A polypeptide and its application in improving learning and memory impairment of alzheimer disease

Abstract

The application discloses a kind of polypeptide and its application in improving learning and memory impairment of Alzheimer's disease.The application utilizes the fusion protein polypeptide TAT-P-1082 of artificially synthesized TAT protein transduction domain and P-1082, and TAT can carry P-1082 protein polypeptide to be taken up by neuron through blood brain barrier by blood, and is applied to mouse model in vivo, can effectively exert its biological effect of blocking E2 ubiquitin binding enzyme UBE2K and GluN2B receptor binding, so that the ubiquitination level of GluN2B receptor is reduced, and protein level is increased, so as to improve learning and memory impairment of Alzheimer's disease.

Description

Technical Field

[0001] This invention relates to the technical field of polypeptides, and more specifically to a polypeptide and its application in improving learning and memory impairment in Alzheimer's disease. Background Technology

[0002] Alzheimer's disease (AD) is the most common neurodegenerative disease, accounting for more than 60% of dementia patients, with a prevalence rate of 33.2% in people aged 85 and above. Early AD symptoms include recent memory impairment, while later stages present with communication difficulties, disorientation, and confusion. By 2050, the elderly will account for one-third of my country's total population, and AD will impose a heavy medical burden on society. Characteristic pathological changes in AD include plaques formed by amyloid-β (Aβ), neurofibrillary tangles formed by hyperphosphorylated Tau protein, and loss of neurons and synapses. AD is incurable, and clinical trials targeting Aβ and Tau have not met expectations.

[0003] Synapses, composed of presynaptic and postsynaptic components, are functional connections between neurons or other cells, serving as the fundamental units for memory storage and information transmission in the brain. Synaptic disorders, including synaptic loss, abnormal synaptic transmission, and dendritic spine atrophy, are significant causes of learning and memory impairment. Synaptic disorders appear early in Alzheimer's disease (AD) and are most closely associated with cognitive impairment; they can be used to predict AD clinical symptoms. Soluble Aβ and Tau oligomers can cause synaptic toxicity and propagate through neural circuits. AD is considered a synaptic disorder, and targeting synaptic disorders can improve AD-like symptoms in mice; therefore, some clinical trials use synaptic integrity as a primary or secondary endpoint of AD treatment. Although synaptic disorders are a prerequisite for learning and memory impairment in AD, the underlying mechanisms remain unclear, and effective treatments to alleviate and prevent synaptic disorders are currently lacking. Summary of the Invention

[0004] The purpose of this invention is to overcome the shortcomings of the aforementioned background technology and provide a polypeptide and its application in improving learning and memory impairment in Alzheimer's disease. This polypeptide is a small molecule polypeptide TAT-P-1082 composed of an amino acid sequence that competitively binds to the GluN2B receptor with UBE2K protein. When applied to an in vivo mouse Alzheimer's disease model, it effectively blocks the binding of UBE2K (Ubiquitin Conjugating Enzyme E2K) to the GluN2B receptor (Glutamate Ionotropic Receptor NMDA Type Subunit 2B), thereby reducing the ubiquitination level of the GluN2B receptor and increasing its protein level, thus improving learning and memory impairment in Alzheimer's disease and providing a method for improving learning and memory impairment in Alzheimer's disease.

[0005] To achieve the above objectives, the present invention provides a polypeptide, the amino acid sequence of which is shown in SEQ ID NO:1.

[0006] The present invention also provides an application of the above-mentioned polypeptide in improving learning and memory impairment in Alzheimer's disease.

[0007] The present invention also provides the application of the above-mentioned polypeptide in the preparation of a drug for improving learning and memory impairment in Alzheimer's disease.

[0008] The present invention also provides a drug for improving learning and memory impairment in Alzheimer's disease, wherein the active ingredient of the drug is the aforementioned polypeptide.

[0009] Furthermore, the drug also contains one or more pharmaceutically acceptable excipients and / or a combination of a carrier.

[0010] Furthermore, the dosage form of the drug is an injection or an oral preparation.

[0011] Furthermore, the carrier is one or more of the following: stabilizer, dispersant, emulsifier, solubilizer, buffer, preservative, lubricant, water-retaining agent, or diluent.

[0012] This invention relates to the application of a polypeptide in improving learning and memory impairment in Alzheimer's disease. By intraperitoneal injection, it was found that the polypeptide can effectively increase GluN2B protein levels, improve synaptic damage, and enhance learning and memory abilities in mice, providing a method for improving learning and memory impairment in Alzheimer's disease.

[0013] Through extensive experimental research, the inventors discovered that UBE2K and GluN2B interact in both cells and mice. Overexpression of UBE2K reduces GluN2B protein levels, while inhibition of UBE2K increases GluN2B protein levels. Based on this discovery, the inventors linked TAT transmembrane peptide (YGRKKRRQRRR) with P-1082 (GNAAKRRKQQYKDSL) to obtain the bioactive small molecule polypeptide TAT-P-1082. This TAT-P-1082 polypeptide was administered via intraperitoneal injection to mice, allowing it to enter the bloodstream, cross the blood-brain barrier, and be taken up by brain neurons to exert its biological functions.

[0014] The application of the small molecule peptide TAT-P-1082 in improving learning and memory impairment in Alzheimer's disease is as follows:

[0015] (1) Application of TAT-P-1082 peptide in improving learning and memory impairment in Alzheimer's disease

[0016] APP / PS1 is a commonly used AD mouse model, exhibiting significant learning and memory impairment and synaptic dysfunction at 12 months of age. Twenty 12-month-old male APP / PS1 mice of similar weight were housed together for one week. Ten mice were randomly selected and administered 15 mg / kg TAT-P-1082 peptide solution, while the other ten were intraperitoneally injected with 15 mg / kg TAT-Scramble peptide solution. After 14 consecutive days of injections, novel object recognition and Morris water maze tests were performed. All solutions were prepared fresh, diluted with injectable physiological saline. The experiments showed that mice injected with the TAT-Scramble control solution showed no significant difference in preference for new or old objects, while mice injected with the TAT-P-1082 solution showed a higher preference for new objects. The Morris water maze test revealed that mice injected with the TAT-P-1082 solution had significantly higher learning and memory abilities than those injected with the TAT-Scramble control solution.

[0017] Immunoprecipitation revealed that UBE2K and GluN2B interacted in both N2a cells and the hippocampus of C57BL / 6 mice. Immunofluorescence staining of primary neurons cultured for 14 days showed co-localization of UBE2K and GluN2B within neurons. Overexpression of UBE2K in N2a cells decreased GluN2B protein levels, while inhibition of UBE2K increased GluN2B protein levels. In N2a cells, overexpression of UBE2K followed by treatment with 10 μM TAT-P-1082 solution, as shown by Western blotting, effectively reversed the UBE2K-induced decrease in GluN2B protein levels. These experiments demonstrate that the TAT-P-1082 peptide can improve learning and memory impairment in Alzheimer's disease.

[0018] (2) The role of TAT-P-1082 peptide in improving synaptic damage in Alzheimer's disease

[0019] Following the Morris water maze test in mice, Golgi staining was used to analyze changes in synapse number, mushroom-shaped dendritic spine ratio, and synaptic complexity. Compared to mice injected with the TAT-Scramble control solution, mice injected with the TAT-P-1082 solution showed significantly increased dendritic spine number, mushroom-shaped dendritic spine ratio, and synaptic complexity, with decreased GluN2B ubiquitination levels and increased protein levels. These experiments demonstrate that the TAT-P-1082 peptide can improve synaptic damage in Alzheimer's disease.

[0020] Compared with the prior art, the present invention has the following advantages:

[0021] Firstly, this invention links TAT ​​transmembrane peptide (YGRKKRRQRRR) with P-1082 (GNAAKRRKQQYKDSL) to obtain a biologically active TAT-P-1082 polypeptide. TAT, derived from the HIV transactivator of transcription, is a highly efficient transport carrier capable of carrying polypeptides to penetrate cell membranes, enter cells, and exert corresponding biological effects. It can cross the blood-brain barrier and enter neurons in the brain without significant toxic side effects. The polypeptides carried into cells by TAT retain their original biological activity and exert their corresponding biological functions. This invention uses intraperitoneal injection in mice to allow the TAT-P-1082 polypeptide to enter the bloodstream, cross the blood-brain barrier, and be taken up by brain neurons to exert its biological functions.

[0022] Secondly, this invention synthesizes a small polypeptide TAT-P-1082 composed of an amino acid sequence that competitively binds to the GluN2B receptor with the UBE2K protein. When applied to an in vivo mouse Alzheimer's disease model, it effectively blocks the binding of UBE2K to the GluN2B receptor, thereby reducing the ubiquitination level of the GluN2B receptor and increasing the protein level, thus improving learning and memory impairment in Alzheimer's disease and providing a method for improving learning and memory impairment in Alzheimer's disease.

[0023] Thirdly, the small molecule polypeptide TAT-P-1082 involved in this invention has high purity, is completely soluble, is suitable for intravenous injection, and has no toxic side effects.

[0024] Fourth, the TAT-P-1082 polypeptide disclosed in this invention can be carried by TAT across the blood-brain barrier and taken up by neurons via the blood, and can be applied to the nervous system to improve learning and memory, making it feasible in practice. Attached Figure Description

[0025] Figure 1 This is the mass spectrometry spectrum of sequence TAT-P-1082 in an embodiment of the present invention.

[0026] Figure 2 The graph shows the effect of UBE2K binding to and inhibiting GluN2B protein levels. Figure 2 A shows the immunoprecipitation diagram of the interaction between UBE2K and GluN2B in N2a cells; Figure 2 B is an immunoprecipitation image of the interaction between UBE2K and GluN2B in the hippocampus of C57BL / 6 mice; Figure 2 C is an immunofluorescence image showing the co-localization of UBE2K and GluN2B in primary cortical neurons cultured in vitro; Figure 2 D shows the effect of UBE2K on inhibiting GluN2B protein levels in N2a cells; Figure 2 E is a graph showing the effect of knocking out UBE2K on promoting GluN2B protein levels in N2a cells; Figure 2 F is a graph showing the effect of TAT-P-1082 peptide in restoring GluN2B protein levels in an embodiment of the present invention.

[0027] Figure 3 This is a diagram illustrating the effect of TAT-P-1082 peptide on improving learning and memory impairment in Alzheimer's disease, as shown in the embodiments of the present invention. Figure 3 A is a schematic diagram of intraperitoneal injection; Figure 3 B represents the trajectory and statistical graph of the new object recognition experiment; Figure 3 C is a statistical graph showing the latency of mice reaching the platform during the Morris water maze experiment training period; Figure 3 D is a statistical graph showing the number of times mice crossed the platform during the Morris water maze test.

[0028] Figure 4 This is a diagram illustrating the effect of TAT-P-1082 peptide on improving synaptic damage in Alzheimer's disease in an embodiment of the present invention. Figure 4 A is a diagram of Golgi-stained synapse morphology; Figure 4 B is a statistical graph of dendritic spine density in mice; Figure 4 C is a statistical chart of the proportion of mushroom-shaped dendritic spines in mice; Figure 4 D is a neuron morphology diagram; Figure 4 E is a statistical graph of mouse dendritic branching; Figure 4 F is a statistical graph of the dendritic complexity index of mice.

[0029] Figure 5 This is a diagram illustrating the effect of TAT-P-1082 peptide on improving GluN2B protein levels in an embodiment of the present invention. Figure 5 A is an immunoprecipitation diagram of the level of GluN2B ubiquitination in the hippocampus of mice after injection of TAT-P-1082 polypeptide; Figure 5 B is an immunoblot image of the level of GluN2B protein in the hippocampus of mice after injection of TAT-P-1082 peptide. Detailed Implementation

[0030] The following examples illustrate the implementation of the present invention in detail, but they do not constitute a limitation on the invention and are merely illustrative. Furthermore, the advantages of the present invention will become clearer and easier to understand by explaining them.

[0031] Example 1:

[0032] 1.1 Experimental Materials:

[0033] This invention links a TAT transmembrane peptide (YGRKKRRQRRR) with P-1082 (GNAAKRRKQQYKDSL) to obtain a bioactive polypeptide (TAT-P-1082). Utilizing the transmembrane function of TAT, the P-1082 polypeptide is delivered into the bloodstream, crosses the blood-brain barrier, and is taken up by neurons in the brain to exert its biological function. The amino acid sequence of the polypeptide TAT-P-1082 is shown in SEQ ID NO.1 of this invention: YGRKKRRQRRRGNAAKRRKQQYKDSL. The control of TAT-P-1082 is TAT-Scramble, whose amino acid sequence is shown in SEQ ID NO.2: YGRKKRRQRRRYPVTQPLAPVHNPIS. Both the TAT-P-1082 polypeptide and the control TAT-Scramble polypeptide were synthesized by Qiangyao Biotechnology Co., Ltd.

[0034] This invention utilizes TAT-P-1082 solution, which is randomly selected and administered via intraperitoneal injection to mice. This effectively blocks the binding of UBE2K to GluN2B receptors, thereby reducing the ubiquitination level of GluN2B receptors and increasing their protein levels, thus improving learning and memory impairment in Alzheimer's disease.

[0035] 1.2 Experimental Subjects:

[0036] 12-month-old male APP / PS1 mice and 4-month-old C57BL / 6 mice (purchased from Changzhou Cavens Laboratory Animal Co., Ltd.), SPF grade, weighing 20-25 grams, were housed in a routine environment. APP / PS1 is a commonly used AD mouse model, exhibiting significant learning and memory impairment and synaptic dysfunction at 12 months of age.

[0037] 1.3 Research Methods:

[0038] (1) Detection of the interaction between UBE2K and GluN2B in N2a cells, C57BL / 6 mice and primary mouse neurons: immunoprecipitation and immunofluorescence;

[0039] (2) UBE2K and GluN2B protein detection: immunoblotting;

[0040] (3) Mouse learning and memory test: intraperitoneal injection, new object recognition and Morris water maze test. Intraperitoneal injection procedure: Weigh the mouse, calculate the injection dose according to 15mg / kg, hold the mouse with its abdomen facing up and its head in a low position, hold the syringe in your right hand, and slowly insert the needle at 45 degrees about 1.5cm from the midline of the line connecting the roots of the mouse's hind legs to perform intraperitoneal injection.

[0041] Novel object recognition experiment: On the training day, two objects designated A and B were introduced into the playing area for mice to explore for 5 minutes. After training, the equipment and playing area were thoroughly cleaned with 75% ethanol. The next day, the test was conducted, and object B was replaced with a completely new object C. A camera was used to capture the mice's movements. The time the mice spent interacting with objects A and C was recorded as TA and TC, respectively. The mice's preference for unfamiliar objects was examined by dividing the sum of TA and TC by the total exploration time (TA+TC).

[0042] Morris water maze experiment: A water maze pool was divided into four quadrants. A platform was placed in one quadrant, 2 cm below the water surface. Mice were trained for 5 consecutive days, undergoing three tests each day. At the start of each test, the mice were released at the edge of the quadrant without the platform. The test ended once the mouse climbed onto the platform and remained there for at least three seconds. If the mouse did not find the platform within one minute, it was manually guided to the platform and allowed to remain there for 15 seconds. On day 6, the mice rested and were not trained. On day 7, the platform was removed during the test. A camera positioned 2 meters above the water maze pool captured the mice's swimming path, recording the time to reach the platform (latency period), the duration of their stay in the target area, and their speed.

[0043] (4) Synaptic and neuronal morphology analysis: Golgi staining;

[0044] (5) GluN2B ubiquitination detection: immunoprecipitation.

[0045] 1.4 Experimental Results

[0046] *P<0.05, compared with the TAT-Scramble group

[0047] **P<0.01, compared with the TAT-Scramble group

[0048] ***P<0.001, compared with the TAT-Scramble group

[0049] The sequence of TAT-P-1082 is shown in SEQ ID NO:1, and the MS analysis is as follows: Figure 1 As shown, the analysis results indicate that the amino acid sequence of the synthesized polypeptide is consistent with SEQ ID NO:1. The synthesized TAT-P-1082 polypeptide has a purity of 95.86%, is a white powder, and is prepared by dilution with physiological saline for injection, and should be used immediately. The TAT-Scramble sequence is shown in SEQ ID NO:2.

[0050] I. Application of TAT-P-1082 peptide in improving learning and memory impairment in Alzheimer's disease

[0051] (1) UBE2K binds to GluN2B and reduces GluN2B protein levels: such as Figure 2 As shown, Figure 2 A plasmid expressing UBE2K was transfected into N2a cells, and cell proteins were collected 48 hours after transfection. The overexpressed UBE2K protein is a fusion protein of UBE2K and GFP. Cell proteins were precipitated with anti-GFP antibody, and the precipitated proteins were detected with anti-GluN2B or UBE2K antibody. The black blot on the PVDF membrane indicated the interaction between UBE2K and GluN2B. RNF138, a known UBE2K binding protein, was used as a positive control. Figure 2 C57BL / 6 mice were euthanized by cervical dislocation and decapitation under anesthesia. Brain tissue was rapidly extracted, and the bilateral hippocampi were quickly separated. Immunoprecipitation was used to detect the binding of UBE2K and GluN2B. Cellular proteins were precipitated with anti-GluN2B antibody, and the precipitated proteins were then detected with anti-GluN2B or UBE2K antibody. The black blot on the PVDF membrane indicated the interaction between UBE2K and GluN2B. Figure 2 Primary cortical neurons were cultured in vitro for 14 days, fixed, incubated with specific antibodies against UBE2K and GluN2B, treated with immunofluorescence secondary antibody, and the distribution of UBE2K and GluN2B was observed under a fluorescence microscope. It was found that UBE2K (red) and GluN2B (green) were expressed in neurons and co-localized. Figure 2 D transfected N2a cells with a plasmid expressing UBE2K, and collected cellular proteins 48 hours after transfection. The overexpressed UBE2K protein was a fusion protein of UBE2K and GFP. Protein levels were detected using anti-GluN2B or UBE2K antibodies. The black blot on the PVDF membrane showed that UBE2K significantly inhibited GluN2B protein levels compared to the control vector. Figure 2 E transfected N2a cells with the UBE2K knockout plasmid (shUBE2K), and collected cellular proteins 72 hours after transfection. Protein levels were detected using anti-GluN2B or UBE2K antibodies. The black blot on the PVDF membrane showed that UBE2K knockout significantly increased GluN2B protein levels compared to the control vector (shControl). Figure 2 F cells were transfected with a plasmid expressing UBE2K. Twelve hours after transfection, cells were incubated with 1 μM and 10 μM TAT-P-1082 or 10 μM TAT-Scramble for 24 hours, after which cell proteins were collected. Protein levels were detected using anti-UBE2K or GluN2B antibodies. The black blot on a PVDF membrane indicated that TAT-P-1082 could reverse the UBE2K-induced decrease in GluN2B protein levels.

[0052] Statistical results showed that transfection of plasmids expressing UBE2K into N2a cells resulted in overexpressed UBE2K protein, a fusion protein of UBE2K and GFP. Cellular proteins were precipitated using anti-GFP antibody, and the precipitated proteins were then detected using anti-GluN2B or UBE2K antibodies. C57BL / 6 mice were euthanized by cervical dislocation and decapitation under anesthesia. Brain tissue was rapidly removed, and the bilateral hippocampuses were quickly isolated. Immunoprecipitation was used to detect the binding of UBE2K and GluN2B. The black blot on the PVDF membrane indicated that UBE2K and GluN2B interact in both cells and animals. Primary cortical neurons were cultured in vitro, and immunofluorescence analysis revealed the distribution of UBE2K and GluN2B, showing that UBE2K (red) and GluN2B (green) were expressed and co-localized in neurons. Transfection of plasmids expressing UBE2K into N2a cells significantly inhibited GluN2B protein levels; transfection of plasmids knocking out UBE2K significantly increased GluN2B protein levels. Transfecting N2a cells with a plasmid expressing UBE2K and administering TAT-P-1082 reversed the decrease in GluN2B protein levels caused by UBE2K.

[0053] (2) Peptides alter the learning and memory abilities of mice: such as Figure 3 As shown, Figure 3 A is a schematic diagram of intraperitoneal injection. Twenty 12-month-old male APP / PS1 mice of similar weight were housed together for one week. Ten mice were randomly selected and given 15 mg / kg TAT-P-1082 peptide solution, while the other 10 mice were given 15 mg / kg TAT-Scramble peptide solution via intraperitoneal injection. After 14 consecutive days of injection, novel object recognition and Morris water maze tests were performed. Figure 3 Mice injected with TAT-Scramble control solution showed no significant difference in preference for new or old things, while mice injected with TAT-P-1082 solution showed a higher preference for new things. Figure 3 C Morris water maze experiments showed that mice injected with TAT-P-1082 solution during the first 5 days of the learning phase had a shorter latency to reach the platform than mice injected with TAT-Scramble. Figure 3 Mice injected with TAT-P-1082 solution crossed the platform significantly more times than control mice injected with TAT-Scramble during the 7th day of testing, indicating enhanced learning and memory abilities.

[0054] Statistical results showed that one group of mice was given an intraperitoneal injection of 15 mg / kg TAT-P-1082 peptide solution, while the other group was given an intraperitoneal injection of TAT-Scramble solution. These injections were administered for 14 consecutive days. Following this, a novel object recognition test was conducted. Mice injected with the TAT-Scramble control solution showed no significant difference in preference for new or old objects, while mice injected with the TAT-P-1082 solution showed a higher preference for new objects. Statistical results from Morris water maze training and testing indicated that mice injected with TAT-P-1082 solution had a shorter latency to reach the platform during the first 5 days of learning compared to mice injected with TAT-Scramble solution. On the 7th day of testing, the number of times the mice traversed the platform increased, indicating enhanced learning and memory abilities.

[0055] The above results indicate that the TAT-P-1082 peptide can improve learning and memory impairment in Alzheimer's disease.

[0056] II. Application of TAT-P-1082 peptide in improving synaptic damage in Alzheimer's disease

[0057] (1) Morphological analysis of mouse synapses and neurons: such as Figure 4 As shown, after the Morris water maze test was completed, mice were euthanized by cervical dislocation and decapitation under anesthesia. Brain tissue was quickly removed, immersed in Golgi-Cox staining solution, and stored at room temperature in the dark for 3 weeks. The brain tissue was then prepared into 200 μm thick sections using a vibratory microtome. After dehydration with ethanol and clearing with toluene, synapses were observed under a microscope. Figure 4 A) and neurons ( Figure 4 D) Morphology. Statistical analysis showed that the number of dendritic spines in mice injected with TAT-P-1082 solution ( Figure 4 B) Proportion of mushroom-shaped dendritic spines ( Figure 4 C) Dendritic branches ( Figure 4 E) and dendrite complexity index are both ( Figure 4 F) was higher than that of control mice injected with TAT-Scramble.

[0058] After the behavioral studies, mice were euthanized by cervical dislocation and decapitation under anesthesia. Synaptic and neuronal morphology were analyzed under a microscope after Golgi-cox staining. Statistical results showed that mice injected with TAT-P-1082 solution had significantly increased dendritic spine number, mushroom-shaped dendritic spine proportion, dendritic branching, and dendritic complexity index, indicating improved synaptic damage compared to mice injected with TAT-Scramble solution.

[0059] (2) Detection of GluN2B ubiquitination and protein levels in mice: such as Figure 5 As shown, Figure 5After the AMorris water maze test was completed, mice were euthanized by cervical dislocation and decapitation under anesthesia. Brain tissue was quickly removed, and proteins were precipitated using anti-GluN2B antibody. The ubiquitination level of GluN2B was then detected using ubiquitin (Ub) antibody. Figure 5 Immunoblotting analysis of GluN2B protein levels showed that the hippocampal GluN2B protein levels in mice injected with TAT-P-1082 solution were significantly higher than those in control mice injected with TAT-Scramble solution.

[0060] Statistical results showed that after precipitating the protein with anti-GluN2B antibody, the ubiquitination level of GluN2B was detected by anti-ubiquitin (Ub) antibody, and the GluN2B protein level was detected by immunoprecipitation. Compared with mice administered TAT-Scramble solution, mice injected with TAT-P-1082 solution had decreased GluN2B ubiquitination levels and increased GluN2B protein levels.

[0061] The above results indicate that the TAT-P-1082 peptide can improve synaptic damage in Alzheimer's disease.

[0062] The above are merely specific embodiments of the present invention. It should be noted that any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the protection scope of the present invention. Any other aspects not described in detail are prior art.

Claims

1. A polypeptide, characterized in that: The amino acid sequence of the polypeptide is shown in SEQ ID NO:

1.

2. The use of the polypeptide as described in claim 1 in the preparation of a drug for improving learning and memory impairment in Alzheimer's disease.

3. A drug for improving learning and memory impairment in Alzheimer's disease, characterized in that: The active ingredient of the drug is the polypeptide described in claim 1.

4. The drug according to claim 3, characterized in that: The drug also contains one or more pharmaceutically acceptable carriers.

5. The drug according to claim 4, characterized in that: The drug is available in either injectable or oral formulation.

6. The drug according to claim 5, characterized in that: The carrier is one or more of the following: stabilizer, dispersant, emulsifier, solubilizer, buffer, preservative, lubricant, water-retaining agent, or diluent.

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