Cyclic peptide for protecting vascular endothelial cells as well as derivative and application of cyclic peptide

Abstract

The invention discloses a cyclic peptide for protecting vascular endothelial cells, a fatty acid derivative and application thereof. The cyclic peptide and the derivative thereof are glucagon-like peptide-1 receptor agonists, can inhibit generation of mitochondrial superoxide radicals, increase release of nitric oxide, protect and promote vascular remodeling, and can be used for treating hyperlipidemia. The compound can be used as an effective raw material for preparing medicines for treating or preventing related ischemic diseases such as diabetic lower limb ischemia, cerebral apoplexy ischemia and peripheral atherosclerosis.

Description

Technical Field

[0001] The present invention relates to a cyclic peptide for protecting vascular endothelial cells, derivatives thereof (such as those chemically modified with fatty acids), and also to their uses. Background Art

[0002] There is a close association between peripheral atherosclerosis and vascular injury. Peripheral atherosclerosis is a chronic inflammatory disease caused by various factors, including hypertension, hyperlipidemia, diabetes, smoking, obesity, etc. These factors can lead to endothelial cell injury. When endothelial cells are damaged, inflammatory mediators and growth factors are released, promoting cell proliferation and lipid accumulation in the vascular wall. These lipid substances gradually form plaques, called atherosclerotic plaques. The formation of plaques leads to stenosis of the vascular lumen and obstruction of blood flow, resulting in tissue ischemia and insufficient oxygen supply. Therefore, the prevention and treatment of peripheral atherosclerosis require considering both reducing risk factors and protecting vascular health. This includes controlling blood pressure, blood lipids and blood glucose levels, and improving lifestyle, including smoking cessation, a healthy diet and moderate exercise. However, there are currently no reported drugs for repairing blood vessels in clinical practice.

[0003] Ischemic stroke is a common central nervous system disease, also known as cerebral infarction. It is caused by interruption or reduction of blood flow supply to the brain, resulting in cerebral ischemia and injury. Ischemic stroke accounts for approximately 80 - 85% of all stroke cases. The causes of ischemic stroke can be diverse, but the most common cause is arterial stenosis or occlusion. Arterial stenosis refers to the blockage or constriction of blood vessels within the arterial wall, resulting in reduced or blocked ability of blood to flow to the brain. Arterial occlusion is generally caused by atherosclerosis (the most common form of vascular injury), where plaques may rupture or form thrombi, blocking the arteries that supply blood to specific regions of the brain. Therefore, ischemic stroke is also closely related to vascular injury. The occurrence of vascular injury can lead to insufficient blood supply to the brain, ultimately resulting in ischemic injury and dysfunction of brain tissue. In summary, the prevention and treatment of vascular injury are of great significance for preventing and improving the occurrence of ischemic stroke.

[0004] Diabetic lower extremity ischemia refers to a condition of insufficient blood supply to the lower extremities caused by diabetes, which is particularly severely damaged in type 2 diabetes patients. The pathogenic reason is that under a hyperglycemic environment, the oxidative stress signaling pathway is activated, generating a large amount of oxygen free radicals (ROS) that damage vascular endothelial cells, thus causing diabetic lower extremity ischemia. Except for surgical treatment, current drug treatments cannot effectively improve the damaged blood vessels.

[0005] The common problem of the above-mentioned diseases is how to effectively prevent the harm caused by vascular injury. The cyclic peptide developed based on this problem in this project can effectively inhibit the release of ROS from mitochondria, and at the same time stimulate vascular endothelial cells to release nitric oxide, thereby promoting the repair of endothelial cells and remodeling blood vessels. In addition, the fatty acid derivative of the cyclic peptide can capture plasma albumin and prolong the drug efficacy of the cyclic peptide. Summary of the Invention

[0006] The object of the present invention is: based on the latest research results of the inventors, to provide a cyclic peptide for protecting vascular endothelial cells, and this cyclic peptide and its fatty acid-modified derivatives can inhibit the generation of mitochondrial superoxide free radicals, increase the release of nitric oxide, and have the effect of protecting and promoting vascular remodeling.

[0007] This cyclic peptide is a glucagon-like peptide-1 receptor agonist, which can inhibit the release of ROS from mitochondria, promote the repair of endothelial cells, and then remodel blood vessels.

[0008] Another object of the present invention is to provide a fatty acid-modified derivative of this cyclic peptide, and this derivative can bind to albumin in plasma and prolong the drug efficacy of the cyclic peptide.

[0009] Another object of the present invention is to provide the uses of the cyclic peptide and its fatty acid-modified derivatives, including the treatment and prevention of three diseases: diabetic lower limb ischemia, stroke ischemia, myeloid radiation sickness, and peripheral atherosclerosis.

[0010] The technical solution of the present invention is as follows:

[0011] A cyclic peptide for protecting vascular endothelial cells, characterized in that it is arranged in sequence from the N-terminus to the C-terminus, including a first amino acid, a second amino acid, a third amino acid, a fourth amino acid, and a fifth amino acid. The first amino acid and the fifth amino acid form a chemical bond (for example: a covalent bond is formed between the N-terminus of the first amino acid and the C-terminus of the fifth amino acid), thus forming a cyclic pentapeptide;

[0012] The first amino acid is Leu (L), the second amino acid is Val (V), the fourth amino acid is Gly (G), and the fifth amino acid is Lys (K) or Arg (R).

[0013] The third amino acid is selected from Ala, Lys, Ile, Met, Trp, Tyr, Phe, or His.

[0014] Another cyclic peptide for protecting vascular endothelial cells further includes a fatty acid (such as: containing 1 to 18 carbon atoms), which is connected to the side chain of any amino acid, for example: the side chain of the fifth amino acid. The fatty acid contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18 carbon atoms.

[0015] Another cyclic peptide for protecting vascular endothelial cells further comprises a fatty acid and several 2-(2-(aminomethoxy)ethoxy)acetyl monomers, and the number of 2-(2-(aminomethoxy)ethoxy)acetyl monomers is 1, 2, 3 or 4. The fatty acid is linked to 2-(2-(aminomethoxy)ethoxy)acetyl, and at least one 2-(2-(aminomethoxy)ethoxy)acetyl is linked to the amino nitrogen atom.

[0016] Another cyclic peptide for protecting vascular endothelial cells is shown by the following formula:

[0017]

[0018] Wherein, na is 1 to 4 repeating units 结 of 构式 2-(2-(aminomethoxy)ethoxy)acetyl; nb is a dicarboxylic acid with a carbon atom length of 1 to 18.

[0019] The use of the cyclic peptide for protecting vascular endothelial cells of the present invention in the preparation of a drug or a pharmaceutical composition for preventing or treating diabetic lower extremity ischemia.

[0020] The use of the cyclic peptide for protecting vascular endothelial cells of the present invention in the preparation of a drug or a pharmaceutical composition for preventing or treating ischemic stroke.

[0021] The use of the cyclic peptide for protecting vascular endothelial cells of the present invention in the preparation of a drug or a pharmaceutical composition for preventing or treating peripheral atherosclerosis.

[0022] The use of the fatty acid-modified derivative of the cyclic peptide for protecting vascular endothelial cells of the present invention in the preparation of a drug or a pharmaceutical composition for preventing or treating diabetic lower extremity ischemia.

[0023] The use of the fatty acid-modified derivative of the cyclic peptide for protecting vascular endothelial cells of the present invention in the preparation of a drug or a pharmaceutical composition for preventing or treating ischemic stroke.

[0024] The use of the fatty acid-modified derivative of the cyclic peptide for protecting vascular endothelial cells of the present invention in the preparation of a drug or a pharmaceutical composition for preventing or treating peripheral atherosclerosis.

[0025] Compared with the prior art, the polypeptide and its fatty acid-modified derivative of the present invention can efficiently prevent vascular injury and have a long-term effect on vascular remodeling. Brief Description of the Drawings

[0026] Figure 1 It is a schematic diagram of the chemical structure of the cyclic peptide synthesized in an embodiment of the present invention;

[0027] Figure 2 It is the mass spectrum of the cyclic peptide prepared in an embodiment of the present invention;

[0028] Figure 3 The result graph of the effect of the cyclic peptide prepared in an embodiment of the present invention on the proliferation of HUVEC cells;

[0029] Figure 4 The result graph of the effect of the cyclic peptide prepared in an embodiment of the present invention on angiogenesis;

[0030] Figure 5 The plasma-time pharmacokinetic curve graph of the cyclic peptide prepared in an embodiment of the present invention;

[0031] Figure 6 It is a blood flow graph, wherein, A is the Doppler blood flow graph of the GLP-1(32-36)a preparation; B is the blood flow statistical graph of the GLP-1(32-36)a preparation. Detailed implementation manners

[0032] The technical solutions of the present invention will be described in detail below with reference to the accompanying drawings. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention rather than to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention, and they should all be covered within the scope of the claims of the present invention.

[0033] Example 1 Synthesis of cyclic peptide

[0034] (1) Select a vertical reactor (20*250mm) and write the name of the polypeptide on the reactor as a label. Weigh 2 mmol of Fmoc-Arg(Pbf)-OH and 2 mmol of DIEA with an electronic balance, put them into the reactor, and add DCM to soak for 90 min.

[0035] (2) Use a disposable pipette to suck the 2-CL-Resin solution dissolved in DMF and add it to the reactor containing it, and react with nitrogen bubbling for 90 min. After the reaction, wash the resin.

[0036] (3) Washing: After drying the liquid in the reactor with a circulating water vacuum pump, add industrial-grade DMF to the reactor with a wash bottle. The reagent volume is about 3 times the volume of the resin, wash for 30 s, and then dry the liquid in the reactor with a circulating water vacuum pump. Repeat this operation 4 times.

[0037] (4) Deprotect Fmoc: Add 20% piperidine / DMF solution to the reactor with a wash bottle. The reagent volume is about 3 times the volume of the resin, and react with nitrogen bubbling for 20 min.

[0038] (5) Washing: Refer to 1.5, and replace the industrial-grade DMF with analytical-grade DMF during the fifth washing process;

[0039] (6) Resin detection: Use a long-necked pipette to take 10 - 20 resin beads from the reactor and place them at the bottom of the test tube. Then, use a dropper to add two drops of each of the detection reagents A and B into the test tube to ensure that the resin is in full contact with the detection reagents. Next, place the test tube in a 100°C constant temperature water bath for 2 minutes. Observe the color of the resin. If the resin shows color, it indicates successful removal of Fmoc; if not, repeat steps (4) - (6).

[0040] (7) Condensation: Weigh 2 mmol of Fmoc-Gly-OH and 6 mmol of HOBT and add them to a centrifuge tube. Then add analytical grade DMF and DIC and shake well. Use a disposable pipette to aspirate the Rink-Resin solution dissolved in DMF and add it to the reactor. Bubble nitrogen through the reaction mixture for 90 minutes. After the reaction is completed, wash the resin, and then add acetic anhydride in DCM solution to block the reaction for 20 minutes.

[0041] (8) Resin detection: Refer to (6), observe the color of the resin. If it is colorless, it indicates complete connection, and proceed to step (9); if it has color, repeat step (7).

[0042] (9) Washing, same as (5).

[0043] (10) Condensation: Weigh 6 mmol of (Dde-Lys(Fmoc)-OH) and 6 mmol of HOBT in a centrifuge tube. After fully dissolving them with 10 ml of DMF, add DIC and mix well. Then add the mixture to the dried resin and bubble nitrogen through the reaction mixture for 1 hour.

[0044] (11) Resin detection: Refer to (6), observe the color of the resin. If it is colorless, it indicates complete connection, and proceed to step (9); if it has color, repeat step (7).

[0045] (12) Washing, same as (5).

[0046] (13) Condensation: Weigh 6 mmol of (2-tBuO-Oct-Glu(AEEA-AEEA-OH)-OtBu) and 6 mmol of HOBT in a centrifuge tube. After fully dissolving them with 10 ml of DMF, add DIC and mix well. Then add the mixture to the dried resin and bubble nitrogen through the reaction mixture for 1 hour.

[0047] (14) Resin detection: Refer to (6), observe the color of the resin. If it is colorless, it indicates complete connection, and proceed to step (9); if it has color, repeat step (7).

[0048] (15) Washing, same as (5).

[0049] (16) Condensation: Weigh 6 mmol of (2-FMOC-Val-OH) and 6 mmol of HOBT into a centrifuge tube. After fully dissolving them with 10 ml of DMF, add DIC and mix well. Then add the mixture to the dried resin and react under nitrogen bubbling for 1 h.

[0050] (17) Resin detection: Refer to 1.8. Observe the color of the resin. If it is colorless, it indicates complete connection, and proceed to operation (9); if it has a color, repeat (14).

[0051] (18) Washing, the same as (5).

[0052] (19) Condensation: Weigh 6 mmol of (2-FMOC-Leu-OH) and 6 mmol of HOBT into a centrifuge tube. After fully dissolving them with 10 ml of DMF, add DIC and mix well. Then add the mixture to the dried resin and react under nitrogen bubbling for 1 h.

[0053] (20) Resin detection: Refer to (6). Observe the color of the resin. If it is colorless, it indicates complete connection, and proceed to operation (9); if it has a color, repeat (13).

[0054] (21) Washing, the same as (5).

[0055] (22) Deprotection of Fmoc: Use a wash bottle to add 20% piperidine / DMF solution to the reactor. The volume of the reagent is about 3 times the volume of the resin, and react under nitrogen bubbling for 20 min.

[0056] (23) Washing, the same as (5).

[0057] (24) Deprotection of Resin: Use a wash bottle to add 20% TFE / DCM solution to the reactor. The volume of the reagent is about 3 times the volume of the resin, and react under nitrogen bubbling for 20 min.

[0058] (25) Washing, the same as (5).

[0059] (26) Condensation: Weigh 6 mmol of NH2-Leu-Val-Lys(tBuO-Oct-Gu(AEEA-AEEA-OH)-tBuO)-Gly-Arg(Pbf)-OH and 6 mmol of HOBT into a centrifuge tube. After fully dissolving them with 10 ml of DMF, add DIC and mix well. Then add the mixture to the dried resin and react under nitrogen bubbling for 1 h.

[0060] (27) Resin detection: Refer to (6). Observe the color of the resin. If it is colorless, it indicates complete connection, and proceed to operation (9); if it has a color, repeat (13).

[0061] (28) Washing, the same as (5).

[0062] (29) Deprotection of Boc: Add 95% TFA / H2O solution to the reactor with a wash bottle. The volume of the reagent is about 3 times that of the resin. React under nitrogen bubbling for 20 min.

[0063] (30) Repeat the operations in (4)-(6) until the Fmoc is finally removed after peptide coupling, and then perform washing.

[0064] (31) Resin detection: Refer to (6), observe the color of the resin, then wash the resin 3 times with methanol according to the washing method, and finally dry the liquid in the reactor with a circulating water vacuum pump.

[0065] (32) Prepare the cleavage reagent (95 mL TFA + 1 mL water + 2 mL EDT + 2 mL Tis). Weigh the dried resin, add the cleavage solution and react for 2 h. Then precipitate with -20°C ether, and then perform peptide purification.

[0066] (33) Use a semi-preparative liquid chromatograph for peptide purification. The specific chromatographic conditions are as follows:

[0067] Chromatographic column: 30*250 mm DAISOGEL 8 μm; Mobile phase: A: 0.1% TFA water, B: 0.1% TFA acetonitrile; Flow rate: 12 ml / min; Load the sample onto the A pump, then start running after equilibrating with 10% acetonitrile level for 5 min. Prepare and collect the detected sample peak, with the analyzed purity greater than 95%, and lyophilize the sample.

[0068] Perform mass spectrometry analysis on the sample using an Agilent 1290 liquid chromatograph - tandem 6490 triple quadrupole mass spectrometer. Figure 2 The mass spectrometry information of the prepared sample is shown. It is confirmed by the molecular weight that the obtained sample is Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg], and the chemical formula is as Figure 1 shown.

[0069] Experimental Example 2 Cellular Evaluation of the Inhibition of ROS Release from Mitochondria by Cyclic Peptide

[0070] Obtain Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg] (cyclic peptide) prepared in Example 1.

[0071] (1) Select HUVEC cells acclimated in low-glucose medium as model cells. Count the prepared cell suspension (1×10 5 cells / ml) with a cell counting chamber, dilute it to an appropriate concentration, and then inoculate the cell suspension into a 96-well plate at a volume of 100 μl per well. Place the 96-well plate in a 37°C CO2 incubator and culture for 24 h.

[0072] (2) When the cells grow to 60%-70% confluence, administer the drug stimulation according to the groups for 24 h. At the same time, set up blank wells and control wells. After 24 h of stimulation, change the cell culture medium. After rinsing twice with PBS, add 100 μL of fresh culture medium to each well.

[0073] (3) Add 10 μL of CCK-8 reagent to each well. At this time, pay attention not to generate bubbles, because bubbles will affect the subsequent detection of absorbance. Place the culture plate on a microplate shaker and shake for 10-15 s. After fully mixing, incubate in the incubator in the dark for 1-4 hours. After sufficient reaction, it can be taken out.

[0074] (4) Measure the OD value at 450 nm with an enzyme-labeled instrument, and calculate the cell viability according to the formula provided in the instruction manual.

[0075] In the established in vitro model of HUVECs under high glucose treatment, it was found that Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg] had no obvious toxicity at a concentration below 80 nM, and could increase the cell survival rate in a concentration-dependent manner ( Figure 3 ). It indicates that Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg] can effectively inhibit the decrease in cell viability induced by high glucose.

[0076] Experimental Example 3 Verification of the promotion of angiogenesis by the cyclic peptide

[0077] Obtain Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg] prepared in Example 1.

[0078] (1) Place the 12-well plate and 1 mL pipette tips in a 4 °C refrigerator for pre-cooling. Place the Matrigel in a 4 °C refrigerator to dissolve. After complete dissolution, aliquot it into pre-cooled centrifuge tubes, 1 mL per tube. After aliquoting, store it at -20 °C to avoid repeated freezing and thawing.

[0079] (2) Select HUVEC cells acclimated in low-glucose medium as the model cells. Count the prepared cell suspension (1*10 5 cells / ml) with a cell counting chamber. Divide the cells into a control group and a Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg] group. Add 80 nM of the drug to each well in the Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg] group for treatment and stimulate for 24 h.

[0080] (3) Use a pre-cooled 1 mL pipette tip to aspirate about 500 μL of Matrigel and spread it evenly on a 12-well plate, avoiding the formation of air bubbles. Conduct the whole process on ice. Subsequently, place the 12-well plate in a 37 °C incubator for gelation for 30 min.

[0081] (4) Prepare the cell suspension during the gelation process. Digest the cells in each group from the pre-treated cell plate. Count the cells using a cell counting chamber and prepare a 1×10 5 suspension.

[0082] (5) After 30 min, take out the 12-well plate coated with Matrigel from the incubator and aspirate the un-gelled liquid. Slowly add the cell suspension, adding 200 μL to each well. After adding, gently mix well, taking care not to generate air bubbles and the pipette tip not to touch the Matrigel. Carefully place it in a 37 °C incubator. Take out the culture plate after 6 - 12 hours, observe the tube formation under a microscope, take pictures, and conduct image analysis.

[0083] Under high glucose stimulation, the tube formation ability of HUVECs was significantly impaired, while the group treated with Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg] showed obvious angiogenesis ( Figure 4 ), indicating that Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg] can effectively alleviate the damage of high glucose to cells.

[0084] Experimental Example 4 Pharmacokinetic Study of Cyclopeptide

[0085] Obtain Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg] prepared in Example 1.

[0086] Select Sprague-Dawley rats (SD rats, male, 200 ± 10 g) as model animals. Intravenous inject 10 micrograms of Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg] into each rat. Collect blood from the tail vein at the predetermined time points. Centrifuge at 1700×g and take the supernatant plasma. Mix the plasma sample with acetonitrile at a volume ratio of 1:3, centrifuge at 1700×g, take the supernatant, and determine the plasma drug concentration by LC-MS. The chromatographic conditions of LC-MS are as follows: C18 column (Waters, 150×4.6 mm, ) The mobile phase was formic acid solution and acetonitrile, the flow rate was 0.3 ml / min, and the injection volume was 5 μl. Mass spectrometry conditions: Using an Agilent 6400 series triple quadrupole mass spectrometer in ESI negative ion mode, and analyzing by multiple reaction ion detection (MRM). The anion electrospray mass spectrometry voltage was -2200 V. The flow rate of dry nitrogen gas was 5.0 L / min, and the gas temperature was 260 °C. Detection ion pairs: Res1227.8→613.6, Res-G 613.6→227.1. Finally, the obtained data was analyzed using (Version 5.2.1, Pharsight Co., Mountain View, USA).

[0087] The half-life of Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg] in vivo was 48 h, and the mean residence time was 800 ± 20 h. This experiment showed that the drug had a long residence time in plasma, indicating the long-acting property of Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg] in preventing vascular injury.

[0088] Experimental Example 5 Pharmacodynamics Study of Cyclic Peptide

[0089] Obtain Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg] prepared in Example 1.

[0090] Select Balb / C mice (male, 20 ± 1 g) as model animals, and establish a diabetic mouse model by injecting streptozotocin (70 mg / kg). Select 18 diabetic mice (male, 21 ± 1 g) and divide them into a model group, a subcutaneous injection of Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg] group (each mouse was subcutaneously administered 10 μg of Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg], and only administered once within 30 days), and a subcutaneous injection of liraglutide group (each mouse was microinjected with 10 μg of liraglutide once a day for 30 consecutive days). There were 6 mice in each group. Use a razor to shave the back hair of the mice. For each group of mice, the blood flow perfusion of the right lower limb before modeling was measured using a lower limb blood flow Doppler instrument. The model group was not treated, and the blood flow perfusion of the healthy and diseased lower limbs of the mice was measured at the predetermined time points to compare the improvement of blood flow perfusion in the lower limbs of mice in different groups.

[0091] Through Figure 6A observed that on the day of surgery, blood flow in the right hind leg of the mice decreased significantly, indicating the successful establishment of the diabetic lower limb ischemia model. Figure 6 A and Figure 6 B showed that after 30 days of treatment, there were significant differences in blood perfusion between the treatment group and the model group, indicating that subcutaneous injection of Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg] could effectively promote microvascular formation. In addition, there was no statistical difference in the drug efficacy between Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg] injected subcutaneously only once within 30 days and liraglutide injected subcutaneously every day. This result proved that Cyclo-[Leu-Val-Lys(AEEA-AEEA-γ-Glu-Oct)-Gly-Arg] had good long-acting properties.

Claims

1. A cyclic peptide for protecting vascular endothelial cells, characterized in that, It is characterized in that It is arranged in sequence from the N-terminal to the C-terminal, including the first amino acid, the second amino acid, the third amino acid, the fourth amino acid and the fifth amino acid. The first amino acid and the fifth amino acid form a chemical bond to form a cyclic pentapeptide; The first amino acid is Leu, the second amino acid is Val, and the fourth amino acid is Gly.

2. The cyclic peptide for protecting vascular endothelial cells according to claim 1, characterized in that, The fifth amino acid is selected from Arg or Lys.

3. The cyclic peptide for protecting vascular endothelial cells according to claim 1, characterized in that, The third amino acid is selected from Ala, Lys, Ile, Met, Trp, Tyr, Phe or His.

4. The cyclic peptide for protecting vascular endothelial cells according to claim 1, wherein It also includes fatty acids.

5. The cyclic peptide for protecting vascular endothelial cells according to claim 1, characterized in that, It also includes fatty acids and several 2-(2-(aminomethoxy)ethoxy)acetyl monomers. The fatty acid is linked to 2-(2-(aminomethoxy)ethoxy)acetyl, and at least 1 2-(2-(aminomethoxy)ethoxy)acetyl is linked to the amino nitrogen atom.

6. The cyclic peptide for protecting vascular endothelial cells according to claim 1, characterized in that, The number of 2-(2-(aminomethoxy)ethoxy)acetyl is 1, 2, 3 or 4.

7. Use of the cyclic peptide for protecting vascular endothelial cells according to claim 1 in the preparation of a drug for preventing or treating diabetic lower limb ischemia.

8. Use of the cyclic peptide for protecting vascular endothelial cells according to claim 1 in the preparation of a drug for preventing or treating ischemic stroke.

9. Use of the cyclic peptide for protecting vascular endothelial cells according to claim 1 in the preparation of a drug for preventing or treating peripheral arteriosclerosis.

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