the present invention (P-6, P-7, and P-8).

[0061] Figure 24 is a graph of qPCR results showing changes in the expression of IL-1β mRNA after treating mouse macrophages with the peptides of the present invention (P-10, P-11, and P-12).

[0062] Figure 25 is a qPCR result graph showing changes in the expression of IL-1β mRNA after treating mouse macrophages with the peptides of the present invention (P-13 and P-16).

[0063] Figure 26 is a qPCR result graph showing changes in the expression of IL-1β mRNA after treating mouse macrophages with the peptides of the present invention (P-17, P-18, and P-20).

[0064] Figure 27 is a graph of qPCR results showing changes in the expression of IL-1β mRNA after treating mouse macrophages with the peptides of the present invention (P-21, P-22, P-23, and P-24).

[0065] Figure 28 is a qPCR result graph showing changes in the expression of IL-1β mRNA after treating mouse macrophages with the peptides of the present invention (P-25, P-26, P-27, and P-28).

[0066] Figure 29 is a graph showing the qPCR results showing changes in the expression of inflammation-related mRNA after treating mouse lacrimal gland tissue with the peptide of the present invention.

[0067] Figure 30 is a qPCR result graph showing changes in the expression of inflammation-related mRNA after treating mouse corneal tissue with the peptide of the present invention.

[0068]

[0069] Hereinafter, with reference to the attached drawings, embodiments and examples of the present invention will be described in detail so that those skilled in the art can easily implement the present invention. However, the present invention may be implemented in various forms and is not limited to the embodiments and examples described herein.

[0070] The term "free" used in the present invention means that the amine at the N-terminus of the peptide is not bound to another molecule, and means a free amine.

[0071] The term "Ac" as used in the present invention means that the amine at the N-terminus of the peptide is acetylated.

[0072] The term "cyclic" as used in the present invention means that the peptide has a cyclic structure. For example, a peptide having a cyclic structure may refer to a cyclic peptide obtained by the reaction of a chloroacetyl group at the N-terminus of the peptide with a thiol residue of cysteine ​​at the C-terminus.

[0073] The term "p" used in the present invention means L-trans-4-hydroxyproline (Hyp).

[0074] The term "caa" as used in the present invention means α-covalently linked-acetyl.

[0075] The term "C'" as used in the present invention means cysteine ​​linked to thiol in caa.

[0076] The term "Aib" used in the present invention means 2-aminoisobutyric acid.

[0077] Throughout this specification, whenever a part is said to "include" a component, this means that it may include other components, but not to the exclusion of other components, unless otherwise stated.

[0078] The term "prevention" as used herein means any action that inhibits or delays the onset of a disease by administering a composition, and "treatment" means any action that improves or beneficially changes the symptoms of a subject suspected of or suffering from a disease by administering a composition.

[0079] The present invention will be described in more detail through the following test examples; however, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0080] The present invention provides a novel peptide. In one embodiment, the novel peptide may comprise the amino acid sequence of pGZX1X2.

[0081] In one embodiment, p is L-trans-4-hydroxyproline (Hyp), Z is glutamine (Q) or asparagine (N), and X1 and X2 can each be alanine (A), leucine (L), valine (V), or 2-aminoisobutyric acid (Aib).

[0082] In one embodiment, the novel peptide may have a linear or cyclic structure. If the novel peptide is linear, the N-terminus of the peptide may be, but is not limited to, a free amine or acetylated, and the C-terminus may be, but is not limited to, an amide.

[0083] In one embodiment, the novel peptide may have a cyclic structure. The cyclic structure may be formed by covalently bonding any one of the amino acids constituting the peptide to another, and is not limited to any structure that can be introduced by a person skilled in the art. For example, a peptide having a cyclic structure may include an amino acid sequence of caa-pGZX1X2C', wherein caa is an α-covalently linked acetyl, C' is a cysteine ​​linked to caa via a thiol group, and the cyclic structure may be formed by a bond between caa and the cysteine.

[0084] In one embodiment, Z is Q, X1 can be A, L, V, or Aib, and X2 can be A, L, V, or Aib. The novel peptide may have a linear or cyclic structure.

[0085] In one embodiment, Z may be Q, X1 may be A, V, or Aib, and X2 may be L or V. The novel peptide may have a linear structure.

[0086] In one embodiment, Z may be Q, X1 may be A or L, and X2 may be A, L, V, or Aib. The novel peptide may have a cyclic structure.

[0087] In one embodiment, Z may be N and X1 may be A. The novel peptide may have a linear or cyclic structure. In one embodiment, X2 may be V.

[0088] In one embodiment, the novel peptide may have a length of 5 to 10 amino acids. Specifically, the novel peptide may have a length of at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 amino acids, or may have a length of at most 10, at most 9, at most 8, at most 7, at most 6, or at most 5 amino acids.

[0089] In one embodiment, the amino acid sequence can be any one of the sequences of SEQ ID NO: 1 to 21. In one embodiment, the amino acid sequence can be the sequence of SEQ ID NO: 4, 7, 16, 18, 20, or 21.

[0090] In one embodiment, the peptide may be, but is not limited to, a monomer, a dimer, a trimer, a tetramer or a multimer of more than one type.

[0091] The present invention provides an anti-inflammatory composition comprising a novel peptide. The present invention provides a method for reducing inflammation, comprising administering the novel peptide to a subject. The present invention provides a novel peptide for use in anti-inflammation or inflammation reduction. The present invention provides the use of the novel peptide in the manufacture of an anti-inflammatory agent.

[0092] The present invention provides a pharmaceutical composition comprising a novel peptide for the prevention or treatment of inflammatory diseases. The present invention also provides a method for the prevention or treatment of inflammatory diseases, comprising administering the novel peptide to a subject. The present invention also provides a novel peptide for use in the prevention or treatment of inflammatory diseases. The present invention also provides the use of the novel peptide in the manufacture of a pharmaceutical agent for the prevention or treatment of inflammatory diseases.

[0093] In one embodiment, the inflammation may be caused by an infectious disease.

[0094] In one embodiment, the novel peptide or composition comprising the same may inhibit the expression of a proinflammatory cytokine, thereby inhibiting an inflammatory response. In one embodiment, the proinflammatory cytokine may be IL-6, IL-1β, or TNF-α.

[0095]

[0096] [Manufacturing Example 1]

[0097] Creation of a new peptide library

[0098]

[0099] Peptides with sequences as shown in Table 1 below were synthesized according to the standard Fmoc peptide synthesis method. A chloroacetyl group was introduced into the cyclic peptide by adding a DMF solution of 0.15 M chloroacetic acid, 0.15 M HOBt (1-hydroxybenzotriazole hydrate), and 0.15 M N,N'-diisopropylcarbodiimide to the N-terminus and stirring at room temperature for 1 hour. Afterwards, according to the general peptide solid-phase synthesis method, the peptide was separated from the resin under acid conditions (95% (v / v) trifluoroacetic acid, 2.5% (v / v) water, 2.5% (v / v) triisopropylsilane), and the peptide pellet was dissolved in 10 mL of DMSO:water (4:1) solution, and DIPEA (N,N-diisopropylethylamine) was added to maintain pH>8 at 42 o The cyclic peptide was obtained by stirring for more than 1 hour at C. The progress of the reaction was confirmed by reverse-phase HPLC.

[0100]

[0101] Sequence NumberPeptide NumberPeptide Name 1 amino acid sequence 2Yield (mg)Molecular weight 1P-1cyclic SH-pGQ01caa-pGQAVC'10.5 mg628.72P-3cyclic SH-pGN02caa-pGNAVC'12.1 mg614.73P-6cyclic SH-pGQ03-dimercaa-pGQALC'3.4 mg1285.54P-7cyclic SH-pGQ05caa-pGQLLC'3.6 mg684.85P-8cyclic SH-pGQ06caa-pGQLAibC'6.1 mg656.86P-10Ac pGQ01Ac-pGQVV18.9 mg555.67P-11free pGQ01free-pGQVV14.0 mg513.68P-12Ac pGQ02Ac-pGQ-Aib-V25.8 mg541.69P-13free pGQ02free-pGQ-Aib-V23.9 mg499.610P-16Ac pGQ04Ac-pGQAL16.6 mg541.611P-17free pGQ04free-pGQAL24.7 mg499.612P-18Ac pGQ06Ac-pGQ-Aib-L29.6 mg555.613P-20cyclic SH-pGQ04caa-pGQLAC'6.2 mg642.714P-21cyclic SH-pGQ04-dimercaa-pGQLAC'3.8 mg1285.515P-22cyclic SH-pGQ04-trimer caa-pGQLAC'1.5 mg1928.216P-23free pGN01free-pGNAV10.1 mg471.517P-24Ac pGN01Ac-pGNAV3.9 mg513.618P-25Ac pGQ05Ac-pGQVL13.7 mg569.719P-26free pGQ05free-pGQVL9.8 mg527.620P-27Ac pGQ07Ac-pGQAV12.4 mg527.621P-28free pGQ06free-pGQ-Aib-L26.3 mg513.6

[0102] 1 Free refers to the free amine at the N-terminus, Ac refers to the acetylated N-terminus. Cyclic refers to a cyclic structure.

[0103] The cyclic peptides in Table 1 above have a cyclic peptide structure obtained by the reaction of the chloroacetyl group at the N-terminus and the thiol residue of Cys at the C-terminus.

[0104] 2 All capitalized amino acids are in the L-form, and the lowercase p stands for L-trans-4-hydroxyproline (Hyp). caa is α-covalently linked acetyl, C' is cysteine ​​linked to caa via a thiol group, and Aib is 2-aminoisobutyric acid.

[0105] The chemical structures of the peptides in Table 1 above are shown in Table 2 below.

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112] [Manufacturing Example 2]

[0113] HPLC purification of a novel peptide library

[0114]

[0115] The purity of the peptides was assessed using an analytical HPLC system (Agilent, Model: 1260 Infinity II) operating at a flow rate of 1 ml / min. A Zorbax C18 (3.5 μm, 4.6 × 150 mm) column was used as the stationary phase. The mobile phase consisted of a linear gradient of water (solvent A) containing 0.1% trifluoroacetic acid (TFA) and acetonitrile (solvent B) containing 0.1% TFA.

[0116] The gradient conditions were as follows: 5% B for 5 min, followed by a linear gradient of 5-70% B over 25 min. Each peptide is indicated in each chromatogram. The molecular weight of the peptides was measured using an UltrafleXtreme MALDI-TOF / TOF mass spectrometer (Bruker Daltonics, Germany). The molecular weight data of the peptides listed in Table 1 were detected as [M+H]+ and are presented in Figures 1 to 21, respectively.

[0117]

[0118] [Example 1]

[0119] Confirmation of anti-inflammatory effects in mouse macrophages

[0120]

[0121] To evaluate the anti-inflammatory effect in mouse macrophage Raw264.7 cells (Korea Cell Line Bank, Accession No.: KCLB 40071), 1x10 cells were seeded in 12-well plates using DMEM (Dulbecco's Modified Eagle Medium, Gibco, Product No.: 11995-065) containing 10% FBS. 5 2 ml was dispensed per well and cultured for 24 hours. After 24 hours of culture, the cells were cultured in DMEM serum-free medium for 6 hours, and the peptides were treated at concentrations of 0.1, 1, or 10 uM, respectively, and the control group, dexamethasone (Sigma, product number: D2915), was treated at 10 uM for 24 hours. After 24 hours of pretreatment, LPS (Invivogen, product number: tlrl-eblps) was treated at a concentration of 100 ng / ml for 2 hours, and mRNA was extracted using Trizol. The expression of IL-1β mRNA, a major factor in inflammation, was confirmed through qPCR using the extracted mRNA, confirming the anti-inflammatory effect, and the results are shown in Figures 22 to 28.

[0122] According to Figures 22 to 28, the peptides of the present invention were confirmed to have an anti-inflammatory effect that inhibits IL-1β expression in a concentration-dependent manner. All peptides disclosed in Table 1 exhibited excellent anti-inflammatory effects.

[0123]

[0124] [Example 2]

[0125] Confirmation of the inhibitory effect of a novel peptide on inflammation-related factors in animals

[0126] In the above cell experiments, three peptides, P-7, P-11, and P-23, which showed excellent anti-inflammatory effects, were selected and their anti-inflammatory effects were confirmed in an animal model. Scopolamine hydrobromide (SC), a parasympathetic nerve inhibitor, is known to cause dry eye and intraocular inflammation by reducing the function of the meibomian gland. A mouse model was created by subcutaneously injecting scopolamine hydrobromide (0.5 mg / 0.2 mL) dissolved in phosphate-buffered saline (PBS) into 8-week-old C57BL / 6 mice three times a day for a total of 24 days. The mice were housed in a desiccation chamber (22°C ± 2°C, humidity 20-40%) where temperature and humidity were maintained throughout the experiment.

[0127] Fifteen days after subcutaneous injection of scopolamine hydrobromide, the selected peptides were administered to the mice as eye drops (PBS or peptide 4 times / day) or CsA (2 times / day) for 10 days, and each experimental group used both eyes of 6 mice for the experiment. In the experiment, the control group was a group that did not receive any treatment, the DS group was a control group that did not receive any treatment after subcutaneous injection of scopolamine hydrobromide, the Vehicle group was a control group that received PBS after subcutaneous injection of scopolamine hydrobromide, and the CsA group was a group that received the anti-inflammatory drug cyclosporine.

[0128] One day after completing peptide administration, RNA was extracted from the cornea and lacrimal gland of the mouse and gene expression was analyzed using qPCR as in Example 1. The results of the lacrimal gland experiment are shown in Figure 29, and the results of the cornea experiment are shown in Figure 30.

[0129] According to Figure 29, it was confirmed that the expression of IL-1β, TNF-α, and IL-6, which are inflammatory factors in the lacrimal gland tissue, was reduced in the peptide administration group of the present invention compared to the control group (P-7>P-23, P-11). According to Figure 30, it was confirmed that the expression of IL-1β and TNF-α, which are inflammatory factors in the corneal tissue, was reduced in the peptide administration group compared to the control group (P-7>P-11>P-23).

Claims

1. A peptide containing the amino acid sequence of pGZX1X2, p is L-trans-4-hydroxyproline, G is glycine, Z is glutamine (Q) or asparagine (N), A peptide or a pharmaceutically acceptable salt thereof, wherein X1 and X2 are each alanine (A), leucine (L), valine (V), or 2-aminoisobutyric acid (Aib).

2. A peptide or a pharmaceutically acceptable salt thereof having a linear or cyclic structure according to paragraph 1.

3. A peptide or a pharmaceutically acceptable salt thereof, wherein the peptide has a linear structure, the N-terminus is a free amine or acetylated, and the C-terminus is an amide.

4. A peptide or a pharmaceutically acceptable salt thereof, wherein the peptide has a cyclic structure and comprises an amino acid sequence of caa-pGZX1X2C', wherein caa is α-covalently linked-acetyl and C' is cysteine ​​linked to caa via a thiol group.

5. In the first paragraph, a peptide comprising the amino acid sequence of pGZX1X2 p is L-trans-4-hydroxyproline, G is glycine, Z is Q, X1 is A, V, or Aib, X2 is L or V, a peptide or a pharmaceutically acceptable salt thereof.

6. In the first paragraph, a peptide comprising the amino acid sequence of pGZX1X2 p is L-trans-4-hydroxyproline, G is glycine, Z is Q, X1 is A or L, X2 is a peptide or a pharmaceutically acceptable salt thereof, wherein X2 is A, L, V, or Aib.

7. In the first paragraph, a peptide comprising the amino acid sequence of pGZX1X2, p is L-trans-4-hydroxyproline, G is glycine, Z is N X1 is A, X2 is a peptide or a pharmaceutically acceptable salt thereof, wherein X2 is A, L, V, or Aib.

8. In the 7th paragraph, a peptide comprising the amino acid sequence of pGZX1X2, p is L-trans-4-hydroxyproline, G is glycine, Z is N X1 is A, X2 is V, a peptide or a pharmaceutically acceptable salt thereof.

9. A peptide or a pharmaceutically acceptable salt thereof having a length of 5 to 10 amino acids according to claim 1.

10. A peptide or a pharmaceutically acceptable salt thereof having a length of 5 or 6 amino acids according to claim 1.

11. A peptide or a pharmaceutically acceptable salt thereof selected from the group consisting of amino acid sequences of SEQ ID NOs: 1 to 21 in the first paragraph. Here, free means that the amine at the N-terminus of the peptide is not bound to another molecule, Ac means that the amine at the N-terminus of the peptide is acetylated, caa means α-covalently linked-acetyl, and C' means cysteine ​​linked to caa with a thiol.

12. In claim 11, a peptide or a pharmaceutically acceptable salt thereof selected from the group consisting of amino acid sequences of SEQ ID NOs: 4, 7, 16, 18, 20 and 21.

13. A peptide or a pharmaceutically acceptable salt thereof, which is a monomer, dimer, trimer, or tetramer, in the first paragraph.

14. In paragraph 1, a peptide or a pharmaceutically acceptable salt thereof selected from the group consisting of compounds having the following chemical structural formula:

15. An anti-inflammatory composition comprising a peptide of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition for preventing or treating an inflammatory disease, comprising a peptide of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

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