Synthetic peptides and their applications

Abstract

The present invention discloses synthetic peptides and their applications, which belong to the pharmaceutical technology field. Its chemical formula is (Gly)x-(beta-Ala-L-His)y-(Gly)z, (Gly)x-(beta-Ala-L-1-Methyl-His)y-(Gly)z or (Gly)x-(beta-Ala-L-3-Methyl-His)y-(Gly)z, where y is 1 or more, x and z are 0-3, and x and z are not 0 at the same time. The synthetic peptide of the present invention is creatively composed of glycine, carnosine, anserine, ophidine, etc. The developed mosaic synthetic peptide unexpectedly breaks through the blood-brain barrier by intravenous injection, enters the brain, and is effectively useful in the treatment of neurological diseases. In the present invention, a remarkable therapeutic effect can be achieved by intravenously administering only 3 mg / kg of synthetic peptide.

Description

[Technical Field]

[0001] The present invention belongs to the pharmaceutical technology field and relates to synthetic peptides and their applications. [Background technology]

[0002] Glycine is the amino acid with the simplest chemical structure. Despite its simple structure, glycine is an important inhibitory neurotransmitter in the central nervous system, playing a key role in controlling neuronal excitability. Animal experiments have confirmed that glycine has significant neuroprotective effects. Several clinical trials have also found that glycine can improve cognitive impairment and dementia.

[0003] Carnosine (L-carnosine) is a dipeptide composed of two amino acids, β-alanine and L-histidine. Carnosine possesses excellent antioxidant properties and is beneficial to the human body. Carnosine has been shown to scavenge reactive oxygen radicals (ROS) and α-β-unsaturated aldehydes, which are produced by the peroxidation of fatty acids in cell membranes under oxidative stress. Due to its anti-inflammatory, anti-glycation, antioxidant, and chelating properties, carnosine is promising as a non-prescription dietary supplement for the prevention and adjuvant treatment of chronic diseases such as cardiovascular disease and neurodegenerative disorders. Animal studies have confirmed that carnosine's neuroprotective mechanism protects against chronic cerebral ischemia. Carnosine is also an important intracellular antioxidant. Not only is carnosine nontoxic, but its potent antioxidant properties have led to widespread interest as a novel food additive and drug. Carnosine is involved in intracellular peroxidation, inhibiting not only the peroxidation process of cell membranes but also related intracellular peroxidation. Since the Russian scientist Gulewitsch first discovered carnosine in 1900, scientists around the world have extracted and isolated other histidine dipeptide derivatives from different muscle tissues. For example, anserine is a dipeptide composed of two amino acids, β-alanine and 1-methyl-L-histidine, and balenine (also known as ophidine) is a dipeptide composed of β-alanine and 3-methyl-L-histidine. The content of these carnosine and carnosine derivatives varies between animals, and the content and ratio of these histidine dipeptides also varies between species, with some degree of specificity. In addition to the presence of histidine dipeptides in muscle tissue, these dipeptides are also present in other tissues, such as brain tissue. These carnosine derivatives are highly water-soluble and have significant antioxidant, anti-aging, and uric acid-lowering properties. They have been used in the food industry as natural antioxidants and uric acid-lowering drugs, and also have some neuroprotective properties.

[0004] Glycine, carnosine, and carnosine derivatives all have some degree of neuroprotective effect, but require relatively large doses. For example, the peripheral dose of glycine is as high as 800 mg / kg. This can cause serious side effects and is inconvenient to use, limiting their practical clinical application. Carnosine, anserine, ophidine, etc., when used alone, are not very effective, and their therapeutic effects are significantly different from those of the new drug NA-1. Summary of the Invention

[0005] The present invention provides synthetic peptides. These synthetic peptides are composed of one or more of glycine, β-alanine, histidine, 1-methylhistidine, and 3-methylhistidine, particularly glycine, carnosine, anserine, or ophidine, and are polypeptide compounds that combine the structural features of carnosine, anserine, or ophidine with glycine. These peptides unexpectedly cross the blood-brain barrier easily and exhibit excellent biological activity upon intravenous administration, making them highly promising for the treatment of neurological disorders, particularly brain injury and stroke. The technical proposal is as follows:

[0006] In one aspect, embodiments of the present invention provide a synthetic peptide having the formula: (Gly)x-(beta-Ala-His)y-(Gly)z, or (Gly)x-(beta-Ala-1-Methyl-His)y-(Gly)z, or (Gly)x-(beta-Ala-3-Methyl-His)y-(Gly)z. In the formula, x is an integer of 0 to 3 (e.g., 0, 1, 2, and 3), y is an integer of 1 to 3 (e.g., 1, 2, and 3), and z is an integer of 0 to 3 (e.g., 0, 1, 2, and 3), and x and z are not simultaneously 0.

[0007] Here, the abbreviations for the amino acids according to the present invention are as follows: Glycine: Gly; β-alanine: β-Ala or beta-Ala; L-histidine: His; 1-methylhistidine: 1-Methyl-His or (1-Methyl-His); 3-methylhistidine: 3-Methyl-His or (3-Methyl-His).

[0008] Here, with respect to the formula (Gly)x-(beta-Ala-His)y-(Gly)z, the chemical formula may be any one selected from the following: (a) beta-Ala-His-Gly; (b) Gly-beta-Ala-His; (c) beta-Ala-His-Gly-Gly; (d) Gly-Gly-beta-Ala-His; (e) Gly-beta-Ala-His-Gly; (f)Gly-Gly-beta-Ala-His-Gly-Gly; (g)beta-Ala-His-beta-Ala-His-Gly; (h)Gly-beta-Ala-His-beta-Ala-His; (i)beta-Ala-His-beta-Ala-His-Gly-Gly; (j)Gly-Gly-beta-Ala-His-beta-Ala-His; (k)Gly-beta-Ala-His-beta-Ala-His-Gly; (l)Gly-Gly-beta-Ala-His-beta-Ala-His-beta-Ala-His-Gly; (m)beta-Ala-His-beta-Ala-His-beta-Ala-His-Gly-Gly-Gly; (n)Gly-Gly-Gly-beta-Ala-His-beta-Ala-His-beta-Ala-His; (o)Gly-beta-Ala-His-beta-Ala-His-beta-Ala-His-Gly-Gly.

[0009] Here, with respect to the formula (Gly)x-(beta-Ala-1-Methyl-His)y-(Gly)z, the chemical formula may be any one selected from the following: (a)beta-Ala-(1-Methyl-His)-Gly; (b)Gly-beta-Ala-(1-Methyl-His); (c)beta-Ala-(1-Methyl-His)-Gly-Gly; (d)Gly-Gly-beta-Ala-(1-Methyl-His); (e)Gly-beta-Ala-(1-Methyl-His)-Gly; (f)Gly-Gly-beta-Ala-(1-Methyl-His)-Gly-Gly; (g)beta-Ala-(1-Methyl-His)-beta-Ala-(1-Methyl-His)-Gly; (h)Gly-beta-Ala-(1-Methyl-His)-beta-Ala-(1-Methyl-His); (i)beta-Ala-(1-Methyl-His)-beta-Ala-(1-Methyl-His)-Gly-Gly; (j)Gly-Gly-beta-Ala-(1-Methyl-His)-beta-Ala-(1-Methyl-His); (k)Gly-beta-Ala-(1-Methyl-His)-beta-Ala-(1-Methyl-His)-Gly; (l)Gly-Gly-beta-Ala-(1-Methyl-His)-beta-Ala-(1-Methyl-His)-beta-Ala-(1-Methyl-His)-Gly; (m)beta-Ala-(1-Methyl-His)-beta-Ala-(1-Methyl-His)-beta-Ala-(1-Methyl-His)-Gly-Gly-Gly; (n)Gly-Gly-Gly-beta-Ala-(1-Methyl-His)-beta-Ala-(1-Methyl-His)-beta-Ala-(1-Methyl-His); (o)Gly-beta-Ala-(1-Methyl-His)-beta-Ala-(1-Methyl-His)-beta-Ala-(1-Methyl-His)-Gly-Gly.

[0010] Here, with respect to the formula (Gly)x-(beta-Ala-3-Methyl-His)y-(Gly)z, the chemical formula may be any one selected from the following: (a)beta-Ala-(3-Methyl-His)-Gly; (b)Gly-beta-Ala-(3-Methyl-His); (c)beta-Ala-(3-Methyl-His)-Gly-Gly; (d)Gly-Gly-beta-Ala-(3-Methyl-His); (e)Gly-beta-Ala-(3-Methyl-His)-Gly; (f)Gly-Gly-beta-Ala-(3-Methyl-His)-Gly-Gly; (g)beta-Ala-(3-Methyl-His)-beta-Ala-(3-Methyl-His)-Gly; (h)Gly-beta-Ala-(3-Methyl-His)-beta-Ala-(3-Methyl-His); (i)beta-Ala-(3-Methyl-His)-beta-Ala-(3-Methyl-His)-Gly-Gly; (j)Gly-Gly-beta-Ala-(3-Methyl-His)-beta-Ala-(3-Methyl-His); (k)Gly-beta-Ala-(3-Methyl-His)-beta-Ala-(3-Methyl-His)-Gly; (l)Gly-Gly-beta-Ala-(3-Methyl-His)-beta-Ala-(3-Methyl-His)-beta-Ala-(3-Methyl-His)-Gly; (m)beta-Ala-(3-Methyl-His)-beta-Ala-(3-Methyl-His)-beta-Ala-(3-Methyl-His)-Gly-Gly-Gly; (n)Gly-Gly-Gly-beta-Ala-(3-Methyl-His)-beta-Ala-(3-Methyl-His)-beta-Ala-(3-Methyl-His); (o)Gly-beta-Ala-(3-Methyl-His)-beta-Ala-(3-Methyl-His)-beta-Ala-(3-Methyl-His)-Gly-Gly.

[0011] Preferably, the chemical formula of the synthetic peptide of the present invention may be any one selected from the following: (a) beta-Ala-His-Gly; (b) Gly-beta-Ala-His; (c) beta-Ala-His-Gly-Gly; (d) Gly-Gly-beta-Ala-His; (e) Gly-beta-Ala-His-Gly; (f)Gly-Gly-beta-Ala-His-Gly-Gly.

[0012] More preferably, the chemical formula of the synthetic peptide of the present invention may be any one selected from the following: (a) beta-Ala-L-His-Gly; (b) Gly-beta-Ala-L-His.

[0013] In another aspect, the present invention provides use of the synthetic peptide or a salt thereof in a pharmaceutical product. The present invention also provides use of the synthetic peptide or a salt thereof in the treatment of a neurological disease. The present invention also provides a method for treating a neurological disease using the synthetic peptide or a salt thereof.

[0014] Specifically, the neurological disease is ischemic stroke, hemorrhagic stroke, brain injury, Alzheimer's disease, Parkinson's disease or other neurodegenerative diseases. Preferably, the neurological disease is ischemic stroke.

[0015] The synthetic peptides or salts thereof provided by the present invention can be prepared as pharmaceuticals. The pharmaceuticals are injections. Specifically, the injections include powder injections or liquid injections. Furthermore, the pharmaceuticals are administered intravenously. The active ingredient of the pharmaceuticals may be in other dosage forms depending on the corresponding medical application. Formulations developed as neuroprotective agents may include oral and sublingual formulations. Formulations developed for emergency stroke treatment of incapacitated patients may include aerosols, rectal formulations, and other formulations. In yet another aspect, the present invention provides a method for preparing various multifunctional polypeptides according to the present invention by solid-phase synthesis, although liquid-phase synthesis is more convenient for some peptides. Salt formation of polypeptide drugs is a common means for improving the physicochemical properties of drug molecules and enhancing drug formability. The drugs may be in any form of salt.

[0016] In this invention, to confirm the use of the synthetic peptides provided in this patent for neurological disorders, SD rats were used as experimental subjects, and a cerebral ischemia model rat was created by middle cerebral artery occlusion (MCAO). One to two hours after ischemia, drugs were intravenously injected, and behavioral observation and scoring of each animal were performed 22 to 24 hours later. After behavioral observation, the experimental rats were euthanized, and their brains were removed. Brain tissue was excised and stained with TTC for quantitative analysis, and the volume percentage of cerebral infarction was calculated.

[0017] The synthetic peptides of the present invention are creatively composed of a combination of glycine, carnosine, anserine, or ophidine. The developed mosaic-type synthetic peptides unexpectedly penetrate the blood-brain barrier and enter the brain via intravenous injection, effectively treating neurological disorders. These synthetic peptides are applicable to the treatment of ischemic cerebral infarction, hemorrhagic cerebral infarction, brain injury, Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. In this invention, significant therapeutic effects are achieved by intravenous administration of only 3 mg / kg of the synthetic peptide, which is equivalent to the therapeutic effects achieved by the clinically active standard polypeptide NA1.

[0018] The synthetic peptides consist of glycine, carnosine, anserine, or ophidine, all of which are natural amino acids or peptides, making them safe and reliable.

[0019] Furthermore, the synthetic peptides of the present invention can be easily synthesized, and in the synthesis process, derivatives of carnosine, anserine, or ophidine can be used as synthetic fragments instead of the corresponding two amino acids, further simplifying the synthesis of the target peptide. Furthermore, such short peptide fragments, for example, beta-Ala-His-Gly, Gly-beta-Ala-His, beta-Ala-His-Gly-Gly, Gly-Gly-beta-Ala-His, Gly-beta-Ala-His-Gly, beta-Ala-(1-Methyl-His)-Gly, Gly-beta-Ala-(1-Methyl-His), beta-Ala-(1-Methyl-His)-Gly-Gly, Gly-Gly-beta-Ala-(1-Methyl-His) ), Gly-beta-Ala-(1-Methyl-His)-Gly, beta-Ala-(3-Methyl-His)-Gly, Gly-beta-Ala-(3-Methyl-His), beta-Ala-(3-Methyl-His)-Gly-Gly, Gly-Gly-beta-Ala-(3-Methyl-His) and Gly-beta-Ala-(3-Methyl-His)-Gly can be obtained by liquid phase synthesis, which is inexpensive and convenient for future large-scale production and product quality control. [Brief explanation of the drawings]

[0020] [Figure 1] Cross-sections of brain tissue from the model group. [Figure 2] Cross-section of brain tissue from group S1. [Figure 3] Cross-section of brain tissue from group S8. [Figure 4] Cross-section of brain tissue from S9 group. [Figure 5] Cross-section of brain tissue from the sham-operated group. DETAILED DESCRIPTION OF THE INVENTION

[0021] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with the accompanying drawings.

[0022] Example 1: Synthesis of beta-Ala-His-Gly

[0023] 1. The solid-supported 2-CTC resin is coupled with Fmoc-Pro-OH in the presence of an activator system (HoBT, DIC) to obtain Fmoc-Pro-CTC resin.

[0024] 2. Remove the Fmoc protecting group on Fmoc-Pro-CTC with 20% piperidine, followed by washing with DMF.

[0025] Weigh out a 3.3-fold excess of Fmoc-His(Trt)-OH and a 3-fold excess of the activator, add a small amount of DMF, and dissolve completely. After dissolution, add the resulting mixture to the washed resin and react for 1 hour, then wash with DMF.

[0026] 4. Repeat steps 2 and 3 to couple beta-Ala to the Fmoc-His-Gly-CTC resin.

[0027] 5. After the synthesis is completed, the peptide resin is decomposed using a decomposition reagent ratio of TFA:EDT:Tis:TA:anisole:HO=80:5:1:5:5:4 (volume ratio). 10 ml of decomposition reagent is used for 1 g of peptide resin. The decomposition is carried out at room temperature for approximately 2 hours (120 r / min). After the decomposition, the peptide resin is precipitated with ice-cold methyl tert-butyl ether. The lower precipitate is the crude product.

[0028] 6. The crude peptide obtained in the previous steps is taken out, dissolved, and purified by preparative HPLC with 0.1% TFA / acetonitrile.

[0029] 7. After purification, freeze-drying is carried out, and then the powder is taken out and subjected to quality control.

[0030] Example 2: Synthesis of Gly-beta-Ala-His

[0031] 1. The solid-phase support 2-CTC resin is coupled with Fmoc-His(Trt)-OH in the presence of an activator system (HoBT, DIC) to obtain Fmoc-His(Trt)-CTC resin.

[0032] 2. Remove the Fmoc protecting group on Fmoc-His(Trt)-CTC with 20% piperidine, and after removal, wash with DMF.

[0033] Weigh out a 3.3-fold excess of Fmoc-beta-Ala-OH and a 3-fold excess of activator, add a small amount of DMF, and dissolve completely. After dissolution, add the mixture to the washed resin and react for 1 hour, then wash with DMF.

[0034] 4. Repeat steps 2 and 3 to couple Gly to the Fmoc-beta-Ala-His-CTC resin.

[0035] 5. After synthesis is complete, decomposition is carried out using a decomposition reagent ratio of TFA:EDT:Tis:TA:anisole:HO = 80:5:1:5:5:4 (volume ratio). 1g of peptide resin is decomposed using 10ml of decomposition reagent at room temperature for approximately 2 hours (120 rpm). After decomposition, the peptide is precipitated with ice-cold methyl tert-butyl ether. The lower precipitate is the crude product.

[0036] 6. The crude peptide obtained in the previous steps is taken out, dissolved, and purified by preparative HPLC with 0.1% TFA / acetonitrile.

[0037] 7. After purification, freeze-drying is carried out, and then the powder is taken out and subjected to quality control.

[0038] Example 3: Synthesis of Gly-beta-Ala-His-beta-Ala-His-Gly

[0039] 1. The solid-phase supported 2-CTC resin is coupled with Fmoc-Gly-OH in the presence of an activator system (HoBT, DIC) to obtain Fmoc-Gly-CTC resin.

[0040] 2. Remove the Fmoc protecting group on Fmoc-Gly-CTC with 20% piperidine, followed by washing with DMF.

[0041] Weigh out a 3.3-fold excess of Fmoc-His(Trt)-OH and a 3-fold excess of the activator, add a small amount of DMF, and dissolve completely. After dissolution, add the resulting mixture to the washed resin and react for 1 hour, then wash with DMF.

[0042] 4. Repeat steps 2 and 3 to sequentially couple beta-Ala, His, beta-Ala, and Gly to the Fmoc-His-Gly-CTC resin.

[0043] 5. After synthesis is complete, decomposition is carried out using a decomposition reagent ratio of TFA:EDT:Tis:TA:anisole:HO = 80:5:1:5:5:4 (volume ratio). 1g of peptide resin is decomposed using 10ml of decomposition reagent at room temperature for approximately 2 hours (120 rpm). After decomposition, the peptide is precipitated with ice-cold methyl tert-butyl ether. The lower precipitate is the crude product.

[0044] 6. The crude peptide obtained in the previous steps is taken out, dissolved, and purified by preparative HPLC with 0.1% TFA / acetonitrile.

[0045] 7. After purification, freeze-drying is carried out, and then the powder is taken out and subjected to quality control.

[0046] Example 4: Synthesis of beta-Ala-His-Gly-Gly

[0047] 1. The solid-phase supported 2-CTC resin is coupled with Fmoc-Gly-OH in the presence of an activator system (HoBT, DIC) to obtain Fmoc-Gly-CTC resin.

[0048] 2. Remove the Fmoc protecting group on Fmoc-Gly-CTC with 20% piperidine, followed by washing with DMF.

[0049] Weigh out a 3.3-fold excess of Fmoc-Gly-OH and a 3-fold excess of activator, add a small amount of DMF, and dissolve completely. After dissolution, add the resulting mixture to the washed resin and react for 1 hour, then wash with DMF.

[0050] 4. Remove the Fmoc protecting group on Fmoc-Gly-Gly-CTC with 20% piperidine, followed by washing with DMF.

[0051] Weigh out a 5.3-fold excess of Fmoc-His(Trt)-OH and a 3-fold excess of the activator, add a small amount of DMF, and dissolve completely. After dissolution, add the resulting mixture to the washed resin and react for 1 hour, then wash with DMF.

[0052] 6. Remove the Fmoc protecting group on Fmoc-His(Trt)-Gly-Gly-CTC with 20% piperidine, followed by washing with DMF.

[0053] Weigh out a 7.3-fold excess of Fmoc-beta-Aly-OH and a 3-fold excess of activator, add a small amount of DMF, and dissolve completely. After dissolution, add the mixture to the washed resin and react for 1 hour, then wash with DMF.

[0054] 8. Remove the Fmoc protecting group with 20% piperidine, and after removal, wash with DMF.

[0055] 9. The volume ratio of the decomposition reagents is TFA:EDT:Tis:TA:anisole:HO=80:5:1:5:5:4. 1g of peptide resin is decomposed at room temperature for approximately 2 hours (120 rpm) using 10ml of decomposition reagent. After decomposition, the resin is precipitated with ice-cold methyl tert-butyl ether. The lower precipitate is the crude product.

[0056] 10. The crude peptide obtained in the previous steps is taken, dissolved, and purified by preparative HPLC with 0.1% TFA / acetonitrile.

[0057] 11. After purification, freeze-drying is carried out, and then the powder is taken out and quality control is carried out.

[0058] Example 5: Synthesis of Gly-Gly-beta-Ala-His

[0059] 1. The solid-phase support 2-CTC resin is coupled with Fmoc-His(Trt)-OH in the presence of an activator system (HoBT, DIC) to obtain Fmoc-His(Trt)-CTC resin.

[0060] 2. Remove the Fmoc protecting group on Fmoc-His(Trt)-CTC with 20% piperidine, and after removal, wash with DMF.

[0061] Weigh out a 3.3-fold excess of Fmoc-beta-Ala-OH and a 3-fold excess of activator, add a small amount of DMF, and dissolve completely. After dissolution, add the mixture to the washed resin and react for 1 hour, then wash with DMF.

[0062] 4. Repeat steps 2 and 3 to sequentially couple Gly and Gly to the Fmoc-His-Gly-CTC resin.

[0063] 5. After synthesis is complete, decomposition is carried out using a decomposition reagent ratio of TFA:EDT:Tis:TA:anisole:HO = 80:5:1:5:5:4 (volume ratio). 1g of peptide resin is decomposed using 10ml of decomposition reagent at room temperature for approximately 2 hours (120 rpm). After decomposition, the peptide is precipitated with ice-cold methyl tert-butyl ether. The lower precipitate is the crude product.

[0064] 6. The crude peptide obtained in the previous steps is taken out, dissolved, and purified by preparative HPLC with 0.1% TFA / acetonitrile.

[0065] 7. After purification, freeze-drying is carried out, and then the powder is taken out and subjected to quality control.

[0066] Example 6: Synthesis of Gly-beta-Ala-His-Gly

[0067] 1. The solid-phase supported 2-CTC resin is coupled with Fmoc-Gly-OH in the presence of an activator system (HoBT, DIC) to obtain Fmoc-Gly-CTC resin.

[0068] 2. Remove the Fmoc protecting group on Fmoc-Gly-CTC with 20% piperidine, followed by washing with DMF.

[0069] Weigh out a 3.3-fold excess of Fmoc-His(Trt)-OH and a 3-fold excess of the activator, add a small amount of DMF, and dissolve completely. After dissolution, add the resulting mixture to the washed resin and react for 1 hour, then wash with DMF.

[0070] 4. Repeat steps 2 and 3 to sequentially couple beta-Ala and Gly to the Fmoc-His-Gly-CTC resin.

[0071] 5. After synthesis is complete, decomposition is carried out using a decomposition reagent ratio of TFA:EDT:Tis:TA:anisole:HO = 80:5:1:5:5:4 (volume ratio). 1g of peptide resin is decomposed using 10ml of decomposition reagent at room temperature for approximately 2 hours (120 rpm). After decomposition, the peptide is precipitated with ice-cold methyl tert-butyl ether. The lower precipitate is the crude product.

[0072] 6. The crude peptide obtained in the previous steps is taken out, dissolved, and purified by preparative HPLC with 0.1% TFA / acetonitrile.

[0073] 7. After purification, freeze-drying is carried out, and then the powder is taken out and subjected to quality control.

[0074] Example 7: Synthesis of Gly-Gly-beta-Ala-His-Gly-Gly

[0075] 1. The solid-phase supported 2-CTC resin is coupled with Fmoc-Gly-OH in the presence of an activator system (HoBT, DIC) to obtain Fmoc-Gly-CTC resin.

[0076] 2. Remove the Fmoc protecting group on Fmoc-Gly-CTC with 20% piperidine, followed by washing with DMF.

[0077] Weigh out a 3.3-fold excess of Fmoc-Gly-OH and a 3-fold excess of activator, add a small amount of DMF, and dissolve completely. After dissolution, add the resulting mixture to the washed resin and react for 1 hour, then wash with DMF.

[0078] 4. Repeat steps 2 and 3 to sequentially couple His, beta-Ala, Gly, and Gly to the CTC resin.

[0079] 5. After synthesis is complete, decomposition is carried out using a decomposition reagent ratio of TFA:EDT:Tis:TA:anisole:HO = 80:5:1:5:5:4 (volume ratio). 1g of peptide resin is decomposed using 10ml of decomposition reagent at room temperature for approximately 2 hours (120 rpm). After decomposition, the peptide is precipitated with ice-cold methyl tert-butyl ether. The lower precipitate is the crude product.

[0080] 6. The crude peptide obtained in the previous steps is taken out, dissolved, and purified by preparative HPLC with 0.1% TFA / acetonitrile.

[0081] 7. After purification, freeze-drying is carried out, and then the powder is taken out and subjected to quality control.

[0082] Example 8: The following polypeptides can be synthesized in a similar manner. beta-Ala-His-Gly-Gly; Gly-Gly-beta-Ala-His; Gly-beta-Ala-His-Gly; beta-Ala-His-beta-Ala-His-Gly; Gly-beta-Ala-His-beta-Ala-His; beta-Ala-His-beta-Ala-His-Gly-Gly; Gly-Gly-beta-Ala-His-beta-Ala-His; beta-Ala-His-beta-Ala-His-beta-Ala-His-Gly; Gly-beta-Ala-His-beta-Ala-His-beta-Ala-His; beta-Ala-His-beta-Ala-His-beta-Ala-His-Gly-Gly; Gly-Gly-beta-Ala-His-beta-Ala-His-beta-Ala-His; beta-Ala-His-beta-Ala-His-beta-Ala-His-Gly-Gly; Gly-Gly-beta-Ala-His-beta-Ala-His beta-Ala-His; beta-Ala-His-beta-Ala-His-beta-Ala-His-Gly-Gly-Gly; Gly-Gly-Gly-beta-Ala-His-beta-Ala-His-beta-Ala-His; Gly-Gly-beta-Ala-His-beta-Ala-His-beta-Ala-His-Gly; beta-Ala-His-beta-Ala-His-beta-Ala-His-beta-Ala-His-Gly-Gly-Gly; Gly-Gly-Gly-beta-Ala-His-beta-Ala-His-beta-Ala-His-beta-Ala-His; Gly-Gly-beta-Ala-His-beta-Ala-His-beta-Ala-His-beta-Ala-His-Gly; beta-Ala-(1-Methyl-His)-Gly; Gly-beta-Ala-(1-Methyl-His); beta-Ala-(1-Methyl-His)-Gly-Gly; Gly-Gly-beta-Ala-(1-Methyl-His); Gly-beta-Ala-(1-Methyl-His)-Gly; beta-Ala-(1-Methyl-His)-beta-Ala-(1-Methyl-His)-Gly; Gly-beta-Ala-(1-Methyl-His)-beta-Ala-(1-Methyl-His); beta-Ala-(1-Methyl-His)-beta-Ala-(1-Methyl-His)-Gly-Gly; Gly-Gly-beta-Ala-(1-Methyl-His)-beta-Ala-(1-Methyl-His); Gly-beta-Ala-(1-Methyl-His)-beta-Ala-(1-Methyl-His)-Gly; beta-Ala-(3-Methyl-His)-Gly; Gly-beta-Ala-(3-Methyl-His); beta-Ala-(3-Methyl-His)-Gly-Gly; Gly-Gly-beta-Ala-(3-Methyl-His); Gly-beta-Ala-(3-Methyl-His)-Gly; beta-Ala-(3-Methyl-His)-beta-Ala-(3-Methyl-His)-Gly; Gly-beta-Ala-(3-Methyl-His)-beta-Ala-(3-Methyl-His); beta-Ala-(3-Methyl-His)-beta-Ala-(3-Methyl-His)-Gly-Gly; Gly-Gly-beta-Ala-(3-Methyl-His)-beta-Ala-(3-Methyl-His); Gly-beta-Ala-(3-Methyl-His)-beta-Ala-(3-Methyl-His)-Gly。

[0083] Example 9: Animal Experiment Method

[0084] Monitor for small animals: Shenzhen Rongxianda Technology Co., Ltd., VT200. SD rat: China Food and Drug Appraisal Institute, 180-200g. JPEG0007779924000001.jpg1083TTC staining solution: Source Bio (R24053).

[0085] Animal model operation procedure: Experimental SD rats were weighed and anesthetized with chloral hydrate. After anesthesia, the rats' limbs were immobilized, they were placed supine, and connected to a small animal monitor to monitor vital physiological parameters such as body temperature, blood pressure, and heart rate. The rat's neck was then depilated and disinfected with 75% alcohol. A 2-cm incision was made in the center of the rat's neck. The rat's submandibular gland was then bluntly separated, avoiding the isolation process as much as possible. The left common carotid artery (CCA) was then bluntly separated, and the internal carotid artery (ICA) and external carotid artery (ECA) were carefully separated upward along the CCA. The vagus nerve was avoided during isolation. After clamping the CCA and ICA with two arterial clips and resecting the distal end of the ECA, a silicone monofilament was inserted through the ECA "port" and into the ICA arterial clip. The clip was briefly released, and the cranial end of the monofilament was quickly inserted through it to re-clamp the ICA. The ICA arterial clip was then gently released, and the monofilament was inserted through the bifurcation of the ECA and ICA. After the cranial end of the monofilament occluded the middle cerebral artery, a suture was tightly tied around the ECA "port" and the monofilament to prevent the monofilament from "pushing out" and bleeding when the rat woke up. The CCA and ICA arterial clips were then loosened and removed, and the tissue was returned to its original position. An appropriate amount of penicillin was added to prevent wound infection. The wound was sutured with a medical suture needle, sealed, and re-sterilized with iodophor. The experimental rat's indicators were monitored using a small animal monitor to ensure normal values. The rat was then placed on a small animal electric blanket to maintain body temperature until it woke up, and then placed in an animal cage.

[0086] Medication Instructions:

[0087] A 3 mg / mL solution of the drug to be tested is prepared and administered via the tail vein 1 to 2 hours after ligation.

[0088] When administering the drug, the rat is fixed with a restrainer, and 3 mg / kg of the drug is drawn up into a 1 mL syringe, and then slowly injected into the tail vein of the rat in order to reduce the cardiopulmonary load of the rat.

[0089] The animals are divided into different experimental groups of six animals each.

[0090] Model group: After ligation, an equal volume of saline was administered into the tail vein;

[0091] Drug groups S1 (NA1), S8 (beta-Ala-His-Gly), and S9 (Gly-beta-Ala-His): After ligation, drugs were administered into the tail vein;

[0092] Sham-operated group: The internal carotid artery (ICA) and external carotid artery (ECA) were isolated, but not ligated, and an equal volume of saline was administered into the tail vein.

[0093] Behavioral Observation:

[0094] Behavioral observations and scoring are performed on each animal 22–24 h after ligation.

[0095] A blinded evaluation will be made by a technician not participating in this study according to the following evaluation criteria: 0 points: Walk normally straight; 1 point: weakness of forelimbs; 2 points: hind limb weakness; 3 points: mild rotation; 4 points: severe rotation; 5 points: Hemiplegia.

[0096] TTC staining and quantitative analysis:

[0097] After behavioral observation, the rats were euthanized and their brains were removed. The brain tissue was cut into six 2-mm-thick slices, transferred to TTC staining solution, and incubated in a 37°C incubator for 10 minutes in the dark. Photographs were then taken. The TTC-stained brain tissue and the remaining small amount of unstained brain tissue were stored at -20°C.

[0098] Photographs after TTC staining were quantitatively analyzed using ImageJ software.

[0099] Cerebral infarct volume % = (total infarct area * section thickness) / (total brain section area * section thickness) * 100%.

[0100] Test Results:

[0101] 1.1 TTC quantification results are shown in Table 1:

[0102] [Table 1]

[0103] As shown in Table 1, the infarct volume of ischemic rats injected with saline was 0.390 ± 0.028 mm, that of ischemic rats injected with 3 mg / kg beta-Ala-L-His-Gly (S8) was 0.172 ± 0.051 mm, that of ischemic rats injected with 3 mg / kg Gly-beta-Ala-His (S9) was 0.197 ± 0.059 mm, and that of ischemic rats intravenously administered 3 mg / kg NA1 was 0.157 ± 0.040 mm. The sham-operated control group had an infarct volume of 0.044 ± 0.005 mm. Compared with the saline group, the other three groups showed significant biological activity, with S8 and S9 not statistically different from S1. Among these, NA1 (Nerinetide) is a neuroprotective agent (Michael Tymianski and Jonathan D. Garman. Model systems and treatment regimes for treatment of neurological disease. 2015, US Patent, US8940699B2). It inhibits postsynaptic density protein 95 (PSD-95) and stops the production of intracellular NO free radicals, thereby reducing infarct size and improving functional outcomes in experimental rhesus monkey cerebral ischemia-reperfusion preclinical ischemic stroke models. Dr. Hill investigated the efficacy and safety of intravenously administered NA-1 (2.6 mg / kg) to patients with acute ischemic stroke (AIS) who underwent endovascular thrombectomy, and found that NA1 administration improved patient outcomes. (Michael D Hill et al. Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomized controlled trial. Lancet. Published online February 20,2020).

[0104] 1.2 The behavioral evaluation results are shown in Table 2.

[0105] [Table 2]

[0106] As can be seen from the results in Table 2, the synthetic peptides provided by the present invention are physiologically active. The behavioral scores of ischemic rats administered with saline were 3.8 ± 0.8, those administered with 3 mg / kg of beta-Ala-His-Gly were 2.2 ± 0.8, and those administered with 3 mg / kg of Gly-beta-Ala-His were 2.0 ± 0.9. In comparison, the score of ischemic rats administered with 3 mg / kg of NA1 intravenously was 2.0 ± 0.6. The result for the sham-operated control group was 1.0 ± 0.0. Compared with the saline group, the other three groups showed significant biological activity, with S8 and S9 not statistically different from S1.

[0107] Example 10: Dose effect studies

[0108] Preparation method: Weigh out the required amount of test substance, dissolve it thoroughly in water for injection, adjust to the required concentration, and filter through a 0.22 μm filter to sterilize. For example, 280 g x 14 animals per group, as shown in Table 3 below.

[0109] [Table 3]

[0110] Preparation method: Weigh out a predetermined amount of test substance (assuming the compound is 100% pure), adjust to the required concentration, and filter through a 0.22 μm filter to sterilize. For example, 280 g x 14 animals, the specific details are as shown in Table 4 below.

[0111] [Table 4]

[0112] Animal type: Sprague-Dawley (SD) rats, Grade: SPF grade. Body weight: 200.01-240.03g at the start of the adaptation period, 213.79-278.79g at the time of group division. Age: Approximately 5-7 weeks old at the start of the adaptation period, 6-8 weeks old at the time of group division. Source: Sprague-Dawley (Beijing) Biotechnology Co., Ltd.

[0113] Animals were allowed to acclimate for 5 days after arrival. Unsuitable animals were not included in the study.

[0114] Rearing environment conditions standard: National Standard of the People's Republic of China GB14925-2010;

[0115] Breeding environment control system: WINCC7.3 EMS series machine room environment monitoring system;

[0116] Temperature: Room temperature 20~26℃ (daily difference less than 4℃);

[0117] Relative humidity: 40~70%;

[0118] Lighting: Artificial lighting, 12 / 12 hour day / night shift;

[0119] Ventilation frequency: Ventilate at least 15 times per hour.

[0120] Food type: Rat food

[0121] Manufacturer: Beijing Keao Xieli Feed Co., Ltd.;

[0122] Feeding method: ad libitum;

[0123] Type of drinking water: drinking water for laboratory animals (reverse osmosis water);

[0124] Water supply method: drinking water bottle, ad libitum;

[0125] Periodic water quality index testing: In accordance with the relevant requirements of the People's Republic of China National Standard GB5749-2006, testing will be entrusted to a third-party certification organization at least once every six months.

[0126] Animal selection: Animals that pass the adaptation test, whose body weight meets the experimental conditions, and whose NSS score is 3 or less are selected as test animals.

[0127] Construction of the rat model: The rat was placed in an anesthesia induction box filled with 3.0% isoflurane and anesthesia was induced. After anesthesia induction, the rat was transferred to the operating table and anesthesia was continued by administering 2.0-2.5% isoflurane at 200 mL / min using a small animal gas anesthesia machine. The rat's eyelid reflex and nociceptive response were observed, and surgery began once the eyelid reflex and nociceptive responses in the limbs and tail disappeared.

[0128] A. Isolation and exposure of blood vessels: After preparing the surgical site, place the rat under a surgical microscope. Cut the rat's skin along the midline to a length of approximately 2 cm using ophthalmic scissors. Bluntly separate and retract the right cervical musculature from the right paracervical region using microscopic scissors to expose the right common carotid artery (CCA). Then, cut the common carotid artery upward along the CCA, subsequently exposing the external carotid artery (ECA) and internal carotid artery (ICA).

[0129] B. Ligate the ECA and clamp the ICA. Thread a suture through the proximal and distal ends of the CCA, tie the distal end tightly, tie the proximal end loosely for backup, and cut a small opening between the two sutures;

[0130] C. Pushing the monofilament: Insert a No. 4-0 monofilament through the CCA incision and slowly and gently push it into the internal carotid artery. Pause when it reaches the ICA artery clip, then pretighten the ligature (to avoid excessive bleeding while pushing the monofilament), remove the artery clip that is blocking blood flow in the ICA, and immediately push the monofilament into the ICA until it enters the intracranial cavity. Be careful not to let the monofilament enter the pterygopalatine artery, a branch of the internal carotid artery. (The pterygopalatine artery is classified as an extracranial branch of the ICA, and once the monofilament has penetrated to a depth of about 10 mm, it will no longer be possible to insert it further. At this point, pull out the monofilament slightly, adjust its direction, and resume insertion.)

[0131] D. Fixing the monofilament and closing the incision: Insert the monofilament approximately 18 mm deep from the bifurcation of the common carotid artery. If slight resistance is felt, this indicates that the tip of the monofilament has entered the anterior cerebral artery (ACA) and that the side wall of the monofilament has occluded the opening of the middle cerebral artery. Stop insertion and record the time. Remove the arterial clip from the CCA, confirm that there is no active bleeding, and close the incision.

[0132] E. Cerebral reperfusion: The ischemic rat was placed at room temperature, and anesthesia was induced 120 minutes later. While maintaining the anesthetized state, the monofilament was slowly and gently pulled to return the head end to the external carotid artery, thereby establishing middle cerebral artery reperfusion.

[0133] F. Disinfect the incision with iodophor.

[0134] Group design: model control group, positive drug treatment group, S8 low dose group, S8 medium dose group, S8 high dose group;

[0135] Gender ratio: According to reports by JW Simpkins (Simpkins JW, Rajakumar G, Zhang YQ, Simpkins CE, Greenwald D, Yu CJ, Bodor N, Day AL (1997) Estrogens may reduce mortality and ischemic damage caused by middle cerebral artery occlusion in the female rat. J Neurosurg 87:724-730) and RL Roof (Roof RL, Duvdevani R, Braswell L, Stein DG (1994) Progesterone facilitates cognitive recovery and reduces secondary neuronal loss caused by cortical contusion injury in male rats. Exp Neurol 129:64-69), estrogen and progesterone have neuroprotective effects against ischemic stroke in adult rats. However, to exclude the influence of estrogen and progesterone on the results of this study, all test animals were male.

[0136] Grouping method: The rats were randomly assigned to groups based on their most recent body weight before grouping.

[0137] Specific grouping information is shown in Table 5 below.

[0138] [Table 5]

[0139] Route of administration: intravenous (iv);

[0140] Administration frequency and interval: Administer once immediately after reperfusion (within 10 minutes), and the day of surgery is defined as D1 (Day 1).

[0141] Animal observation: All living experimental animals are included in the observation;

[0142] Observation time: once a day, if any abnormalities are found in the animals, the number of observations can be increased;

[0143] Observations include, but are not limited to, general appearance, behavior, and signs of toxicity in the eyes, mouth, nose, ears, hair, skin, feces, urine, and genitals. Any abnormalities must be detailed.

[0144] Animal measurements: All living experimental animals are included in the measurements;

[0145] Measurement time: During the adaptation period, the animals were weighed at least twice a day, once on the day before surgery and once on the day of autopsy, to calculate the dosage of drugs and anesthetics. After surgery, the animals were weighed twice a week.

[0146] Bederson scoring

[0147] Measurement time: 1 hour after ischemia on the day of model construction;

[0148] Animals measured: all animals that survived surgery;

[0149] Detection method: Animals are scored according to the Bederson scoring criteria.

[0150] [Table 6]

[0151] Rat neurological function scoring

[0152] Measurement time: before and 24 hours after model construction;

[0153] Measurement animals: All living experimental animals are included in the measurement;

[0154] Detection methods: Animal motor function tests, sensory tests, balance tests, reflex and abnormal movement tests, specifically refer to the rat neurological scoring scale (NSS).

[0155] [Table 7]

[0156] Pathological (TTC staining) evaluation

[0157] Testing method: The brains of euthanized animals were quickly removed, and the rat brains were placed in a -20°C refrigerator and frozen until the brain tissue hardened. They were then removed and cut into 2mm-thick slices, starting from the olfactory bulb and ending at the back. A total of six slices were placed in a 6-well plate containing 0.5% TTC solution (prepared with 0.9% sodium chloride injection), and then incubated in a 37°C incubator for 20 minutes away from light. They were then removed and placed in a 4% formaldehyde solution and stored away from light.

[0158] Normal tissue is stained pink, and infarcted tissue is stained white. Each brain plane is placed on filter paper in turn and photographed with a digital camera. The white tissue is carefully removed and weighed, and the ratio of the infarcted tissue weight to the total brain weight is taken as the infarct area (%). The ratio of the infarcted tissue weight to the total brain weight in the infarct area is taken as the inhibition rate (%), and is calculated as follows:

[0159] JPEG0007779924000009.jpg21157

[0160] Statistical analysis:

[0161] Measurements are expressed as mean ± standard deviation. Groups with fewer than three samples were not included in statistical comparisons.

[0162] Data were entered and statistical analysis was performed by Excel 2010, GraphPad Prism 7, SPSS 22.0, and Stata 15.0 software. For the measurement indices, the Levene test for homogeneity of variance was first used. If the variances were consistent (p > 0.05), the results of the analysis of variance were directly used to determine whether the overall differences were statistically significant. If the overall differences were statistically significant (p < 0.05), the Dunnett t-test was used to compare the differences between groups. If the overall differences were not statistically significant (p ≥ 0.05), statistical analysis was terminated. If the Levene test for homogeneity of variance showed that the variances were not consistent (p ≤ 0.05), a nonparametric test (Kruskal-Wallis H test) was used. If the Kruskal-Wallis H test showed that the overall differences were statistically significant (p < 0.05), the Mann-Whitney U test was used to compare the differences between groups. If the Kruskal-Wallis H test showed that the overall differences were not statistically significant (p ≥ 0.05), statistical analysis was terminated. Pathological data (if available) are described in detail.

[0163] Test results

[0164] The effect of the test product on the degree of cerebral infarction in model animals

[0165] Pharmacological treatments for acute ischemic stroke can be broadly divided into two approaches: thrombolytic therapy to restore blood flow, and administration of neuroprotective agents to treat secondary neuronal damage caused by ischemia. In this study, SD rats were subjected to 120 minutes of ischemia followed by reperfusion to simulate vascular recanalization. The test product was administered via tail vein injection immediately (within 10 minutes) after recanalization. Brain tissue was collected 24 hours after administration. The infarct area of ​​each group was measured by TTC staining, and the inhibition rate was calculated to evaluate the neuroprotective effect of the test product. S1 (3 mg / kg) was used as the active drug in this study. The cerebral infarction area and inhibition rate of cerebral infarction in the experimental animals are shown in Table 8. One day after surgery, TTC staining was performed to calculate the extent of cerebral infarction in the animals. The cerebral infarction area in the model control group was 24.84 ± 3.39%, and the cerebral infarction area in the positive drug group was 16.74 ± 3.14%. The positive drug S1 showed a significant reduction in cerebral infarction area at 3 mg / kg, with a significant difference compared to the model control group (P < 0.0001). The cerebral infarction areas in the low, medium, and high dose groups of test product S8 were 20.37 ± 4.61%, 16.94 ± 3.90%, and 15.76 ± 2.68%, respectively. Test product S8 showed an effect of improving brain tissue infarction at doses of 3 mg / kg and 15 mg / kg (P < 0.0001 and P < 0.0001, respectively). In addition, the cerebral infarction suppression rate of animals in each treatment group was calculated, and the cerebral infarction suppression rates for the positive control group, the low-dose group of test product S8, the medium-dose group of S8, and the high-dose group of S8 were 33%, 18%, 32%, and 37%, respectively. These results suggest that under the experimental conditions, all test products S8 have good neuroprotective effects.

[0166] [Table 8]

[0167] The primary goal of clinical stroke treatment is to restore neurological function and improve the patient's daily living functions. In this study, the animals were scored by Bederson one hour after ischemia to determine their ischemic state. One day after model construction, the animals' neurobehavioral function was evaluated using the NSS scoring criteria to assess the neurological improvement effects of the test product. The results of the Bederson scores are shown in Table 9, and the NSS scores are shown in Table 10. One hour after ischemia, the Bederson scores of all animals in each group were 3, indicating ischemia in the model animals. One day after model construction, the NSS scores for the model control group, positive drug group, low-dose S8 group, medium-dose S8 group, and high-dose S8 group were 8.62±0.84, 8.00±0.76, 8.36±1.61, 7.14±1.81, and 7.93±0.59, respectively. The NSS score for the medium-dose S8 group was significantly lower than that of the model group, with a significant difference between the two groups (P<0.01). These results indicate that, under these experimental conditions, test item S8 was effective in improving neurological function damage in stroke animals.

[0168] [Table 9]

[0169] [Table 10]

[0170] Effects of test products on the body weight of model animals: Cerebral ischemia-reperfusion was used as an acute injury model. After the MCAO model was established, the body weight of the experimental animals decreased significantly. The body weight of the test animals is one of the most basic and sensitive indicators that comprehensively reflects the health status of the animals. In this experiment, the body weight of all animals was monitored on the first postoperative day, and the results of the weight changes of the animals are shown in Table 11. There was no difference in the body weight of the animals in each group before model construction. One day after surgery, the body weight of the animals in each group decreased significantly. The body weights of the animals in the model control group, positive drug treatment group, S5 low dose group, S5 medium dose group, and S5 high dose group decreased by 48.92±5.78g, 48.22±8.23g, 42.73±8.59g, 48.83±5.18g, and 46.66±10.90g, respectively. There was no significant difference in the amount of weight loss among the groups. The above results suggest that the positive drug S1 and the test article S5 do not have a significant effect on the body weight of the rats.

[0171] [Table 11]

[0172] In this experiment, the neuroprotective effect of test product S8 was evaluated using a classic monofilament MCAO model. The test product was administered to the animals immediately after reperfusion (within 10 minutes). One day after administration, the area of ​​cerebral infarction was measured by TTC staining, the inhibition rate, NSS scoring, grid walking test, and body weight change to evaluate the neuroprotective effect of the test product on ischemic cerebral infarction in rats. The results are as follows:

[0173] 1) Test product S8 has excellent neuroprotective effects, and after administration of the test product to model animals, the area of ​​cerebral infarction was significantly reduced. Test product S8 began to show significant therapeutic effects at a dose of 3 mg / kg;

[0174] 2) Test article S8 has the effect of repairing the neurological damage in MCAO animals. After the model animals received test article S8 (3 mg / kg), the NSS scores of the animals were significantly reduced compared to the model control group.

[0175] 3) Test product S8 did not significantly affect the body weight of stroke rats, and on the first postoperative day, all model animals showed a significant weight loss, with no significant difference in the amount of weight loss between groups.

[0176] From the above, this study established an animal model suitable for the pharmacological evaluation of ischemic stroke. The results of the pharmacological evaluation using this model showed that test product S8 has a significant therapeutic effect on all types of ischemic stroke.

[0177] The above contents are only preferred embodiments of the present invention and are not intended to limit the present invention, and any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. 1. A synthetic peptide for use in medicine or for the treatment of ischemic stroke, hemorrhagic stroke, brain injury, Alzheimer's disease, Parkinson's disease or other neurodegenerative diseases, comprising: A synthetic peptide having a chemical formula selected from the following: (b) Gly-beta-Ala-His; (e) Gly-beta-Ala-His-Gly; (g)beta-Ala-His-beta-Ala-His-Gly; (h)Gly-beta-Ala-His-beta-Ala-His; (k)Gly-beta-Ala-His-beta-Ala-His-Gly.

2. 2. The synthetic peptide of claim 1, having a chemical formula selected from the following: (b) Gly-beta-Ala-His; (e) Gly-beta-Ala-His-Gly.

3. 2. The synthetic peptide of claim 1, whose chemical formula is: (b) Gly-beta-Ala-His.

4. A drug comprising one or more synthetic peptides or salts thereof selected from the following: The drug is an injection, oral, sublingual, spray or anal administration drug. (a) beta-Ala-His-Gly; (b) Gly-beta-Ala-His; (e) Gly-beta-Ala-His-Gly; (g)beta-Ala-His-beta-Ala-His-Gly; (h)Gly-beta-Ala-His-beta-Ala-His; (k)Gly-beta-Ala-His-beta-Ala-His-Gly.

5. The drug according to claim 4, wherein the drug is a powder injection or an injection liquid.

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