WO2022188878A1 - 一类多功能多肽及其在医药领域的应用 - Google Patents
一类多功能多肽及其在医药领域的应用 Download PDFInfo
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- WO2022188878A1 WO2022188878A1 PCT/CN2022/080446 CN2022080446W WO2022188878A1 WO 2022188878 A1 WO2022188878 A1 WO 2022188878A1 CN 2022080446 W CN2022080446 W CN 2022080446W WO 2022188878 A1 WO2022188878 A1 WO 2022188878A1
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- carnosine
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Definitions
- the invention belongs to the technical field of medicine, and particularly relates to a class of multifunctional polypeptides and their application in the field of medicine.
- thrombotic diseases are the leading cause of morbidity and mortality. Cerebrovascular thrombosis leads to cerebral infarction, which is clinically ischemic stroke, or stroke. Stroke causes a large number of disability, which seriously affects people's quality of life. Therefore, there is an urgent need to develop safe and effective drugs for this aspect.
- the problems encountered in the treatment of cerebral infarction are very complicated. The first is that the existing thrombolytic drugs cannot cross the blood-brain barrier. Even if the blood-brain barrier is crossed and thrombolysis is successful, the ischemia-reperfusion process will lead to the production of a large number of free radicals, which will damage the brain tissue and lead to death. Therefore, the drug for the treatment of stroke is still tPA.
- tPA's effect is also limited, it only works within three hours of the patient's illness. It can cause bleeding all over the body and cause harm to the patient. At the same time, tPA could not solve the brain tissue damage caused by ischemia-reperfusion process.
- Carnosine is a dipeptide composed of two amino acids, ⁇ -alanine and L-histidine. Carnosine has strong antioxidant capacity and is beneficial to the human body. Carnosine has been shown to scavenge reactive oxygen radicals (ROS) and ⁇ - ⁇ unsaturated aldehydes formed during oxidative stress by overoxidizing fatty acids in cell membranes. Carnosine has anti-inflammatory, anti-glycation, antioxidant, and chelating properties, and as an over-the-counter food supplement, it holds great promise in the prevention and adjunctive treatment of chronic diseases such as cardiovascular disease and neurodegenerative disease. In animal experiments, the neuroprotective mechanism of carnosine prevents permanent cerebral ischemia.
- ROS reactive oxygen radicals
- ⁇ - ⁇ unsaturated aldehydes formed during oxidative stress by overoxidizing fatty acids in cell membranes.
- Carnosine has anti-inflammatory, anti-glycation, antioxidant, and chelating properties, and as an over-the-counter food supplement, it holds great promise in
- Carnosine supplementation is thought to help relieve some of the age-related neurological diseases, such as Alzheimer's disease, Parkinson's disease, etc.
- Carnosine is also an important intracellular antioxidant.
- Carnosine is not only non-toxic, but also has strong antioxidant properties, so it has attracted widespread attention as a new type of food additive and medicinal reagent.
- Carnosine participates in intracellular peroxidation. In addition to inhibiting the peroxidation process of cell membranes, it can also inhibit related intracellular peroxidation. In medicine, carnosine can also prevent, prevent Alzheimer's disease, prevent nerve and brain degeneration.
- these dipeptides are also present in other tissues, such as brain tissue.
- These carnosine derivatives are water-soluble and strong, and have significant anti-oxidation, anti-aging, uric acid-lowering and other functions. They have been used as natural antioxidants and uric acid-lowering diets in the food industry, and also have certain neuroprotective functions. .
- carnosine and carnosine derivatives have obvious neuroprotective effects, they often require large doses, which can lead to side effects, and they do not have the ability to dissolve thrombosis, which limits its practical clinical application.
- the peptides with thrombolytic activity themselves have the function of dissolving thrombosis, they cannot protect or repair nerve cell damage.
- the invention provides a kind of multifunctional polypeptide and its application in the field of medicine, which is composed of oligopeptide with thrombolytic function and carnosine composed of histidine, 1-methylhistidine and 3-methylhistidine , Anserine or snake carnosine, etc., form a series of polypeptide compounds that have both the protective function of carnosine, anserine or snake carnosine, and the thrombolytic function of the thrombolytic oligopeptide.
- These peptides are unexpectedly easy to pass through the blood-brain barrier, and show good biological activity by intravenous administration, thus showing broad prospects in the treatment of neurological diseases, especially brain injury and stroke.
- the technical solution is as follows:
- the embodiments of the present invention provide a class of multifunctional polypeptides consisting of at least one of Pro-Ala-Lys, Ala-Lys-Pro, Lys-Ala-Pro, fragments and derived peptides thereof.
- the fragment is selected from Pro-Ala, Ala-Lys, Lys-Pro, Lys-Ala, Ala-Pro, Pro, Ala or Lys, derived peptides Selected from Ala-Arg-Pro-Ala-Lys, Arg-Pro-Ala-Lys, Ala-Arg-Ala-Lys-Pro, Ala-Arg-Lys-Ala-Pro, Arg-Ala-Lys-Pro, Arg- Lys-Ala-Pro, Gly-Arg-Pro-Ala-Lys, Gly-Arg-Ala-Lys-Pro, Gly-Arg-Ala-Lys-Pro, Gln-Arg-Pro-Ala-Lys, Gln-Arg- Ala-Lys-Pro or Gln-Arg-Lys-Ala-Pro.
- the multifunctional polypeptide in the present invention is composed of one or more of Pro-Ala-Lys, Ala-Lys-Pro, Lys-Ala-Pro and dipeptide fragments (forming dipeptide, tripeptide or pentapeptide) etc.), and its C-terminus and/or N-terminus has carnosine, anserine or snake carnosine; including: ⁇ -Ala-His-Pro-Ala-Lys, ⁇ -Ala-His-Ala-Lys-Pro, ⁇ -Ala -His-Lys-Ala-Pro, Pro-Ala-Lys- ⁇ -Ala-His, Ala-Lys-Pro- ⁇ -Ala-His, Lys-Ala-Pro- ⁇ -Ala-His, ⁇ -Ala-His -Pro-Ala, ⁇ -Ala-His-Pro-Ala, ⁇ -Ala-His-Pro-Ala, ⁇ -Ala-His-
- His is His, 1-Methyl-His or 3-Methyl-His
- ⁇ -Ala forms carnosine, anserine or snake carnosine, respectively, the same below.
- the multifunctional polypeptide in the present invention is composed of two of Pro-Ala-Lys, Ala-Lys-Pro and Lys-Ala-Pro to form a hexapeptide, and its C-terminus and/or N-terminus has carnosine, goose Carnosine or snake carnosine; includes:
- His is His, 1-Methyl-His or 3-Methyl-His.
- the multifunctional polypeptide in the present invention is composed of (Pro-Ala-Lys)n, (Ala-Lys-Pro)n or (Lys-Ala-Pro)n, and its C-terminus and/or N-terminus has Carnosine, Anserine or Snake Carnosine; n is an integer from 2 to 6, including: ⁇ -Ala-His-Pro-Ala-Lys-Pro-Ala-Lys,
- His is His, 1-Methyl-His or 3-Methyl-His.
- the multifunctional polypeptide in the present invention is composed of a derivative peptide of Pro-Ala-Lys, Ala-Lys-Pro or Lys-Ala-Pro, and its C-terminus and/or N-terminus has carnosine, anserine or snake Carnosine; includes:
- His is His, 1-Methyl-His or 3-Methyl-His.
- the multifunctional polypeptide in the present invention consists of Pro-Ala-Lys, Ala-Lys-Pro or Lys-Ala-Pro and amino acids Pro, Ala or/and Lys (amino acid fragment), and its C-terminal and/ Or carnosine, anserine or snake carnosine at the N-terminus; including: ⁇ -Ala-His-Pro-Pro-Ala-Lys, ⁇ -Ala-His-Pro-Ala-Lys-Pro, ⁇ -Ala-His-Ala- Pro-Ala-Lys, ⁇ -Ala-His-Pro-Ala-Lys-Ala, ⁇ -Ala-His-Lys-Pro-Ala-Lys, ⁇ -Ala-His-Pro-Ala-Lys-Lys, ⁇ -Ala-His-Pro-Ala-Lys-Lys, ⁇ - Ala-His-Pro-Ala-Lys-
- His is His, 1-Methyl-His or 3-Methyl-His.
- the multifunctional polypeptides in the present invention include: ⁇ -Ala-His-Pro-Ala-Lys, ⁇ -Ala-His-Ala-Lys-Pro, ⁇ -Ala-His-Lys-Ala-Pro, ⁇ -Ala-His-Lys-Ala-Pro, Ala-His-Arg-Pro-Ala-Lys, ⁇ -Ala-His-Arg-Ala-Lys-Pro, ⁇ -Ala-His-Arg-Lys-Ala-Pro, ⁇ -Ala-His-Pro-Pro- Ala-Lys, ⁇ -Ala-His-Pro-Ala-Lys-Pro, ⁇ -Ala-His-Ala-Pro-Ala-Lys-Pro, ⁇ -Ala-His-Ala-Pro-Ala-Lys, ⁇ -Ala-His-Pro-Ala-Lys-Ala, ⁇ -Ala-Hi
- His is His, 1-Methyl-His or 3-Methyl-His.
- His is His, ie it forms carnosine with ⁇ -Ala.
- the multifunctional polypeptide in the present invention consists of one of Pro-Ala-Lys, Ala-Lys-Pro and Lys-Ala-Pro and is coupled to a carnosine, anserine or snake at its C-terminus and/or N-terminus Carnosine formation, including:
- His is His, 1-Methyl-His or 3-Methyl-His.
- His is His, ie it forms carnosine with ⁇ -Ala.
- the multifunctional polypeptide in the present invention is formed by Pro-Ala-Lys coupled to a carnosine, anserine or snake carnosine at its C-terminus and/or N-terminus, including:
- His is His, 1-Methyl-His or 3-Methyl-His.
- His is His, ie it forms carnosine with ⁇ -Ala.
- the multifunctional polypeptide in the present invention is formed by coupling Ala-Lys-Pro to a carnosine, anserine or snake carnosine at its C-terminus and/or N-terminus, including:
- His is His, 1-Methyl-His or 3-Methyl-His.
- His is His, ie it forms carnosine with ⁇ -Ala.
- the multifunctional polypeptide of the present invention is formed by coupling a carnosine, anserine or snake carnosine at its C-terminus and/or N-terminus with Lys-Ala-Pro, including:
- His is His, 1-Methyl-His or 3-Methyl-His.
- His is His, ie it forms carnosine with ⁇ -Ala.
- the multifunctional polypeptides in the present invention include:
- His is His, 1-Methyl-His or 3-Methyl-His.
- the multifunctional polypeptides of the present invention include:
- His is His, that is, it forms carnosine with ⁇ -Ala.
- the present invention also provides the aforementioned multifunctional polypeptide or its salt for use in medicine.
- the present invention also provides the aforementioned multifunctional polypeptides or salts thereof for treating nervous system diseases.
- the present invention also provides a method for treating nervous system diseases using the aforementioned multifunctional polypeptides or salts thereof.
- the neurological disease may be ischemic stroke, hemorrhagic stroke, brain trauma, Alzheimer's disease, Parkinson's disease or other neurodegenerative diseases.
- the neurological disease is ischemic stroke.
- the multifunctional polypeptide or its salt provided by the present invention can be prepared as a medicine.
- the aforementioned drugs are injections. Specifically, the injection is powder injection or injection. Further, the aforementioned drugs are administered intravenously.
- the aforementioned drugs can also be developed into other different dosage forms according to the application, including sprays, oral tablets, capsules, lozenges, granules, suppositories, and the like.
- the aforementioned drug may be the compound itself, or may be any form of salt, such as acetate, hydrochloride, and the like. Salt formation of polypeptide drugs is one of the common means to improve the physicochemical properties of drug molecules and improve their druggability.
- the aforementioned drugs can be salts in any form.
- the present invention also provides a method for preparing various multifunctional polypeptides of the present invention by solid-phase synthesis, but it is more convenient to use liquid-phase synthesis for some of the peptides.
- the present invention uses SD rats as the experimental object, adopts the middle cerebral artery occlusion method (MCAO) to prepare a rat model of cerebral ischemia, ischemia for 1-2 hours After intravenous injection of drugs, behavioral observation and scoring of each animal were performed 22-24 hours later. After the behavioral observation, the experimental rats were euthanized and their brains were taken out. The brain tissue was sectioned, and then quantitatively analyzed after TTC staining, and the % cerebral infarction volume was calculated.
- MCAO middle cerebral artery occlusion method
- the synthetic peptide of the present invention creatively combines the thrombolytic functional oligopeptide with carnosine, anserine or snake carnosine, etc.
- the developed mosaic synthetic peptide unexpectedly penetrates the blood-brain barrier through intravenous injection and enters the brain, effectively Played a role in the treatment of neurological diseases.
- Such synthetic peptides are preferably used in the treatment of ischemic stroke, hemorrhagic stroke, brain trauma, Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases.
- the present invention only needs an intravenous injection dose of 3 mg/kg of the multifunctional polypeptide to achieve a significant therapeutic effect, and achieves the same effect as the clinically active standard polypeptide NA1.
- the synthetic peptide is composed of thrombolytic active oligopeptide and carnosine, anserine or snake carnosine, all of which are natural amino acids or peptides, and are safe and reliable.
- the hemolytic active oligopeptide used in the present invention is a polypeptide containing Pro-Ala-Lys, Ala-Lys-Pro or Lys-Ala-Pro, which can be composed of any two different or identical fragments, or can be combined with smaller fragments combine.
- polypeptides include Pro-Ala-Lys, Ala-Lys-Pro or polypeptides formed by the linking of Lys-Ala-Pro with each other, including Pro-Ala-Lys-Ala-Lys-Pro; Pro-Ala-Lys-Lys- Ala-Pro;Ala-Lys-Pro-Pro-Ala-Lys;Lys-Ala-Pro-Pro-Ala-Lys;Ala-Lys-Pro-Lys-Ala-Pro;Pro-Ala-Lys-Ala-Lys- Pro; Lys-Ala-Pro-Ala-Lys-Pro; Lys-Ala-Pro-Ala-Lys, Lys-Ala-Pro-Lys-Ala-Pro.
- Pro-Ala-Lys, Ala-Lys-Pro and Lys-Ala-Pro can also self-couple multimers, such as (Pro-Ala-Lys)n, (Ala-Lys-Pro)n or (Lys-Ala- Pro)n, n can be 2 to 6, especially 2.
- the hemolytic active oligopeptide used in the present invention also includes the degradation products of fibrin beta chain P6A, Ala-Arg-Pro-Ala-Ly and the further metabolized product Arg-Pro-Ala-Ly, and also includes related thrombolytic activities Oligopeptides Ala-Arg-Ala-Lys-Pro; Ala-Arg-Lys-Ala-Pro; Arg-Ala-Lys-Pro; Arg-Lys-Ala-Pro, etc.
- the hemolytic active oligopeptides used in the present invention further include Gly-Arg-Pro-Ala-Ly and Gln-Arg-Pro-Ala-Ly, as well as Gly-Arg-Ala-Lys-Pro, Gly-Arg-Lys-Ala-Pro , Gln-Arg-Ala-Lys-Pro and Gln-Arg-Lys-Ala-Pro.
- the present invention also includes combinations of Pro-Ala-Lys, Ala-Lys-Pro or Lys-Ala-Pro with any one of Pro, Ala or Lys amino acids, such as: Pro-Pro-Ala-Lys; Pro-Ala-Lys -Pro;Ala-Pro-Ala-Lys;Pro-Ala-Lys-Ala;Lys-Pro-Ala-Lys-Lys;Pro-Ala-Lys-Pro;Ala-Lys-Pro-Pro ;Ala-Lys-Pro-Pro ;Ala-Ala-Lys-Pro;Ala-Lys-Pro-Ala;Lys-Ala-Lys-Pro;Ala-Lys-Ala-Pro;Lys-Ala-Pro-Pro;Ala - Lys-Ala-Pro;Ala - Lys-Ala-Pro;Ala - Lys-Ala-Pro; Lys-Ala-Pro; Lys
- the present invention also includes Pro-Ala-Lys, Ala-Lys-Pro or a combination of Lys-Ala-Pro and any one of Pro-Ala, Ala-Lys, Lys-Pro, Lys-Ala and Ala-Pro, such as: Pro-Ala-Lys-Pro-Ala;Pro-Ala-Pro-Ala-Lys;Pro-Ala-Lys-Ala-Lys;Ala-Lys-Pro-Ala-Lys;Pro-Ala-Lys-Lys-Pro; Lys-Pro-Pro-Ala-Lys;Pro-Ala-Lys-Lys-Ala;Lys-Ala-Pro-Ala-Lys;Pro-Ala-Lys-Ala-Pro;Ala-Pro-Ala-Lys; Ala-Lys-Pro-Ala-Lys; Ala-Lys-Pro-Ala-Lys-Pro-Ala-Pro
- Patents CN101190941, CN103665107, and CN105884905 also introduce such thrombolytic functional peptides, and the described polypeptides are naturally included in this patent.
- the multifunctional polypeptide of this patent can be obtained by coupling carnosine, anserine or snake carnosine to the C-terminal and/or N-terminal of the above hemolytic active oligopeptide.
- the synthetic peptide of the present invention is easy to synthesize.
- carnosine, anserine or snake carnosine derivatives can be used as synthetic fragments to replace the corresponding two amino acids to further simplify the synthesis of the target peptide.
- some of the short peptides involved, such as peptides with a total number of amino acids not greater than six amino acids, can be obtained by liquid-phase synthesis, with lower cost, which is convenient for large-scale production and product quality supervision in the future.
- the polypeptide of the present invention provides a new option for the treatment of nervous system diseases, and is especially applied to the treatment of ischemic stroke, hemorrhagic stroke, brain trauma, Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases.
- Fig. 1 is the slice diagram of the brain tissue of the model group
- Fig. 2 is the slice diagram of the brain tissue of S1 group
- Fig. 3 is the slice diagram of the brain tissue of S4 group
- Fig. 4 is the slice diagram of the brain tissue of S5 group
- Fig. 5 is a slice view of the brain tissue of the sham-operated group.
- the Fmoc-Pro-CTC resin is obtained by coupling the solid support 2-CTC resin and Fmoc-Pro-OH.
- the ratio of 10ml of cleavage reagent, the cleavage at room temperature is about 2h (120r/min), after cleavage, it is precipitated with ice methyl tert-butyl ether, and the lower precipitate is the crude product.
- the Fmoc-His(Trt)-CTC resin is obtained by coupling the solid support 2-CTC resin and Fmoc-His(Trt)-OH.
- the ratio of 10ml of cleavage reagent, the cleavage at room temperature is about 2h (120r/min), after cleavage, it is precipitated with ice methyl tert-butyl ether, and the lower precipitate is the crude product.
- the Fmoc-His(Trt)-CTC resin is obtained by coupling the solid support 2-CTC resin and Fmoc-His(Trt)-OH.
- the ratio of 10ml of cleavage reagent, the cleavage at room temperature is about 2h (120r/min), after cleavage, it is precipitated with ice methyl tert-butyl ether, and the lower precipitate is the crude product.
- the Fmoc-His(Trt)-CTC resin is obtained by coupling the solid support 2-CTC resin and Fmoc-His(Trt)-OH.
- the ratio of 10ml of cleavage reagent, the cleavage at room temperature is about 2h (120r/min), after cleavage, it is precipitated with ice methyl tert-butyl ether, and the lower precipitate is the crude product.
- SD rat China Institute of Food and Drug Evaluation, 180-200g.
- TTC staining solution source leaf biology (R24053).
- the experimental SD rats were weighed and anesthetized with chloral hydrate. After anesthesia, the limbs of the rats were fixed, supine, and connected to a small animal monitor to monitor important physiological indicators such as the body temperature, blood pressure, and heart rate of the rats.
- the neck of the rat was depilated. After disinfection with 75% alcohol cotton balls, a median incision of about 2 cm in length was made on the neck of the experimental rat.
- the submandibular glands of the rats were bluntly separated. During the separation process, try to avoid damage to the glands.
- the left common carotid artery (CCA) of the experimental rat was bluntly dissected, and the internal carotid artery (ICA) and external carotid artery (ECA) were carefully dissected upward along the CCA. Avoid damage to the vagus nerve during dissection.
- CCA left common carotid artery
- ICA internal carotid artery
- ECA external carotid artery
- the arterial clips on the CCA and ICA were loosened and removed, the tissue was returned to its original position, and an appropriate amount of penicillin was dripped to prevent wound infection.
- the drug to be tested was made into a 3 mg/mL solution. Administered in the tail vein 1-2 h after ligation.
- the rats were fixed with a fixator, and a 1 mL syringe was used to absorb the test drug at a dose of 3 mg/kg, and then the rats were injected into the tail vein, and the injection was slowly injected to reduce the cardiopulmonary load of the experimental rats.
- Drug group S1 (NA1), S4 ( ⁇ -Ala-His-Lys-Ala-Pro) and S5 (Pro-Ala-Lys- ⁇ -Ala-His): administered by tail vein after ligation;
- NA1 Neinetide
- PSD postsynaptic density protein 95
- ICA internal carotid artery
- ECA external carotid artery
- the experimental rats were euthanized and their brains were removed.
- the brain tissue was cut into 6 slices with a thickness of 2 mm, then transferred to TTC staining solution, incubated in a 37°C incubator for 10 min in the dark, and photographed. Then, the TTC-stained brain tissue and a small amount of the remaining non-TTC-stained brain tissue were stored at -20°C.
- Cerebral infarction volume % (total infarct area*slice thickness)/(total brain slice area*slice thickness)*100%.
- the synthetic peptide provided by the present invention has physiological activity. Cerebral ischemia rats injected with normal saline, the behavioral score was 3.8 ⁇ 0.8; cerebral ischemia rats injected with 3mg/kg ⁇ -Ala-His-Lys-Ala-Pro, the score was 2.0 ⁇ 0.9; injected 3mg/kg Pro -Ala-Lys- ⁇ -Ala-His cerebral ischemia rats, the score was 1.8 ⁇ 0.8; as a comparison, cerebral ischemia rats intravenously administered 3 mg/kg NA1, the score was 2.0 ⁇ 0.6. The result for the sham-operated group as a control was 1.0 ⁇ 0.0. Compared with normal saline, the other three groups had obvious biological activity and there was no statistical difference between S4 and S5 and S1.
- Preparation method Weigh a certain test substance and dissolve it fully with water for injection, prepare it to the required concentration, and filter and sterilize it with a 0.22 ⁇ m filter. Take 280g ⁇ 14 animals in each group as an example, the specific information is shown in Table 3 below.
- Negative control substance water for injection; positive control substance: S1 (NA1)
- Preparation method Weigh a certain test substance (the purity of the compound is calculated as 100%), prepare it to the required concentration, and filter and sterilize it with a 0.22 ⁇ m filter; take 280g ⁇ 14 animals as an example, the specific information is shown in Table 4 below.
- Animal strain Sprague-Dawley (SD) rat; grade: SPF grade.
- Body weight 200.01-240.03 g in the adaptation period, 213.79-278.79 g in the grouping; age: about 5-7 weeks in the adaptation period, and 6-8 weeks in the test grouping.
- Source Speifu (Beijing) Biotechnology Co., Ltd.
- Feeding environment control system WINCC7.3EMS series computer room environment monitoring system
- Lighting artificial lighting, 12/12 hours day and night alternating light and dark;
- Number of air changes no less than 15 air changes per hour.
- Types of feed breeding feed for rats and mice;
- Feeding method free intake
- Drinking water type experimental animal drinking water (reverse osmosis water);
- Water supply method drinking water bottle, free intake
- Routine water quality index testing According to the relevant requirements of the National Standard GB5749-2006 of the People's Republic of China, a third-party qualified unit is commissioned to test at least once every six months.
- Animal selection Animals that passed the acclimatization examination, met the experimental requirements, and had a total NSS score of less than or equal to 3 were selected as test animals.
- rat model The rats were placed into an anesthesia induction box filled with 3.0% isoflurane for induction of anesthesia. After induction of anesthesia, the animals were transferred to the operating table, and anesthesia was maintained using a small animal gas anesthesia machine with 2.0% to 2.5% isoflurane at 200 mL/min. The eyelid reflex and pain response of the rats were observed. Surgery can be started only after the pain response in the tail disappears.
- A. Isolation of exposed blood vessels After skin preparation of the surgical area, place the rat under the operating microscope. The rat skin was cut along the midline with ophthalmic scissors, with a length of about 2 cm. Through the right paracervical approach of the rat, microtweezers were used to bluntly dissect and retract the muscle tissue of the right neck to expose the right common carotid artery (CCA), and then separate upward along the common carotid artery. Expose the external carotid artery (ECA) and the internal carotid artery (ICA);
- ECA external carotid artery
- ICA internal carotid artery
- E. Cerebral reperfusion The ischemic rat is placed at room temperature, and anesthesia can be induced after 120 minutes. While maintaining anesthesia, the suture is gently pulled slowly and the head end is returned to the external carotid artery, that is, the middle cerebral artery is regenerated. perfusion;
- Group design model control group, positive drug treatment group, S5 low-dose group, S5 medium-dose group, and S5 high-dose group;
- Grouping method Random grouping was performed according to the most recent body weight of the rats before grouping.
- Dosing frequency and cycle once after reperfusion (within 10 min), the day of operation was defined as D1 (Day1).
- Observation time observe once a day, if the animal is abnormal, the observation frequency can be increased;
- Observation content including but not limited to general manifestations, behavioral status, eyes, mouth, nose and mouth, ears, hair and skin, feces, urine, genitals and other toxic symptoms. If there is any abnormality, a detailed description is required.
- Measurement time during the adaptation period, the body weight was measured at least twice, and each batch was weighed once on the day before the operation and on the day of the anatomy to calculate the amount of drug administration and anesthesia; twice a week after the operation.
- Detection time 1h after ischemia on the day of modeling
- Detection method The animals were scored with reference to the Bederson scoring standard.
- Rats with a score greater than or equal to 1 after ischemia and reperfusion are considered successful in modeling, and those with unsuccessful modeling are eliminated.
- Detection method Motor function test, sensory test, balance test and reflex and abnormal movement test were carried out on the animals, and the specific reference was made to the rat neurological function score (NSS).
- Examination method euthanize the animal and quickly take the brain, and freeze the rat brain in a -20°C refrigerator until the brain tissue becomes hard and then take it out.
- the rat brain is cut into 2mm thick slices, and the slice position is from the olfactory bulb to the back, a total of 6 slices , were placed in a six-well plate containing 0.5% TTC solution (prepared with 0.9% sodium chloride injection), and then placed in a 37°C incubator for 20 minutes in the dark, and then placed in a 4% formaldehyde solution. Keep away from light.
- Measurement indicators are expressed as mean ⁇ standard deviation. When the number of samples was less than 3, the data in this group were not included in the statistical comparison.
- the drug treatment of acute ischemic stroke mainly includes two aspects: one is to restore blood flow through thrombolysis; the other is to give neuroprotective agents to treat secondary neuronal damage caused by ischemia.
- SD rats were subjected to reperfusion after ischemia for 120 minutes to simulate blood vessel recanalization.
- the test article was injected through the tail vein.
- the infarct size of animals and the inhibition rate were calculated to evaluate the neuroprotective effect of the test article.
- S1 (3 mg/kg) was used as the positive drug in this test.
- the scope of cerebral infarction and the inhibition rate of cerebral infarction in animals are shown in Table 8.
- the cerebral infarction range of the model control group and the positive drug group was: 24.84 ⁇ 3.39%, 16.74 ⁇ 3.14%, and the positive drug S1 was at a dose of 3 mg/kg. It showed a good effect of reducing the scope of cerebral infarction, and compared with the model control group, there was a significant difference (P ⁇ 0.0001).
- the range of cerebral infarction in the low-dose group, middle-dose group, and high-dose group of test article S5 was 20.20 ⁇ 4.07%, 18.76 ⁇ 2.50%, and 15.70 ⁇ 2.80%, respectively.
- the test article S5 had the effect of improving cerebral infarction at the set dose.
- test article S5 has a good neuroprotective effect under the experimental conditions, wherein the effective dose of the test article S5 is 0.6 mg/kg, and there is a dose-effect relationship.
- Table 8 Scope of cerebral infarction and inhibition rate of cerebral infarction in experimental animals
- the main purpose of clinical treatment of cerebral infarction is to restore the patient's neurological function as much as possible and improve the quality of life after stroke.
- the Bederson score was performed on the animals 1 hour after ischemia to judge the ischemia condition of the animals, and the reference was made 1 day after modeling.
- the neurobehavioral function of the animals was evaluated by the NSS score sheet, and the improvement effect of the test article on the neurological function was evaluated.
- the animal Bederson score results are shown in Table 9, and the NSS score results are shown in Table 10.
- One hour after ischemia the Bederson score of animals in each group was 3, indicating that the model animals were successfully ischemia.
- NSS scores of the animals in the model control group, positive drug group, test article S5 low-dose group, S5 medium-dose group and S5 high-dose group were 8.62 ⁇ 0.84, 8.00 ⁇ 0.76, 8.23 ⁇ 0.97, 7.92 ⁇ 0.62, and 7.85 ⁇ 0.66.
- the effect of the test article on the body weight of model animals As an acute injury model of cerebral ischemia and reperfusion, the body weight of experimental animals will drop sharply after MCAO modeling. The body weight of all animals was monitored 1 day after the experiment, and the results of changes in animal body weight are shown in Table 11. There was no difference in the body weight of animals in each group before modeling. On the 1st day after the operation, the body weight of animals in each group decreased significantly. The body weight of the animals decreased by 48.92 ⁇ 5.78g, 48.22 ⁇ 8.23g, 42.73 ⁇ 8.59g, 48.83 ⁇ 5.18g, and 46.66 ⁇ 10.90g respectively, and there was no significant difference in the amount of body weight loss between the groups. The above results suggest that the positive drug S1, the test product S5 had no significant effect on rat body weight.
- test article S5 has a good neuroprotective effect, which mainly reflects that the cerebral infarction scope of the model animals is significantly reduced after the test article treatment.
- the effective dose of the test article S5 is 0.6 mg/kg, and there is a dose-effect relationship;
- test article S5 had no obvious effect on the body weight of the stroke rats. On the 1st day after the operation, the body weight of the model animals decreased significantly, and there was no significant difference in the amount of body weight loss between the groups.
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Abstract
提供一种多功能多肽，由至少一个Pro-Ala-Lys、Ala-Lys-Pro、Lys-Ala-Pro及其片段和衍生肽中的一种或多种构成，且其C端和/或N端具有肌肽、鹅肌肽或者蛇肌肽。该多肽由具有溶血栓功能寡肽以及由组氨酸，1-甲基组氨酸，3-甲基组氨酸组成的肌肽，鹅肌肽或蛇肌肽等链接组成，容易透过血脑屏障，通过静脉途径给药，应用于治疗神经系统疾病，尤其是脑损伤，脑卒中。
Description
本发明属于药物技术领域，特别涉及一类多功能多肽及其在医药领域的应用。
在全球范围内，血栓性疾病的发病率个死亡率都居首位。脑血管血栓导致脑梗，即临床上的缺血性中风，或脑卒中。脑卒中导致大量人员残疾，严重影响人们的生活素质。由此急需开发针对这方面的安全有效药物。脑梗治疗遇到的问题很复杂，首先是现有的溶栓药物不能跨过血脑屏障。即使跨过血脑屏障，成功溶栓，但该缺血再灌注过程会导致大量自由基的产生，使脑组织损伤并导致死亡。因此至今治疗脑卒中的药物依然是tPA。但是tPA的作用也很有限，它只在患者得病后的三个小时内起作用。它可能会导致全身出血，给病人带来伤害。同时tPA不能解决缺血再灌注过程带来的脑组织伤害。
肌肽(L-Carnosine)，是一种由β-丙氨酸和L-组氨酸两种氨基酸组成的二肽。肌肽具有很强的抗氧化能力，对人体有益。肌肽已被证实可清除在氧化应激过程中使细胞膜的脂肪酸过度氧化而形成的活性氧自由基(ROS)以及α-β不饱和醛。肌肽具有抗炎、抗糖化、抗氧化和螯合作用，可作为一种非处方食品补充剂，在预防和辅助治疗心血管疾病和神经退行性等慢性疾病方面具有良好的前景。在动物实验里，肌肽的神经保护机制可以防止永久性脑部缺血。补充肌肽被认为有助于缓解部分与年龄有关的神经疾病，例如阿尔茨海默症、帕金森症等。肌肽还是一种重要的细胞内抗氧化剂。肌肽不仅无毒，而且具备强的抗氧化性，因此以它作为一种新型的食品添加剂与药用试剂已经引起广泛关注。肌肽参与细胞内的过氧化反应，除了具有抑制细胞膜的过氧化过程，还能抑制细胞内的相关的过氧化反应。在医学上，肌肽还可以防止，预防阿滋海默症，防止神经和脑部退化。1900年，俄国学者Gulewitsch最早发现了肌肽，之后各国学者又在不同的肌肉组织中还提取分离了其它组氨酸二肽衍生物，如鹅肌肽(Anserine)，其是一种由β-丙氨酸和1-甲基-L-组氨酸两种氨基酸组成的二肽，以及鲸肌肽或蛇肌肽(Balenine，又称Ophidine,)，蛇肌肽则是由β-丙氨酸和3-甲 基-L-组氨酸组成的二肽。不同动物的这些肌肽和肌肽衍生物的含量也不同，不同物种之间这几种组氨酸二肽的含量及比例也各不相同，具有一定的特异性。除了在肌肉组织中存在着组氨酸二肽以外，这些二肽还存在于别的组织中，如脑组织。这些肌肽衍生物具有水溶性和较强的而且具有显著的抗氧化、抗衰老、降尿酸等功能，在食品工业中已用作天然的抗氧化剂和降尿酸食疗，也同样具有一定的神经保护功能。
尽管肌肽以及肌肽衍生物都有明显的神经细胞保护作用，但是它们往往需要较大的剂量,这可导致副反应，同时它们也不具备溶解血栓，导致它的实际临床应用受到限制。具有溶血栓活性的肽本身虽然拥有溶解血栓的功能，但它们不能保护或修复神经细胞的损伤。
发明内容
本发明提供了一类多功能多肽及其在医药领域的应用，它是由具有溶血栓功能寡肽以及由组氨酸，1-甲基组氨酸，3-甲基组氨酸组成的肌肽，鹅肌肽(Anserine)或蛇肌肽等链接组成，形成了一系列具有兼具肌肽，鹅肌肽或蛇肌肽的保护功能，和溶血栓功能寡肽的溶血栓功能这一特征的系列多肽化合物。这些肽类出乎意外地容易透过血脑屏障，通过静脉途径给药展示了很好的生物活性，从而在治疗神经系统疾病，尤其是脑损伤，脑卒中方面显示了广阔的前景。所述技术方案如下：
一方面，本发明实施例提供了一类多功能多肽，其由至少一个Pro-Ala-Lys、Ala-Lys-Pro、Lys-Ala-Pro及其片段和衍生肽中的一种或多种构成，且其C端和/或N端具有肌肽、鹅肌肽或者蛇肌肽；片段选自Pro-Ala、Ala-Lys、Lys-Pro、Lys-Ala、Ala-Pro、Pro、Ala或Lys，衍生肽选自Ala-Arg-Pro-Ala-Lys、Arg-Pro-Ala-Lys、Ala-Arg-Ala-Lys-Pro、Ala-Arg-Lys-Ala-Pro、Arg-Ala-Lys-Pro、Arg-Lys-Ala-Pro、Gly-Arg-Pro-Ala-Lys、Gly-Arg-Ala-Lys-Pro、Gly-Arg-Lys-Ala-Pro、Gln-Arg-Pro-Ala-Lys、Gln-Arg-Ala-Lys-Pro或Gln-Arg-Lys-Ala-Pro。其中，衍生肽中Ala-Arg-Pro-Ala-Lys和Arg-Pro-Ala-Lys为溶血活性寡肽纤维蛋白beta链的降解或代谢产物(P6A)。
具体地，本发明中的多功能多肽由Pro-Ala-Lys、Ala-Lys-Pro、Lys-Ala-Pro及两肽片段中的一种或多种构成(形成二肽、三肽或五肽等)，且其C端和/或N 端具有肌肽、鹅肌肽或者蛇肌肽；包括：β-Ala-His-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Pro，β-Ala-His-Lys-Ala-Pro，Pro-Ala-Lys-β-Ala-His，Ala-Lys-Pro-β-Ala-His，Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala，β-Ala-His-Ala-Lys，β-Ala-His-Lys-Pro，β-Ala-His-Lys-Ala，β-Ala-His-Ala-Pro，Pro-Ala-β-Ala-His，Ala-Lys-β-Ala-His，Lys-Pro-β-Ala-His，Lys-Ala-β-Ala-His，Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-β-Ala-His，β-Ala-His-Ala-Lys-β-Ala-His，β-Ala-His-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-β-Ala-His，β-Ala-His-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Pro-Ala，β-Ala-His-Pro-Ala-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Ala-Lys，β-Ala-His-Ala-Lys-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Lys-Pro，β-Ala-His-Lys-Pro-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Lys-Ala，β-Ala-His-Lys-Ala-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Ala-Pro，β-Ala-His-Ala-Pro-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Pro-Pro-Ala，β-Ala-His-Pro-Ala-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Lys-Pro，β-Ala-His-Lys-Pro-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Lys-Ala，β-Ala-His-Lys-Ala-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Ala-Pro，β-Ala-His-Ala-Pro-Ala-Lys-Pro，β-Ala-His-Lys-Ala-Pro-Pro-Ala，β-Ala-His-Pro-Ala-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Lys-Pro，β-Ala-His-Lys-Pro-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Lys-Ala，β-Ala-His-Lys-Ala-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Ala-Pro，β-Ala-His-Ala-Pro-Lys-Ala-Pro，Pro-Ala-Lys-Pro-Ala-β-Ala-His，Pro-Ala-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Ala-Lys-β-Ala-His，Ala-Lys-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Lys-Pro-β-Ala-His，Lys-Pro-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Lys-Ala-β-Ala-His，Lys-Ala-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Ala-Pro-β-Ala-His，Ala-Pro-Pro-Ala-Lys-β-Ala-His，Ala-Lys-Pro-Pro-Ala-β-Ala-His， Pro-Ala-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Ala-Lys-β-Ala-His，Ala-Lys-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Lys-Pro-β-Ala-His，Lys-Pro-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Lys-Ala-β-Ala-His，Lys-Ala-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Ala-Pro-β-Ala-His，Ala-Pro-Ala-Lys-Pro-β-Ala-His，Lys-Ala-Pro-Pro-Ala-β-Ala-His，Pro-Ala-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Ala-Lys-β-Ala-His，Ala-Lys-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-Pro-β-Ala-His，Lys-Pro-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-Ala-β-Ala-His，Lys-Ala-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Ala-Pro-β-Ala-His，Ala-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Pro-Ala-β-Ala-His，β-Ala-His-Pro-Ala-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Lys-Ala-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Ala-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Pro-Ala-β-Ala-His，β-Ala-His-Pro-Ala-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Lys-Ala-β-Ala-His，β-Ala-His-Lys-Ala-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-Pro-β-Ala-His，β-Ala-His-Ala-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Pro-Ala-β-Ala-His， β-Ala-His-Pro-Ala-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-Ala-β-Ala-His，β-Ala-His-Lys-Ala-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-Pro-β-Ala-His，β-Ala-His-Ala-Pro-Lys-Ala-Pro-β-Ala-His；
其中，His为His、1-Methyl-His或者3-Methyl-His，与β-Ala分别形成肌肽、鹅肌肽或者蛇肌肽，后同。
其中，本发明中的多功能多肽，其由Pro-Ala-Lys、Ala-Lys-Pro和Lys-Ala-Pro中的两种构成六肽，且其C端和/或N端具有肌肽、鹅肌肽或者蛇肌肽；包括：
Pro-Ala-Lys-Ala-Lys-Pro-β-Ala-His，Pro-Ala-Lys-Lys-Ala-Pro-β-Ala-His，
Ala-Lys-Pro-Pro-Ala-Lys-β-Ala-His，Lys-Ala-Pro-Pro-Ala-Lys-β-Ala-His，
Ala-Lys-Pro-Lys-Ala-Pro-β-Ala-His，Pro-Ala-Lys-Ala-Lys-Pro-β-Ala-His，
Lys-Ala-Pro-Ala-Lys-Pro-β-Ala-His，Lys-Ala-Pro-Pro-Ala-Lys-β-Ala-His，
Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-Lys-Pro，
β-Ala-His-Pro-Ala-Lys-Lys-Ala-Pro，β-Ala-His-Ala-Lys-Pro-Pro-Ala-Lys，
β-Ala-His-Lys-Ala-Pro-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Pro-Lys-Ala-Pro，
β-Ala-His-Pro-Ala-Lys-Ala-Lys-Pro，β-Ala-His-Lys-Ala-Pro-Ala-Lys-Pro，
β-Ala-His-Lys-Ala-Pro-Pro-Ala-Lys，β-Ala-His-Lys-Ala-Pro-Lys-Ala-Pro，
β-Ala-His-Pro-Ala-Lys-Ala-Lys-Pro-β-Ala-His，
β-Ala-His-Pro-Ala-Lys-Lys-Ala-Pro-β-Ala-His，
β-Ala-His-Ala-Lys-Pro-Pro-Ala-Lys-β-Ala-His，
β-Ala-His-Lys-Ala-Pro-Pro-Ala-Lys-β-Ala-His，
β-Ala-His-Ala-Lys-Pro-Lys-Ala-Pro-β-Ala-His，
β-Ala-His-Pro-Ala-Lys-Ala-Lys-Pro-β-Ala-His，
β-Ala-His-Lys-Ala-Pro-Ala-Lys-Pro-β-Ala-His，
β-Ala-His-Lys-Ala-Pro-Pro-Ala-Lys-β-Ala-His，
β-Ala-His-Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His；
其中，His为His、1-Methyl-His或者3-Methyl-His。
其中，本发明中的多功能多肽，其由(Pro-Ala-Lys)n、(Ala-Lys-Pro)n或(Lys-Ala-Pro)n构成，且其C端和/或N端具有肌肽、鹅肌肽或者蛇肌肽；n为2-6的整数，包括：β-Ala-His-Pro-Ala-Lys-Pro-Ala-Lys，
Pro-Ala-Lys-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-Lys-Pro，，Ala-Lys-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-Ala-Pro，，Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-Lys-Pro-β-Ala-His，
β-Ala-His-Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His；
其中，His为His、1-Methyl-His或者3-Methyl-His。
其中，本发明中的多功能多肽，其由Pro-Ala-Lys、Ala-Lys-Pro或Lys-Ala-Pro的衍生肽构成，且其C端和/或N端具有肌肽、鹅肌肽或者蛇肌肽；包括：
Ala-Arg-Pro-Ala-Lys-β-Ala-His，Arg-Pro-Ala-Lys-β-Ala-His，
Ala-Arg-Ala-Lys-Pro-β-Ala-His，Ala-Arg-Lys-Ala-Pro-β-Ala-His，
Arg-Ala-Lys-Pro-β-Ala-His，Arg-Lys-Ala-Pro-β-Ala-His，
Gly-Arg-Pro-Ala-Lys-β-Ala-His，Gln-Arg-Pro-Ala-Lys-β-Ala-His，
Gly-Arg-Ala-Lys-Pro-β-Ala-His，Gly-Arg-Lys-Ala-Pro-β-Ala-His，
Gln-Arg-Ala-Lys-Pro-β-Ala-His，Gln-Arg-Lys-Ala-Pro-β-Ala-His，
β-Ala-His-Ala-Arg-Pro-Ala-Lys，β-Ala-His-Arg-Pro-Ala-Lys，
β-Ala-His-Ala-Arg-Ala-Lys-Pro，β-Ala-His-Ala-Arg-Lys-Ala-Pro，
β-Ala-His-Arg-Ala-Lys-Pro，β-Ala-His-Arg-Lys-Ala-Pro，
β-Ala-His-Gly-Arg-Pro-Ala-Lys，β-Ala-His-Gln-Arg-Pro-Ala-Lys，
β-Ala-His-Gly-Arg-Ala-Lys-Pro，β-Ala-His-Gly-Arg-Lys-Ala-Pro，
β-Ala-His-Gln-Arg-Ala-Lys-Pro，β-Ala-His-Gln-Arg-Lys-Ala-Pro，
β-Ala-His-Ala-Arg-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Arg-Pro-Ala-Lys-β-Ala-His，
β-Ala-His-Ala-Arg-Ala-Lys-Pro-β-Ala-His，
β-Ala-His-Ala-Arg-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Arg-Ala-Lys-Pro-β-Ala-His，
β-Ala-His-Arg-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Gly-Arg-Pro-Ala-Lys-β-Ala-His，
β-Ala-His-Gln-Arg-Pro-Ala-Lys-β-Ala-His，
β-Ala-His-Gly-Arg-Ala-Lys-Pro-β-Ala-His，
β-Ala-His-Gly-Arg-Lys-Ala-Pro-β-Ala-His，
β-Ala-His-Gln-Arg-Ala-Lys-Pro-β-Ala-His，
β-Ala-His-Gln-Arg-Lys-Ala-Pro-β-Ala-His；
其中，His为His、1-Methyl-His或者3-Methyl-His。
其中，本发明中的多功能多肽，其由Pro-Ala-Lys、Ala-Lys-Pro或Lys-Ala-Pro及氨基酸Pro、Ala或/和Lys(氨基酸片段)构成，且其C端和/或N端具有肌肽、鹅肌肽或者蛇肌肽；包括：β-Ala-His-Pro-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Pro，β-Ala-His-Ala-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Ala，β-Ala-His-Lys-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Lys，β-Ala-His-Pro-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Pro，β-Ala-His-Ala-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Ala，β-Ala-His-Lys-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Lys，β-Ala-His-Pro-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Pro，β-Ala-His-Ala-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Ala，β-Ala-His-Lys-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Lys，Pro-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Pro-β-Ala-His，Ala-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Ala-β-Ala-His，Lys-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Lys-β-Ala-His，Pro-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Pro-β-Ala-His，Ala-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Ala-β-Ala-His，Lys-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Lys-β-Ala-His，Pro-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Pro-β-Ala-His,Ala-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Ala-β-Ala-His，Lys-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-β-Ala-His， β-Ala-His-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-β-Ala-His，β-Ala-His-Lys-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Pro-β-Ala-His，β-Ala-His-Ala-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-β-Ala-His，β-Ala-His-Lys-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Lys-β-Ala-His，β-Ala-His-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-β-Ala-His，β-Ala-His-Lys-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-β-Ala-His；
其中，His为His、1-Methyl-His或者3-Methyl-His。
进一步地，本发明中的多功能多肽包括：β-Ala-His-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Pro，β-Ala-His-Lys-Ala-Pro，β-Ala-His-Arg-Pro-Ala-Lys，β-Ala-His-Arg-Ala-Lys-Pro，β-Ala-His-Arg-Lys-Ala-Pro，β-Ala-His-Pro-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Pro，β-Ala-His-Ala-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Ala，β-Ala-His-Lys-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Lys，β-Ala-His-Pro-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Pro，β-Ala-His-Ala-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Ala，β-Ala-His-Lys-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Lys，β-Ala-His-Pro-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Pro，β-Ala-His-Ala-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Ala，β-Ala-His-Lys-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Lys，β-Ala-His-Ala-Arg-Pro-Ala-Lys，β-Ala-His-Ala-Arg-Ala-Lys-Pro，β-Ala-His-Ala-Arg-Lys-Ala-Pro，β-Ala-His-Gly-Arg-Pro-Ala-Lys，β-Ala-His-Gln-Arg-Pro-Ala-Lys，β-Ala-His-Gly-Arg-Ala-Lys-Pro，β-Ala-His-Gly-Arg-Lys-Ala-Pro，β-Ala-His-Gln-Arg-Ala-Lys-Pro，β-Ala-His-Gln-Arg-Lys-Ala-Pro，β-Ala-His-Pro-Ala-Lys-Pro-Ala，β-Ala-His-Pro-Ala-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Ala-Lys，β-Ala-His-Ala-Lys-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Lys-Pro，β-Ala-His-Lys-Pro-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Lys-Ala， β-Ala-His-Lys-Ala-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Ala-Pro，β-Ala-His-Ala-Pro-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Pro-Pro-Ala，β-Ala-His-Pro-Ala-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Lys-Pro，β-Ala-His-Lys-Pro-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Lys-Ala，β-Ala-His-Lys-Ala-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Ala-Pro，β-Ala-His-Ala-Pro-Ala-Lys-Pro，β-Ala-His-Lys-Ala-Pro-Pro-Ala，β-Ala-His-Pro-Ala-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Lys-Pro，β-Ala-His-Lys-Pro-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Lys-Ala，β-Ala-His-Lys-Ala-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Ala-Pro，β-Ala-His-Ala-Pro-Lys-Ala-Pro，β-Ala-His-Pro-Ala-Lys-Ala-Lys-Pro，β-Ala-His-Pro-Ala-Lys-Lys-Ala-Pro，β-Ala-His-Ala-Lys-Pro-Pro-Ala-Lys，β-Ala-His-Lys-Ala-Pro-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Pro-Lys-Ala-Pro，β-Ala-His-Pro-Ala-Lys-Ala-Lys-Pro，β-Ala-His-Lys-Ala-Pro-Ala-Lys-Pro，β-Ala-His-Lys-Ala-Pro-Pro-Ala-Lys，β-Ala-His-Lys-Ala-Pro-Lys-Ala-Pro，β-Ala-His-Pro-Ala-Lys-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Pro-Ala-Lys-Pro，β-Ala-His-Lys-Ala-Pro-Lys-Ala-Pro，Pro-Ala-Lys-β-Ala-His，Ala-Lys-Pro-β-Ala-His，Lys-Ala-Pro-β-Ala-His，Arg-Pro-Ala-Ly-β-Ala-His，Arg-Ala-Lys-Pro-β-Ala-His，Arg-Lys-Ala-Pro-β-Ala-His，Pro-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Pro-β-Ala-His，Ala-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Ala-β-Ala-His，Lys-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Lys-β-Ala-His，Pro-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Pro-β-Ala-His，Ala-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Ala-β-Ala-His，Lys-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Lys-β-Ala-His，Pro-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Pro-β-Ala-His，Ala-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Ala-β-Ala-His，Lys-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-β-Ala-His，Ala-Arg-Pro-Ala-Ly-β-Ala-His，Ala-Arg-Ala-Lys-Pro-β-Ala-His， Ala-Arg-Lys-Ala-Pro-β-Ala-His，Gly-Arg-Pro-Ala-Lys-β-Ala-His，Gln-Arg-Pro-Ala-Ly-β-Ala-His，Gly-Arg-Ala-Lys-Pro-β-Ala-His，Gly-Arg-Lys-Ala-Pro-β-Ala-His，Gln-Arg-Ala-Lys-Pro-β-Ala-His，Gln-Arg-Lys-Ala-Pro-β-Ala-His，Pro-Ala-Lys-Pro-Ala-β-Ala-His，Pro-Ala-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Ala-Lys-β-Ala-His，Ala-Lys-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Lys-Pro-β-Ala-His，Lys-Pro-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Lys-Ala-β-Ala-His，Lys-Ala-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Ala-Pro-β-Ala-His，Ala-Pro-Pro-Ala-Lys-β-Ala-His，Ala-Lys-Pro-Pro-Ala-β-Ala-His，Pro-Ala-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Ala-Lys-β-Ala-His，Ala-Lys-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Lys-Pro-β-Ala-His，Lys-Pro-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Lys-Ala-β-Ala-His，Lys-Ala-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Ala-Pro-β-Ala-His，Ala-Pro-Ala-Lys-Pro-β-Ala-His，Lys-Ala-Pro-Pro-Ala-β-Ala-His，Pro-Ala-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Ala-Lys-β-Ala-His，Ala-Lys-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-Pro-β-Ala-His，Lys-Pro-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-Ala-β-Ala-His，Lys-Ala-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Ala-Pro-β-Ala-His，Ala-Pro-Lys-Ala-Pro-β-Ala-His，Pro-Ala-Lys-Ala-Lys-Pro-β-Ala-His，Pro-Ala-Lys-Lys-Ala-Pro-β-Ala-His，Ala-Lys-Pro-Pro-Ala-Lys-β-Ala-His，Lys-Ala-Pro-Pro-Ala-Lys-β-Ala-His，Ala-Lys-Pro-Lys-Ala-Pro-β-Ala-His，Pro-Ala-Lys-Ala-Lys-Pro-β-Ala-His，Lys-Ala-Pro-Ala-Lys-Pro-β-Ala-His，Lys-Ala-Pro-Pro-Ala-Lys-β-Ala-His，Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His，Pro-Ala-Lys-Pro-Ala-Lys-β-Ala-His，Ala-Lys-Pro-Ala-Lys-Pro-β-Ala-His，Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Arg-Pro-Ala-Ly-β-Ala-His，β-Ala-His-Arg-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Arg-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-β-Ala-His，β-Ala-His-Lys-Pro-Ala-Lys-β-Ala-His， β-Ala-His-Pro-Ala-Lys-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Pro-β-Ala-His，β-Ala-His-Ala-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-β-Ala-His，β-Ala-His-Lys-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Lys-β-Ala-His，β-Ala-His-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-β-Ala-His，β-Ala-His-Lys-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-β-Ala-His，β-Ala-His-Ala-Arg-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Arg-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Arg-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Gly-Arg-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Gln-Arg-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Gly-Arg-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Gly-Arg-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Gln-Arg-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Gln-Arg-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Pro-Ala-β-Ala-His，β-Ala-His-Pro-Ala-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Lys-Ala-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Ala-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Pro-Ala-β-Ala-His，β-Ala-His-Pro-Ala-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Lys-Pro-β-Ala-His， β-Ala-His-Lys-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Lys-Ala-β-Ala-His，β-Ala-His-Lys-Ala-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-Pro-β-Ala-His，β-Ala-His-Ala-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Pro-Ala-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-Ala-β-Ala-His，β-Ala-His-Lys-Ala-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-Pro-β-Ala-His，β-Ala-His-Ala-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His，
β-Ala-His-Pro-Ala-Lys-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His；
其中，His为His、1-Methyl-His或者3-Methyl-His。
优选地，His为His，即其与β-Ala形成肌肽。
其中，本发明中的多功能多肽由Pro-Ala-Lys、Ala-Lys-Pro和Lys-Ala-Pro中 的一种并在其C端和/或N端偶联一个肌肽、鹅肌肽或者蛇肌肽形成，包括：
β-Ala-His-Pro-Ala-Lys，
β-Ala-His-Ala-Lys-Pro，
β-Ala-His-Lys-Ala-Pro，
Pro-Ala-Lys-β-Ala-His，
Ala-Lys-Pro-β-Ala-His，
Lys-Ala-Pro-β-Ala-His，
β-Ala-His-Pro-Ala-Lys-β-Ala-His，
β-Ala-His-Ala-Lys-Pro-β-Ala-His，
β-Ala-His-Lys-Ala-Pro-β-Ala-His；
其中，His为His、1-Methyl-His或者3-Methyl-His。优选地，His为His，即其与β-Ala形成肌肽。
优选地，本发明中的多功能多肽由Pro-Ala-Lys在其C端和/或N端偶联一个肌肽、鹅肌肽或者蛇肌肽形成，包括：
β-Ala-His-Pro-Ala-Lys，
Pro-Ala-Lys-β-Ala-His，
β-Ala-His-Pro-Ala-Lys-β-Ala-His；
其中，His为His、1-Methyl-His或者3-Methyl-His。优选地，His为His，即其与β-Ala形成肌肽。
优选地，本发明中的多功能多肽由Ala-Lys-Pro在其C端和/或N端偶联一个肌肽、鹅肌肽或者蛇肌肽形成，包括：
β-Ala-His-Ala-Lys-Pro，
Ala-Lys-Pro-β-Ala-His，
β-Ala-His-Ala-Lys-Pro-β-Ala-His；
其中，His为His、1-Methyl-His或者3-Methyl-His。优选地，His为His，即其与β-Ala形成肌肽。
优选地，本发明中的多功能多肽由Lys-Ala-Pro在其C端和/或N端偶联一个肌肽、鹅肌肽或者蛇肌肽形成，包括：
β-Ala-His-Lys-Ala-Pro，
Lys-Ala-Pro-β-Ala-His，
β-Ala-His-Lys-Ala-Pro-β-Ala-His；
其中，His为His、1-Methyl-His或者3-Methyl-His。优选地，His为His，即其与β-Ala形成肌肽。
更优选地，本发明中的多功能多肽包括：
β-Ala-His-Lys-Ala-Pro，
Pro-Ala-Lys-β-Ala-His。
其中，His为His、1-Methyl-His或者3-Methyl-His。
最优选地，本发明中的多功能多肽包括：
β-Ala-His-Lys-Ala-Pro，
Pro-Ala-Lys-β-Ala-His，
其中，His为His，即其与β-Ala形成肌肽。
另一方面，本发明还提供了前述多功能多肽或其盐用在医药中。本发明还提供了前述多功能多肽或其盐用于治疗神经系统疾病。本发明还提供了利用前述多功能多肽或其盐治疗神经系统疾病的方法。
具体地，神经系统疾病可以是缺血性脑卒中、出血性脑卒中、脑创伤、阿尔茨海默病、帕金森病或其它神经退行性疾病。优选地，神经系统疾病是缺血性脑卒中。
本发明提供的多功能多肽或其盐可以制备为药物。前述药物为注射剂。具体地，注射剂为粉针剂或者注射液。进一步地，前述药物采用静脉的方式给药。前述药物也可以按用途开发其它不同的剂型，包括喷雾剂、口服片剂、胶囊、舌含片、颗粒和栓剂等。前述药物可以是化合物本身，也可以是任何形式的盐，如醋酸盐，盐酸盐等。多肽药物成盐是改善药物分子理化性质、提高其成药性的常见手段之一，前述药物可以是任何形式的盐。
又一方面，本发明还提供了通过固相合成制备本发明各类多功能多肽的方法，但其中的一些肽用液相合成更加方便。
为了确定本专利提供的合成肽在神经系统疾病方面的应用，本发明用SD大鼠作为实验对象，采用脑中动脉阻断法(MCAO)制备脑缺血大鼠模型，缺血1-2小时后静脉注射药物，22-24小时对每只动物做行为学观察和评分。行为学观察之后，将实验大鼠进行安乐死并取出其大脑，脑组织切片，TTC染色后进行量化分析，计算脑梗死体积％。
本发明的合成肽创造性地把溶血栓功能寡肽，与肌肽，鹅肌肽或蛇肌肽等组合起来，开发的镶嵌式合成肽出乎意料地通过静脉注射透过血脑屏障，进入大脑，有效地在治疗神经系统疾病中发挥了作用。该类合成肽优选地应用于治疗缺血性脑卒中，出血性脑卒中，脑创伤，阿尔茨海默病，帕金森病及其他神经退行性疾病。本发明只需要3mg/kg的多功能多肽静脉注射剂量，即可达到显著的治疗效果，与已有临床活性的标准多肽NA1达到了同样的效果。该合成肽的为溶血栓活性寡肽以及肌肽，鹅肌肽或蛇肌肽组成，其全部为天然的氨基酸或肽，安全可靠。
本发明使用的溶血活性寡肽为含有Pro-Ala-Lys，Ala-Lys-Pro或者Lys-Ala-Pro的多肽，可以由任何两个不同或相同的片段组合起来，也可以与更小的片段组合起来。这些多肽包括Pro-Ala-Lys，Ala-Lys-Pro或者Lys-Ala-Pro相互之间链接起来形成的多肽，包括Pro-Ala-Lys-Ala-Lys-Pro；Pro-Ala-Lys-Lys-Ala-Pro；Ala-Lys-Pro-Pro-Ala-Lys；Lys-Ala-Pro-Pro-Ala-Lys；Ala-Lys-Pro-Lys-Ala-Pro；Pro-Ala-Lys-Ala-Lys-Pro；Lys-Ala-Pro-Ala-Lys-Pro；Lys-Ala-Pro-Pro-Ala-Lys，Lys-Ala-Pro-Lys-Ala-Pro。Pro-Ala-Lys，Ala-Lys-Pro和Lys-Ala-Pro也可以自身耦合得多聚体，如(Pro-Ala-Lys)n,(Ala-Lys-Pro)n或者(Lys-Ala-Pro)n，n可以是2到6，尤其2。
本发明使用的溶血活性寡肽也包括纤维蛋白beta链的降解产物P6A,Ala-Arg-Pro-Ala-Ly以及进一步得代谢的产物Arg-Pro-Ala-Ly,也包含了相关的溶血栓活性寡肽Ala-Arg-Ala-Lys-Pro；Ala-Arg-Lys-Ala-Pro；Arg-Ala-Lys-Pro；Arg-Lys-Ala-Pro等。本发明使用的溶血活性寡肽进一步包括Gly-Arg-Pro-Ala-Ly和Gln-Arg-Pro-Ala-Ly,以及Gly-Arg-Ala-Lys-Pro，Gly-Arg-Lys-Ala-Pro，Gln-Arg-Ala-Lys-Pro和Gln-Arg-Lys-Ala-Pro。
本发明也包括Pro-Ala-Lys，Ala-Lys-Pro或者Lys-Ala-Pro与Pro,Ala或者Lys中的任何一个氨基酸的组合，比如：Pro-Pro-Ala-Lys；Pro-Ala-Lys-Pro；Ala-Pro-Ala-Lys；Pro-Ala-Lys-Ala；Lys-Pro-Ala-Lys；Pro-Ala-Lys-Lys；Pro-Ala-Lys-Pro；Ala-Lys-Pro-Pro；Ala-Ala-Lys-Pro；Ala-Lys-Pro-Ala；Lys-Ala-Lys-Pro；Ala-Lys-Pro-Lys；Pro-Lys-Ala-Pro；Lys-Ala-Pro-Pro；Ala-Lys-Ala-Pro；Lys-Ala-Pro-Ala；Lys-Lys-Ala-Pro；Lys-Ala-Pro-Lys。
本发明还包括Pro-Ala-Lys、Ala-Lys-Pro或者Lys-Ala-Pro与Pro-Ala、Ala-Lys、 Lys-Pro、Lys-Ala和Ala-Pro中的任何一个的组合，比如：Pro-Ala-Lys-Pro-Ala；Pro-Ala-Pro-Ala-Lys；Pro-Ala-Lys-Ala-Lys；Ala-Lys-Pro-Ala-Lys；Pro-Ala-Lys-Lys-Pro；Lys-Pro-Pro-Ala-Lys；Pro-Ala-Lys-Lys-Ala；Lys-Ala-Pro-Ala-Lys；Pro-Ala-Lys-Ala-Pro；Ala-Pro-Pro-Ala-Lys；Ala-Lys-Pro-Pro-Ala；Pro-Ala-Ala-Lys-Pro；Ala-Lys-Pro-Ala-Lys；Ala-Lys-Ala-Lys-Pro；Ala-Lys-Pro-Lys-Pro；Lys-Pro-Ala-Lys-Pro；Ala-Lys-Pro-Lys-Ala；Lys-Ala-Ala-Lys-Pro；Ala-Lys-Pro-Ala-Pro；Ala-Pro-Ala-Lys-Pro；Lys-Ala-Pro-Pro-Ala；Pro-Ala-Lys-Ala-Pro；Lys-Ala-Pro-Ala-Lys；Ala-Lys-Lys-Ala-Pro；Lys-Ala-Pro-Lys-Pro；Lys-Pro-Lys-Ala-Pro；Lys-Ala-Pro-Lys-Ala；Lys-Ala-Lys-Ala-Pro；Lys-Ala-Pro-Ala-Pro；Ala-Pro-Lys-Ala-Pro。
专利CN101190941,CN103665107,以及CN105884905同样介绍了这类的溶血栓功能肽，描述的多肽自然包括在本专利里面。
在以上溶血活性寡肽的C端和/或N端偶联肌肽、鹅肌肽或者蛇肌肽即可得到本专利的多功能多肽。
同时本发明的合成肽便于合成，合成过程中还可以使用肌肽，鹅肌肽或蛇肌肽的衍生物作为合成片段，代替对应的两个氨基酸来进一步简化目标肽的合成。另外其中涉及的一些短肽，如氨基酸总数不大于六个氨基酸的多肽更是可以通过液相合成而得，成本更低，便于以后规模化生产与产品质量监管。本发明的多肽为治疗神经系统疾病提供了全新的选择，尤其应用于治疗缺血性脑卒中，出血性脑卒中，脑创伤，阿尔茨海默病，帕金森病及其他神经退行性疾病。
图1是模型组的脑组织的切片图；
图2是S1组的脑组织的切片图；
图3是S4组的脑组织的切片图；
图4是S5组的脑组织的切片图；
图5是假手术组的脑组织的切片图。
为使本发明的目的、技术方案和优点更加清楚，下面将结合附图对本发明作进一步地详细描述。
实例1：β-Ala-His-Lys-Ala-Pro的合成
1.在活化剂系统(HoBT,DIC)的存在下，由固相载体2-CTC树脂和Fmoc-Pro-OH偶联得到Fmoc-Pro-CTC树脂。
2.用20％哌啶脱除Fmoc-Pro-CTC上的Fmoc保护基，脱除干净后用DMF洗涤干净。
3.称取3倍过量的Fmoc-Ala-OH，与三倍过量的活化剂，加入少量DMF充分溶解，溶解完之后加入至洗涤干净的树脂中，反应1h后用DMF洗涤干净。
4.重复第二步骤与第三步骤，按照主链顺序从Lys到β-Ala依次偶联具有N端Fmoc保护且侧链带保护的氨基酸。
5.合成完毕之后进行裂解，裂解试剂配比为TFA:EDT:Tis:TA:苯甲醚:H
2O＝80:5:1:5:5:4(体积比)，按1g肽树脂需10ml裂解试剂配比，室温下裂解约2h(120r/min)，裂解之后用冰甲基叔丁基醚沉淀，下层沉淀即为粗品。
6.取上步的粗肽溶解，在制备型HPLC上用0.1％TFA/乙腈纯化。
7.纯化完之后进行冻干，冻干结束后取出粉末进行分装质检。
实例2：Pro-Ala-Lys-β-Ala-His的合成
1.在活化剂系统(HoBT,DIC)的存在下，由固相载体2-CTC树脂和Fmoc-His(Trt)-OH偶联得到Fmoc-His(Trt)-CTC树脂。
2.用20％哌啶脱除Fmoc-His(Trt)-CTC上的Fmoc保护基，脱除干净后用DMF洗涤干净。
3.称取3倍过量的Fmoc-β-Ala-OH，与三倍过量的活化剂，加入少量DMF充分溶解，溶解完之后加入至洗涤干净的树脂中，反应1h后用DMF洗涤干净。
4.重复第二步骤与第三步骤，按照主链顺序从Lys,Ala到Pro依次偶联具有N端Fmoc保护且侧链带保护的氨基酸。
5.合成完毕之后进行裂解，裂解试剂配比为TFA:EDT:Tis:TA:苯甲醚:H
2O＝80:5:1:5:5:4(体积比)，按1g肽树脂需10ml裂解试剂配比，室温下裂解约2h(120r/min)，裂解之后用冰甲基叔丁基醚沉淀，下层沉淀即为粗品。
6.取上步的粗肽溶解，在制备型HPLC上用0.1％TFA/乙腈纯化。
7.纯化完之后进行冻干，冻干结束后取出粉末进行分装质检。
实例3：β-Ala-His-Lys-Ala-Pro-β-Ala-His的合成
1.在活化剂系统(HoBT,DIC)的存在下，由固相载体2-CTC树脂和Fmoc-His(Trt)-OH偶联得到Fmoc-His(Trt)-CTC树脂。
2.用20％哌啶脱除Fmoc-His(Trt)-CTC上的Fmoc保护基，脱除干净后用DMF洗涤干净。
3.称取3倍过量的Fmoc-β-Ala-OH，与三倍过量的活化剂，加入少量DMF充分溶解，溶解完之后加入至洗涤干净的树脂中，反应1h后用DMF洗涤干净。
4.重复第二步骤与第三步骤，按照主链顺序从Pro,Ala,Lys,His到β-Ala依次偶联具有N端Fmoc保护且侧链带保护的氨基酸。
5.合成完毕之后进行裂解，裂解试剂配比为TFA:EDT:Tis:TA:苯甲醚:H
2O＝80:5:1:5:5:4(体积比)，按1g肽树脂需10ml裂解试剂配比，室温下裂解约2h(120r/min)，裂解之后用冰甲基叔丁基醚沉淀，下层沉淀即为粗品。
6.取上步的粗肽溶解，在制备型HPLC上用0.1％TFA/乙腈纯化。
7.纯化完之后进行冻干，冻干结束后取出粉末进行分装质检。
实例4：Ala-Lys-Pro-β-Ala-His
1.在活化剂系统(HoBT,DIC)的存在下，由固相载体2-CTC树脂和Fmoc-His(Trt)-OH偶联得到Fmoc-His(Trt)-CTC树脂。
2.用20％哌啶脱除Fmoc-His(Trt)-CTC上的Fmoc保护基，脱除干净后用DMF洗涤干净。
3.称取3倍过量的Fmoc-β-Ala-OH，与三倍过量的活化剂，加入少量DMF充分溶解，溶解完之后加入至洗涤干净的树脂中，反应1h后用DMF洗涤干净。
4.重复第二步骤与第三步骤，按照主链顺序从Pro,Lys到Ala依次偶联具有N端Fmoc保护且侧链带保护的氨基酸。
5.合成完毕之后进行裂解，裂解试剂配比为TFA:EDT:Tis:TA:苯甲醚:H
2O＝80:5:1:5:5:4(体积比)，按1g肽树脂需10ml裂解试剂配比，室温下裂解约2h(120r/min)，裂解之后用冰甲基叔丁基醚沉淀，下层沉淀即为粗品。
6.取上步的粗肽溶解，在制备型HPLC上用0.1％TFA/乙腈纯化。
7.纯化完之后进行冻干，冻干结束后取出粉末进行分装质检。
实例5：动物实验方法
小动物监护仪：深圳市荣显达科技有限公司，VT200。
SD大鼠：中国食品药品鉴定研究院，180-200g。
线栓：迈越生物(M8507)。
TTC染色液：源叶生物(R24053)。
动物模型操作步骤：
对实验用SD大鼠进行称重，使用水合氯醛麻醉。麻醉后对大鼠四肢进行固定，仰卧，连接小动物监护仪，对大鼠体温、血压和心率等重要生理指标进行监护。对大鼠颈部进行脱毛，用75％酒精棉球消毒后对实验大鼠颈部进行长度2cm左右的正中切口，通过钝性分开大鼠颌下腺，分离过程中尽量避免对腺体的破坏，然后钝性分离出实验大鼠左侧的颈总动脉(CCA)，沿着CCA向上小心分离出颈内动脉(ICA)和颈外动脉(ECA)。分离过程中避免损伤迷走神经。使用两个动脉夹分别将CCA和ICA夹闭，剪断ECA远端并将硅胶线栓从ECA“端口”插入，插到ICA动脉夹处短暂松一下动脉夹并迅速将线栓头端插过动脉夹后再次夹闭ICA，然后轻轻松开ICA上的动脉夹并不断使线栓插入，直到线栓黑标插过ECA和ICA的分叉，线栓头端堵住大脑中动脉后用缝合线将ECA“端口”和线栓紧紧系紧，以防止大鼠醒后线栓“退出”或出血。松开并拿掉CCA和ICA上的动脉夹，使组织恢复原位，并滴加适量的青霉素以防伤口感染。使用医用带线缝合针进行缝合，封好之后再次用碘伏消毒。观察小动物监护仪判断实验大鼠指标是否正常，然后将大鼠放在小动物电热毯上使其保持体温直至苏醒放置动物笼中。
给药流程：
将待测药物配成3mg/mL的溶液。在结扎后1-2h尾静脉给药。
给药时将大鼠用固定器固定，利用1mL注射器按照3mg/kg剂量吸取待测药物，然后对大鼠进行尾静脉推注，注射时缓缓推注以降低实验大鼠的心肺负荷。
动物分为不同的试验小组，每组六只。
模型组：结扎后尾静脉给等量的生理盐水；
药物组S1(NA1),S4(β-Ala-His-Lys-Ala-Pro)和S5(Pro-Ala-Lys-β-Ala-His)：结扎后尾静脉给药；
其中，NA1(Nerinetide)是一种神经保护剂(Michael Tymianski and Jonathan D.Garman.Model systems and treatment regimes for treatment of neurological disease.2015,US Patent,US8940699B2)，可干扰突触后密度蛋白95(PSD-95)，通过终止细胞内NO自由基的产生来实现，在临床前缺血性脑卒中模型中可减少动物实验性(猕猴)脑缺血再灌注的梗死面积，并改善其功能预后，因此是一个很好的阳性对照产品。Hill博士研究了静脉注射新型神经肽NA-1(2.6mg/kg)用于血管内血栓切除术的急性缺血性脑卒中(AIS)患者的疗效和安全性，结果表明使用NA1治疗可改善患者预后。(Michael D Hill et al.Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke(ESCAPE-NA1):a multicentre,double-blind,randomised controlled trial.Lancet.Published online February 20,2020)。
假手术组：分离颈内动脉(ICA)和颈外动脉(ECA)后不做结扎处理，尾静脉给等量的生理盐水。
行为学观察：
结扎后22-24h对每只动物做行为学观察和评分。
按照如下评分表，让未参与该实验的技术员盲评。
0分：正常直线行走；
1分：前肢无力；
2分：后肢无力；
3分：轻度转圈；
4分:严重转圈；
5分：偏瘫。
TTC染色和量化分析：
行为学观察之后，将实验大鼠进行安乐死并取出其大脑。将脑组织横切成6片2mm厚的切片，再移至TTC染色液中，37℃孵箱中避光孵育10min，拍照。然后将TTC染色后的脑组织和剩余的少量未进行TTC染色的脑组织-20℃保存。
使用Image J软件对TTC染色后的照片做量化分析。
脑梗死体积％＝(总梗死面积*切片厚度)/(总脑切片面积*切片厚度)*100％。
实验结果：
1.1、TTC量化结果如表1所示：
表1
从表1的结果可见,TTC染色后进行量化分析的结果可见,注射生理盐水的脑缺血大鼠，梗死体积0.390±0.028；注射3mg/kgβ-Ala-His-Lys-Ala-Pro的脑缺血大鼠，梗死体积0.155±0.044；注射3mg/kg Pro-Ala-Lys-β-Ala-His的脑缺血大鼠，梗死体积0.147±0.051；作为比较，静脉给于3mg/kg NA1的脑缺血大鼠，梗死体积0.157±0.040。作为对照的假手术组的结果则为梗死体积0.044±0.005。与生理盐水比较，其它三组有明显的生物活性且S4和S5与S1没有统计学上的区别。
1.2行为学测评结果如表2所示：
表2
从表2可以看出本发明提供的合成肽具有生理活性。注射生理盐水的脑缺血大鼠，行为学评分为3.8±0.8；注射3mg/kgβ-Ala-His-Lys-Ala-Pro的脑缺血大鼠，评分为2.0±0.9；注射3mg/kg Pro-Ala-Lys-β-Ala-His的脑缺血大鼠，评分为 1.8±0.8；作为比较，静脉给药3mg/kg NA1的脑缺血大鼠，评分为2.0±0.6。作为对照的假手术组的结果则为1.0±0.0。与生理盐水比较，其它三组有明显的生物活性且S4和S5与S1没有统计学上的区别。
实例6：剂量影响实验
配制方法：称取一定受试物用注射用水充分溶解，配制到所需浓度，0.22μm滤器过滤除菌。以每组动物280g×14只举例，具体信息见下表3.
表3
阴性对照品(溶媒)：注射用水；阳性对照品：S1(NA1)
配制方法：称取一定受试物(化合物纯度按100％计算)，配制到所需浓度，0.22μm滤器过滤除菌；以动物280g×14只举例，具体信息见下表4。
表4
动物品系：Sprague-Dawley(SD)大鼠；等级：SPF级。体重：进入适应期时200.01～240.03g，分组时体重213.79～278.79g；年龄：适应期时约5～7周龄，试验分组时6～8周龄。来源：斯贝福(北京)生物科技有限公司。
动物接收后适应环境5天；不合格的动物不纳入本试验。
饲养环境条件标准：中华人民共和国国家标准GB14925-2010；
饲养环境控制系统：WINCC7.3EMS系列机房环境监控系统；
温度：室温20～26℃(日温差≤4℃)；
相对湿度：40～70％；
光照：人工照明，12/12小时昼夜明暗交替；
换气次数：每小时空气更换不少于15次。
饲料种类：大小鼠育成饲料；
生产单位：北京科澳协力饲料有限公司；
给料方法：自由摄取；
饮水种类：实验动物饮用水(反渗透水)；
供水方法：饮水瓶盛装，自由摄取；
水质常规指标检测：按中华人民共和国国家标准GB5749-2006的相关要求，每半年委托第三方有资质单位检测至少一次。
动物选择：选择适应期检查合格、体重符合实验要求且NSS评分总分小于等于3分的动物作为受试动物。
建立大鼠模型：将大鼠放入充满3.0％异氟烷的麻醉诱导盒进行麻醉诱导。经过麻醉诱导的动物转移至操作台上，使用小动物气体麻醉机以2.0％～2.5％异氟烷按200mL/min进行麻醉维持，观察大鼠眼睑反射和痛觉反应，在眼睑反射反应及四肢和尾部痛觉反应消失后方可开始手术。
A.分离暴露血管：手术区域备皮后，将大鼠置于手术显微镜下。沿正中线用眼科剪剪开大鼠皮肤，长度约2cm。经大鼠右侧颈旁入路，显微镊钝性分离并牵开右侧颈部的肌肉组织，显露右侧颈总动脉(common carotid artery，CCA)，然后沿颈总动脉向上分离，继续显露颈外动脉(external carotid artery，ECA)、颈内动脉(internal carotid artery，ICA)；
B.结扎ECA，暂时夹闭ICA；在CCA近心端、远心端分别穿线，远心端系紧，近心端系一松结备用，在两线间剪一小口；
C.线栓推入：将4-0号线栓经CCA的切口插入，再缓慢轻轻地推入颈内动脉，到达ICA的动脉夹处暂停，进一步套紧预结扎线(避免推线栓时出血过多)，然后将阻断ICA血流的动脉夹取出，立即将线栓推入ICA直到进入颅内。此时注意不要将线栓插入颈内动脉的另一分支翼腭动脉(翼腭动脉属于ICA在颅外的分支，当线栓进入该动脉深度为10mm左右时即不能继续插入，此时，稍微退出线栓，调整方向，重新操作)；
D.固定线栓、缝合切口：当线栓插入深度距离颈总动脉分叉约18mm左右时，如果有轻微阻力感，说明线栓的头端已经进入大脑前动脉(cerebral anterior artery，ACA)，线栓侧壁已经堵塞了大脑中动脉开口，此时停止插入，并记录时间。移去CCA上的动脉夹，观察无活动性出血后关闭切口；
E.大脑再灌注：缺血大鼠置于室温，120min后即可进行诱导麻醉，在维持麻醉状态下缓慢地轻拉线栓，使其头端回到颈外动脉内，即实现大脑中动脉再灌注；
F.碘伏消毒切口。
组别设计：分别为模型对照组、阳性药物治疗组、S5低剂量组、S5中剂量组、S5高剂量组；
性别比例：根据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)和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)等的报道，在成年大鼠中雌性激素和黄体酮等对缺血性脑梗死具有神经保护作用，为排除雌激素和黄体酮等对试验结果的影响，本试验全部动物均为雄性；
分组方法：根据分组前最近一次大鼠体重进行随机分组。
具体分组信息见下表5。
表5：给药方案及分组信息表
给药途径：静脉注射(i.v.)；
给药频率及周期：再灌注后立即(10min内)给药1次，手术当天定义为D1(Day1)。
观察动物：所有计划观察的存活实验动物；
观察时间：每天观察一次，如果动物出现异常，可增加观察频率；
观察内容：包括但不限于包括但不限于一般表现、行为状态、眼睛、口腔、鼻口部、耳、毛发及皮肤、粪便、尿、生殖器等毒性症状，若出现异常，需进行详细描述。
测定动物：所有计划测定的存活实验动物；
测定时间：适应期至少测量体重2次，各批次进行手术前一天和解剖当天称量一次，用于计算给药量和麻药量；术后一周两次。
Bederson评分
检测时间：造模当天缺血后1h；
测定动物：所有手术存活动物；
检测方法：参考Bederson评分标准对动物进行评分。
表6：大鼠Bederson评分标准
备注：缺血和再灌注后评分大于等于1分的大鼠为造模成功，造模未成功大鼠则淘汰。
大鼠神经功能评分
检测时间：造模前及造模后24h；
测定动物：所有计划测定的存活实验动物；
检测方法：对动物进行运动功能测试、感觉测试、平衡测试和反射和异常动作测试，具体参考大鼠神经功能评分表(NSS)。
表7：大鼠神经功能评分表(NSS)
病理学(TTC染色)评价
检查方法：安乐死动物快速取脑，并将鼠脑置于-20℃冰箱内冷冻至脑组织变硬后取出，将大鼠大脑切成2mm厚的切片，切片位置从嗅球向后，总共6片，分别放置于装有0.5％TTC溶液(0.9％氯化钠注射液配制)的六孔板格中，然后置于37℃恒温箱中避光温孵20min，取出后置于4％甲醛溶液中避光保存。
正常组织经染色后呈玫瑰红色，梗死组织呈白色。将每个脑平面按序摆放在滤纸上，数码相机拍照，小心取下白色组织并称重，以梗死组织重量占全脑重量的百分比作为梗塞范围(％)。并以梗塞范围计算各药物治疗组的抑制率(％)，抑制率计算公式如下：
统计分析：
计量指标采用均数±标准差表示。样本数小于3时，该组数据不纳入统计比较。
数据经Excel 2010、GraphPad Prism 7、SPSS 22.0和Stata 15.0软件进行录入与统计分析。计量指标先采用LEVENE方差齐性检验，当方差齐时(p＞0.05)，可直接引用方差分析的结果判断总体差异是否有统计学意义，总体差异有统计学意义时(p＜0.05)，用Dunnett-t检验对组间差异进行比较，总体差异无统计学意义时(p≥0.05)，统计分析结束；当LEVENE方差齐性检验显示方差不齐时(p≤0.05)，则采用非参数检验(Kruskal-Wallis H检验)，Kruskal-Wallis H检验显示总体差异有统计学意义时(p＜0.05)，用Mann-Whitney U检验进行组间差 异的比较，当Kruskal-Wallis H检验显示总体差异无统计学意义时(p≥0.05)，统计分析结束。病理等资料(如有)详细描述。
试验结果
测试品对模型动物脑梗死范围的影响
急性缺血性脑卒中的药物治疗主要包括二个方面，一是通过溶栓治疗恢复血流；二是给予神经保护剂治疗缺血引起的继发性神经元损害。本实验采用对SD大鼠缺血120min后进行再灌注模拟血管再通，再通后立即(10min内)通过尾静脉注射给予测试品干预，治疗结束后24h取脑组织，通过TTC染色测定各组动物梗死范围并计算抑制率开展测试品神经保护作用评价。采用S1(3mg/kg)作为本试验的阳性药物。动物脑梗死范围及脑梗死抑制率见表8。术后1天，对动物脑组织进行TTC染色计算动物脑梗死范围，模型对照组和阳性药物组动物脑梗死范围为：24.84±3.39％、16.74±3.14％，阳性药物S1在3mg/kg剂量下显现出良好的降低脑梗死范围的作用，与模型对照组相比较具有显著性差异(P<0.0001)。测试品S5低剂量组、中剂量组、高剂量组脑梗死范围分别为20.20±4.07％、18.76±2.50％和15.70±2.80％，测试品S5在设定剂量下均有改善脑组织梗死的作用，于模型对照组比较均有显著性差异(P<0.05、P<0.001和P<0.0001)。另外计算各治疗组动物脑梗死抑制率得阳性药物组、测试品S5低剂量组、S5中剂量组、S5高剂量组动物脑梗死抑制率分别为：33％、19％、24％和37％。以上结果提示在本实验条件下测试品S5均有良好的神经保护作用，其中测试品S5的起效剂量为0.6mg/kg，并且具有剂量效应关系。
表8：实验动物脑梗死范围和脑梗死抑制率
注：表中数据均以均值±标准差(Mean±SD)表示；“N”代表各组进行统计分析的动物数量，“—”表示该项没有数据，*表示与模型对照组动物相比P<0.05， ***表示与模型对照组动物相比P<0.001，****表示与模型对照组动物相比P<0.0001。
临床上脑梗死治疗的主要目的是尽量恢复患者的神经功能，提高卒中后生活质量；本试验于缺血后1h对动物进行Bederson评分，对动物缺血情况进行判断，于造模后1天参照NSS评分表对动物的神经行为功能进行评价，对测试品神经功能改善效果进行评估。动物Bederson评分结果见表9，NSS评分结果见表10。缺血后1h，各组动物Bederson评分均为3分，提示模型动物缺血成功。造模后1天，模型对照组、阳性药物组、测试品S5低剂量组、S5中剂量组和S5高剂量组动物NSS得分为8.62±0.84、8.00±0.76、8.23±0.97、7.92±0.62、和7.85±0.66。
表9：动物Bederson评分结果
注：表中数据均以均值±标准差(Mean±SD)表示；“N”代表各组进行统计分析的动物数量。
表10：动物NSS评分结果
注：表中数据均以均值±标准差(Mean±SD)表示；“N”代表各组进行统计分析的动物数量；“D0”代表术前1天，“D2”代表术后1天；**表示与模型对照组动物相比P<0.01。
测试品对模型动物体重的影响：脑缺血再灌注作为一个急性损伤模型，实验动物在MCAO造模后体重会急剧下降，试验动物体重作为综合反映动物健康状况最基本的灵敏指标之一，本试验在术后1天对所有动物的进行体重监测，动物体重变化结果见表11。造模前各组动物体重无组间差异，术后1天，各组动物体重均下降明显，模型对照组、阳性药物组、测试品S5低剂量组、S5中剂量组、S5高剂量组组动物体重各下降了48.92±5.78g、48.22±8.23g、42.73±8.59g、48.83±5.18g、和46.66±10.90g，各组间体重缺失量无显著差异，以上结果提示阳性药物S1、测试品S5对大鼠体重无明显影响。
表11：存活动物体重变化
注：表中数据均以均值±标准差(Mean±SD)表示；“N”代表各组进行统计分析的动物数量；“D0”代表术前1天，“D2”代表术后1天，体重缺失量＝D0体重-D2体重。
本试验采用经典的线栓法MCAO模型，对测试品S5的神经保护作用进行 评价。动物于再灌注即刻(10min内)给予测试品干预，治疗后1天，通过TTC染色测定脑梗死范围、抑制率、NSS评分、网格行走试验和体重变化，评价测试品对大鼠缺血性脑卒中的神经保护作用，结果表明：
1)测试品S5有良好的神经保护作用，主要体现模型动物经过测试品治疗后脑梗死范围显著减小，测试品S5的起效剂量为0.6mg/kg，并且具有剂量效应关系；
2)测试品S5对脑卒中大鼠体重无明显影响，在术后1天，模型动物体重均明显下降，组间体重缺失量无明显差异。
综上所述本试验在该模型上的药效评价结果表明测试品S5对缺血性脑卒中均有明显治疗效果。
以上所述仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (15)
- 一类多功能多肽，其特征在于，其由至少一个Pro-Ala-Lys、Ala-Lys-Pro、Lys-Ala-Pro及其片段和衍生肽中的一种或多种构成，且其C端和/或N端具有肌肽、鹅肌肽或者蛇肌肽；所述片段选自Pro-Ala、Ala-Lys、Lys-Pro、Lys-Ala、Ala-Pro、Pro、Ala或Lys，所述衍生肽选自Ala-Arg-Pro-Ala-Lys、Arg-Pro-Ala-Lys、Ala-Arg-Ala-Lys-Pro、Ala-Arg-Lys-Ala-Pro、Arg-Ala-Lys-Pro、Arg-Lys-Ala-Pro、Gly-Arg-Pro-Ala-Lys、Gly-Arg-Ala-Lys-Pro、Gly-Arg-Lys-Ala-Pro、Gln-Arg-Pro-Ala-Lys、Gln-Arg-Ala-Lys-Pro或Gln-Arg-Lys-Ala-Pro。
- 根据权利要求1所述的多功能多肽，其特征在于，其由Pro-Ala-Lys、Ala-Lys-Pro、Lys-Ala-Pro及其两肽片段中的一种或多种构成，且其C端和/或N端具有肌肽、鹅肌肽或者蛇肌肽；包括：β-Ala-His-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Pro，β-Ala-His-Lys-Ala-Pro，Pro-Ala-Lys-β-Ala-His，Ala-Lys-Pro-β-Ala-His，Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala，β-Ala-His-Ala-Lys，β-Ala-His-Lys-Pro，β-Ala-His-Lys-Ala，β-Ala-His-Ala-Pro，Pro-Ala-β-Ala-His，Ala-Lys-β-Ala-His，Lys-Pro-β-Ala-His，Lys-Ala-β-Ala-His，Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-β-Ala-His，β-Ala-His-Ala-Lys-β-Ala-His，β-Ala-His-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-β-Ala-His，β-Ala-His-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Pro-Ala，β-Ala-His-Pro-Ala-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Ala-Lys，β-Ala-His-Ala-Lys-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Lys-Pro，β-Ala-His-Lys-Pro-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Lys-Ala，β-Ala-His-Lys-Ala-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Ala-Pro，β-Ala-His-Ala-Pro-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Pro-Pro-Ala，β-Ala-His-Pro-Ala-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Lys-Pro，β-Ala-His-Lys-Pro-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Lys-Ala，β-Ala-His-Lys-Ala-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Ala-Pro，β-Ala-His-Ala-Pro-Ala-Lys-Pro，β-Ala-His-Lys-Ala-Pro-Pro-Ala，β-Ala-His-Pro-Ala-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Lys-Pro，β-Ala-His-Lys-Pro-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Lys-Ala，β-Ala-His-Lys-Ala-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Ala-Pro，β-Ala-His-Ala-Pro-Lys-Ala-Pro，Pro-Ala-Lys-Pro-Ala-β-Ala-His，Pro-Ala-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Ala-Lys-β-Ala-His，Ala-Lys-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Lys-Pro-β-Ala-His，Lys-Pro-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Lys-Ala-β-Ala-His，Lys-Ala-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Ala-Pro-β-Ala-His，Ala-Pro-Pro-Ala-Lys-β-Ala-His，Ala-Lys-Pro-Pro-Ala-β-Ala-His，Pro-Ala-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Ala-Lys-β-Ala-His，Ala-Lys-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Lys-Pro-β-Ala-His，Lys-Pro-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Lys-Ala-β-Ala-His，Lys-Ala-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Ala-Pro-β-Ala-His，Ala-Pro-Ala-Lys-Pro-β-Ala-His，Lys-Ala-Pro-Pro-Ala-β-Ala-His，Pro-Ala-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Ala-Lys-β-Ala-His，Ala-Lys-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-Pro-β-Ala-His，Lys-Pro-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-Ala-β-Ala-His，Lys-Ala-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Ala-Pro-β-Ala-His，Ala-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Pro-Ala-β-Ala-His，β-Ala-His-Pro-Ala-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Lys-Ala-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Ala-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Pro-Ala-β-Ala-His，β-Ala-His-Pro-Ala-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Lys-Ala-β-Ala-His，β-Ala-His-Lys-Ala-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-Pro-β-Ala-His，β-Ala-His-Ala-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Pro-Ala-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-Ala-β-Ala-His，β-Ala-His-Lys-Ala-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-Pro-β-Ala-His，β-Ala-His-Ala-Pro-Lys-Ala-Pro-β-Ala-His；其中，His为His、1-Methyl-His或者3-Methyl-His。
- 根据权利要求1所述的多功能多肽，其特征在于，其由Pro-Ala-Lys、Ala-Lys-Pro和Lys-Ala-Pro中的两种构成六肽，且其C端和/或N端具有肌肽、鹅肌肽或者蛇肌肽；包括：Pro-Ala-Lys-Ala-Lys-Pro-β-Ala-His，Pro-Ala-Lys-Lys-Ala-Pro-β-Ala-His，Ala-Lys-Pro-Pro-Ala-Lys-β-Ala-His，Lys-Ala-Pro-Pro-Ala-Lys-β-Ala-His，Ala-Lys-Pro-Lys-Ala-Pro-β-Ala-His，Pro-Ala-Lys-Ala-Lys-Pro-β-Ala-His，Lys-Ala-Pro-Ala-Lys-Pro-β-Ala-His，Lys-Ala-Pro-Pro-Ala-Lys-β-Ala-His，Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-Lys-Pro，β-Ala-His-Pro-Ala-Lys-Lys-Ala-Pro，β-Ala-His-Ala-Lys-Pro-Pro-Ala-Lys，β-Ala-His-Lys-Ala-Pro-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Pro-Lys-Ala-Pro，β-Ala-His-Pro-Ala-Lys-Ala-Lys-Pro，β-Ala-His-Lys-Ala-Pro-Ala-Lys-Pro，β-Ala-His-Lys-Ala-Pro-Pro-Ala-Lys，β-Ala-His-Lys-Ala-Pro-Lys-Ala-Pro，β-Ala-His-Pro-Ala-Lys-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His；其中，His为His、1-Methyl-His或者3-Methyl-His。
- 根据权利要求1所述的多功能多肽，其特征在于，由(Pro-Ala-Lys)n、(Ala-Lys-Pro)n或(Lys-Ala-Pro)n构成，且其C端和/或N端具有肌肽、鹅肌肽或者蛇肌肽；n为2-6的整数，包括：β-Ala-His-Pro-Ala-Lys-Pro-Ala-Lys，Pro-Ala-Lys-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-Lys-Pro，Ala-Lys-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-Ala-Pro，Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His；其中，His为His、1-Methyl-His或者3-Methyl-His。
- 根据权利要求1所述的多功能多肽，其特征在于，其由Pro-Ala-Lys、 Ala-Lys-Pro或Lys-Ala-Pro的衍生肽构成，且其C端和/或N端具有肌肽、鹅肌肽或者蛇肌肽；包括：Ala-Arg-Pro-Ala-Lys-β-Ala-His，Arg-Pro-Ala-Lys-β-Ala-His，Ala-Arg-Ala-Lys-Pro-β-Ala-His，Ala-Arg-Lys-Ala-Pro-β-Ala-His，Arg-Ala-Lys-Pro-β-Ala-His，Arg-Lys-Ala-Pro-β-Ala-His，Gly-Arg-Pro-Ala-Lys-β-Ala-His，Gln-Arg-Pro-Ala-Lys-β-Ala-His，Gly-Arg-Ala-Lys-Pro-β-Ala-His，Gly-Arg-Lys-Ala-Pro-β-Ala-His，Gln-Arg-Ala-Lys-Pro-β-Ala-His，Gln-Arg-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Ala-Arg-Pro-Ala-Lys，β-Ala-His-Arg-Pro-Ala-Lys，β-Ala-His-Ala-Arg-Ala-Lys-Pro，β-Ala-His-Ala-Arg-Lys-Ala-Pro，β-Ala-His-Arg-Ala-Lys-Pro，β-Ala-His-Arg-Lys-Ala-Pro，β-Ala-His-Gly-Arg-Pro-Ala-Lys，β-Ala-His-Gln-Arg-Pro-Ala-Lys，β-Ala-His-Gly-Arg-Ala-Lys-Pro，β-Ala-His-Gly-Arg-Lys-Ala-Pro，β-Ala-His-Gln-Arg-Ala-Lys-Pro，β-Ala-His-Gln-Arg-Lys-Ala-Pro，β-Ala-His-Ala-Arg-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Arg-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Arg-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Arg-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Arg-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Arg-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Gly-Arg-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Gln-Arg-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Gly-Arg-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Gly-Arg-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Gln-Arg-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Gln-Arg-Lys-Ala-Pro-β-Ala-His；其中，His为His、1-Methyl-His或者3-Methyl-His。
- 根据权利要求1所述的多功能多肽，其特征在于，其由Pro-Ala-Lys、Ala-Lys-Pro或Lys-Ala-Pro及氨基酸Pro、Ala或Lys构成，且其C端和/或N端具有肌肽、鹅肌肽或者蛇肌肽；包括：β-Ala-His-Pro-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Pro，β-Ala-His-Ala-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Ala，β-Ala-His-Lys-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Lys，β-Ala-His-Pro-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Pro，β-Ala-His-Ala-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Ala，β-Ala-His-Lys-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Lys，β-Ala-His-Pro-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Pro，β-Ala-His-Ala-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Ala，β-Ala-His-Lys-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Lys，Pro-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Pro-β-Ala-His，Ala-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Ala-β-Ala-His，Lys-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Lys-β-Ala-His，Pro-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Pro-β-Ala-His，Ala-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Ala-β-Ala-His，Lys-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Lys-β-Ala-His，Pro-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Pro-β-Ala-His，Ala-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Ala-β-Ala-His，Lys-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-β-Ala-His，β-Ala-His-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-β-Ala-His，β-Ala-His-Lys-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Pro-β-Ala-His，β-Ala-His-Ala-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-β-Ala-His，β-Ala-His-Lys-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Lys-β-Ala-His，β-Ala-His-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-β-Ala-His，β-Ala-His-Lys-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-β-Ala-His；其中，His为His、1-Methyl-His或者3-Methyl-His。
- 根据权利要求1所述的多功能多肽，其特征在于，包括：β-Ala-His-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Pro，β-Ala-His-Lys-Ala-Pro，β-Ala-His-Arg-Pro-Ala-Lys，β-Ala-His-Arg-Ala-Lys-Pro，β-Ala-His-Arg-Lys-Ala-Pro，β-Ala-His-Pro-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Pro，β-Ala-His-Ala-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Ala，β-Ala-His-Lys-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Lys，β-Ala-His-Pro-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Pro，β-Ala-His-Ala-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Ala，β-Ala-His-Lys-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Lys，β-Ala-His-Pro-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Pro，β-Ala-His-Ala-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Ala，β-Ala-His-Lys-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Lys，β-Ala-His-Ala-Arg-Pro-Ala-Lys，β-Ala-His-Ala-Arg-Ala-Lys-Pro，β-Ala-His-Ala-Arg-Lys-Ala-Pro，β-Ala-His-Gly-Arg-Pro-Ala-Lys，β-Ala-His-Gln-Arg-Pro-Ala-Lys，β-Ala-His-Gly-Arg-Ala-Lys-Pro，β-Ala-His-Gly-Arg-Lys-Ala-Pro，β-Ala-His-Gln-Arg-Ala-Lys-Pro，β-Ala-His-Gln-Arg-Lys-Ala-Pro，β-Ala-His-Pro-Ala-Lys-Pro-Ala，β-Ala-His-Pro-Ala-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Ala-Lys，β-Ala-His-Ala-Lys-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Lys-Pro，β-Ala-His-Lys-Pro-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Lys-Ala，β-Ala-His-Lys-Ala-Pro-Ala-Lys，β-Ala-His-Pro-Ala-Lys-Ala-Pro，β-Ala-His-Ala-Pro-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Pro-Pro-Ala，β-Ala-His-Pro-Ala-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Lys-Pro，β-Ala-His-Lys-Pro-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Lys-Ala，β-Ala-His-Lys-Ala-Ala-Lys-Pro，β-Ala-His-Ala-Lys-Pro-Ala-Pro，β-Ala-His-Ala-Pro-Ala-Lys-Pro，β-Ala-His-Lys-Ala-Pro-Pro-Ala，β-Ala-His-Pro-Ala-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Lys-Pro，β-Ala-His-Lys-Pro-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Lys-Ala，β-Ala-His-Lys-Ala-Lys-Ala-Pro，β-Ala-His-Lys-Ala-Pro-Ala-Pro，β-Ala-His-Ala-Pro-Lys-Ala-Pro，β-Ala-His-Pro-Ala-Lys-Ala-Lys-Pro，β-Ala-His-Pro-Ala-Lys-Lys-Ala-Pro，β-Ala-His-Ala-Lys-Pro-Pro-Ala-Lys，β-Ala-His-Lys-Ala-Pro-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Pro-Lys-Ala-Pro，β-Ala-His-Pro-Ala-Lys-Ala-Lys-Pro，β-Ala-His-Lys-Ala-Pro-Ala-Lys-Pro，β-Ala-His-Lys-Ala-Pro-Pro-Ala-Lys，β-Ala-His-Lys-Ala-Pro-Lys-Ala-Pro，β-Ala-His-Pro-Ala-Lys-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Pro-Ala-Lys-Pro，β-Ala-His-Lys-Ala-Pro-Lys-Ala-Pro，Pro-Ala-Lys-β-Ala-His，Ala-Lys-Pro-β-Ala-His，Lys-Ala-Pro-β-Ala-His，Arg-Pro-Ala-Ly-β-Ala-His，Arg-Ala-Lys-Pro-β-Ala-His，Arg-Lys-Ala-Pro-β-Ala-His，Pro-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Pro-β-Ala-His，Ala-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Ala-β-Ala-His，Lys-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Lys-β-Ala-His，Pro-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Pro-β-Ala-His，Ala-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Ala-β-Ala-His，Lys-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Lys-β-Ala-His，Pro-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Pro-β-Ala-His，Ala-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Ala-β-Ala-His，Lys-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-β-Ala-His，Ala-Arg-Pro-Ala-Ly-β-Ala-His，Ala-Arg-Ala-Lys-Pro-β-Ala-His，Ala-Arg-Lys-Ala-Pro-β-Ala-His，Gly-Arg-Pro-Ala-Lys-β-Ala-His，Gln-Arg-Pro-Ala-Ly-β-Ala-His，Gly-Arg-Ala-Lys-Pro-β-Ala-His，Gly-Arg-Lys-Ala-Pro-β-Ala-His，Gln-Arg-Ala-Lys-Pro-β-Ala-His，Gln-Arg-Lys-Ala-Pro-β-Ala-His，Pro-Ala-Lys-Pro-Ala-β-Ala-His，Pro-Ala-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Ala-Lys-β-Ala-His，Ala-Lys-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Lys-Pro-β-Ala-His，Lys-Pro-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Lys-Ala-β-Ala-His，Lys-Ala-Pro-Ala-Lys-β-Ala-His，Pro-Ala-Lys-Ala-Pro-β-Ala-His，Ala-Pro-Pro-Ala-Lys-β-Ala-His，Ala-Lys-Pro-Pro-Ala-β-Ala-His，Pro-Ala-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Ala-Lys-β-Ala-His，Ala-Lys-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Lys-Pro-β-Ala-His，Lys-Pro-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Lys-Ala-β-Ala-His，Lys-Ala-Ala-Lys-Pro-β-Ala-His，Ala-Lys-Pro-Ala-Pro-β-Ala-His，Ala-Pro-Ala-Lys-Pro-β-Ala-His，Lys-Ala-Pro-Pro-Ala-β-Ala-His，Pro-Ala-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Ala-Lys-β-Ala-His，Ala-Lys-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-Pro-β-Ala-His，Lys-Pro-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Lys-Ala-β-Ala-His，Lys-Ala-Lys-Ala-Pro-β-Ala-His，Lys-Ala-Pro-Ala-Pro-β-Ala-His，Ala-Pro-Lys-Ala-Pro-β-Ala-His，Pro-Ala-Lys-Ala-Lys-Pro-β-Ala-His，Pro-Ala-Lys-Lys-Ala-Pro-β-Ala-His，Ala-Lys-Pro-Pro-Ala-Lys-β-Ala-His，Lys-Ala-Pro-Pro-Ala-Lys-β-Ala-His，Ala-Lys-Pro-Lys-Ala-Pro-β-Ala-His，Pro-Ala-Lys-Ala-Lys-Pro-β-Ala-His，Lys-Ala-Pro-Ala-Lys-Pro-β-Ala-His，Lys-Ala-Pro-Pro-Ala-Lys-β-Ala-His，Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His，Pro-Ala-Lys-Pro-Ala-Lys-β-Ala-His，Ala-Lys-Pro-Ala-Lys-Pro-β-Ala-His，Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Arg-Pro-Ala-Ly-β-Ala-His，β-Ala-His-Arg-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Arg-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-β-Ala-His，β-Ala-His-Lys-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Pro-β-Ala-His，β-Ala-His-Ala-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-β-Ala-His，β-Ala-His-Lys-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Lys-β-Ala-His，β-Ala-His-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-β-Ala-His，β-Ala-His-Lys-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-β-Ala-His，β-Ala-His-Ala-Arg-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Arg-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Arg-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Gly-Arg-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Gln-Arg-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Gly-Arg-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Gly-Arg-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Gln-Arg-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Gln-Arg-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Pro-Ala-β-Ala-His，β-Ala-His-Pro-Ala-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Lys-Ala-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Ala-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Pro-Ala-β-Ala-His，β-Ala-His-Pro-Ala-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Lys-Ala-β-Ala-His，β-Ala-His-Lys-Ala-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-Pro-β-Ala-His，β-Ala-His-Ala-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Pro-Ala-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-Ala-β-Ala-His，β-Ala-His-Lys-Ala-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-Pro-β-Ala-His，β-Ala-His-Ala-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-Lys-Ala-Pro-β-Ala-His。
- 根据权利要求1所述的多功能多肽，其特征在于，其由Pro-Ala-Lys、Ala-Lys-Pro和Lys-Ala-Pro中的一种并在其C端和/或N端偶联一个肌肽、鹅肌肽或者蛇肌肽形成，包括：β-Ala-His-Pro-Ala-Lys，β-Ala-His-Ala-Lys-Pro，β-Ala-His-Lys-Ala-Pro，Pro-Ala-Lys-β-Ala-His，Ala-Lys-Pro-β-Ala-His，Lys-Ala-Pro-β-Ala-His，β-Ala-His-Pro-Ala-Lys-β-Ala-His，β-Ala-His-Ala-Lys-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-β-Ala-His；其中，His为His、1-Methyl-His或者3-Methyl-His。
- 根据权利要求1所述的多功能多肽，其特征在于，其由Pro-Ala-Lys在其C端和/或N端偶联一个肌肽、鹅肌肽或者蛇肌肽形成，包括：β-Ala-His-Pro-Ala-Lys，Pro-Ala-Lys-β-Ala-His，β-Ala-His-Pro-Ala-Lys-β-Ala-His；其中，His为His、1-Methyl-His或者3-Methyl-His。
- 根据权利要求1所述的多功能多肽，其特征在于，其由Ala-Lys-Pro在其C端和/或N端偶联一个肌肽、鹅肌肽或者蛇肌肽形成，包括：β-Ala-His-Ala-Lys-Pro，Ala-Lys-Pro-β-Ala-His，β-Ala-His-Ala-Lys-Pro-β-Ala-His；其中，His为His、1-Methyl-His或者3-Methyl-His。
- 根据权利要求1所述的多功能多肽，其特征在于，其由Lys-Ala-Pro在其C端和/或N端偶联一个肌肽、鹅肌肽或者蛇肌肽形成，包括：β-Ala-His-Lys-Ala-Pro，Lys-Ala-Pro-β-Ala-His，β-Ala-His-Lys-Ala-Pro-β-Ala-His；其中，His为His、1-Methyl-His或者3-Methyl-His。
- 根据权利要求1所述的多功能多肽，其特征在于，包括：β-Ala-His-Lys-Ala-Pro，Pro-Ala-Lys-β-Ala-His。
- 权利要求1-12任一项所述的多功能多肽或其盐用在医药中。
- 包含权利要求1-12任一项所述的多功能多肽或其盐的药物，例如所述药物是注射剂、口服用药、舌下用药、喷雾用药或肛门用药。
- 根据权利要求1-12任一项所述的多功能多肽或其盐，用于治疗缺血性脑卒中、出血性脑卒中、脑创伤、阿尔茨海默病、帕金森病或其它神经退行性疾病。
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| CN113121641B (zh) * | 2021-03-11 | 2022-11-01 | 武汉英纳氏药业有限公司 | 一类多功能多肽及其在医药领域的应用 |
| CN113735939A (zh) * | 2021-07-30 | 2021-12-03 | 英纳氏(珠海)药业有限公司 | 一种组合多肽及其应用 |
| CN113735938A (zh) * | 2021-07-30 | 2021-12-03 | 英纳氏(珠海)药业有限公司 | 一种神经保护多肽化合物及其应用 |
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| KR20160058940A (ko) * | 2013-09-25 | 2016-05-25 | 프로뉴트리아 바이오사이언시스, 인코퍼레이티드 | 근육량, 강도 및 성능을 유지하기 위한 조성물 및 제형, 그리고 이의 생산방법 및 용도 |
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| US20240158442A1 (en) | 2024-05-16 |
| CN113121641A (zh) | 2021-07-16 |
| CN113121641B (zh) | 2022-11-01 |
| EP4306534A1 (en) | 2024-01-17 |
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