CN117327168A - B2M-GluN1封闭肽、其药物组合物及用途 - Google Patents
B2M-GluN1封闭肽、其药物组合物及用途 Download PDFInfo
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Abstract
本发明属于生物医药领域,涉及一种B2M‑GluN1封闭肽、其药物组合物及用途。具体地,本发明涉及一种分离的多肽,其为SEQ ID NO:8所示的多肽或SEQ ID NO:8所示多肽的截短片段。本发明的分离的多肽能够有效地治疗或预防唐氏综合征、阿尔兹海默病、或者唐氏综合征或阿尔兹海默病所导致的认知损伤,具有良好的应用前景。
Description
技术领域
本发明属于生物医药领域,涉及B2M-GluN1封闭肽、其药物组合物及用途。
背景技术
唐氏综合征(Down syndrome,DS)也称21三体综合征,是最常见的智力障碍疾病之一,全球约800例新生儿中就有1例患有此病。唐氏综合征患者体内多了一条或部分21号染色体,21号染色体基因拷贝数的增加,导致基因表达异常,最终引起多种疾病症状,包括发育迟缓,智力障碍、语言延迟、免疫和内分泌系统异常以及骨骼、心脏和消化系统的缺陷等。智力落后是唐氏综合征最突出、最严重的症状,绝大部分患儿都有不同程度的智力发育障碍,智商大多约25~50(正常人90以上),随年龄的增长逐渐明显,语言、记忆、抽象思维等均会受损。此外,几乎所有的唐氏综合征患者在40岁后均会发展出类似阿尔茨海默病(Alzheimer’s disease,AD)的神经病理学特征,其中60%的唐氏综合征患者在65岁会表现出明显的阿尔茨海默病痴呆症状。但是目前,唐氏患者的智力障碍仍然缺乏有效的药物治疗及干预手段。
阿尔兹海默病是人类最常见的神经退行性疾病之一,根据世界阿尔茨海默病2018年报告,2018年全球有5000万人患有阿尔茨海默病,到2050年,这一数字将增至1.52亿。该病的主要病理特征包括脑内淀粉样前体蛋白(Amyloid precursor protein,APP)切割产生的β-淀粉样蛋白(Aβ)寡聚化形成的淀粉样沉积、胞内微管结合蛋白tau异常磷酸化后聚集形成的神经纤维缠结(Neurofibrillary tangles,NFTs)、神经元丢失和过度的神经炎症等。阿尔茨海默病患者的临床表现主要是记忆力的衰退和认知障碍,并且这种衰退随着病程的发展而恶化,最终丧失一切记忆和生活自理能力直至死亡。鉴于全球老龄化的到来,加之阿尔茨海默病发病率的持续升高,以及目前尚未发现有效的治疗措施,致使阿尔茨海默病成为严重威胁人类健康的疾病之一。
GluN1是NMDA受体的组成亚基,由人类的9号染色体基因编码,包含938个氨基酸,为三次跨膜蛋白,包括N-端胞外段、C-端胞内段、跨膜结构和细胞外环肽段(extracellularloop)。NMDA受体被认为是多种神经疾病的一种潜在致病特征,如缺血性脑卒中、创伤性脑损伤、阿尔茨海默病、癫痫、情绪障碍及精神分裂症等。NMDA受体在亚单位组成、生物物理和药理学特性、相互作用和亚细胞定位等方面具有多样性。在发育过程中和疾病状态下,不同中枢神经系统区域的亚基组成各不相同。因此,NMDA受体一直是神经药理学领域的研究热点及药物靶点。近年来,NMDA受体调节剂作为治疗药物的兴趣也显著增加。因此,这些化合物将为研究NMDA受体信号的生理学提供新的工具,从而揭示新的治疗机会。目前FDA批准的一个阿尔茨海默病治疗药物—美金刚,其为NMDA型谷氨酸受体的可逆性阻断剂,但其作用机制和方式与本发明完全不同。
β2-微球蛋白(β2-microglobulin,B2M)是近年来逐渐受到广泛关注的促衰老因子,B2M是主要组织相容性复合体I(Major histocompatibility complex I,MHC-I)的组成亚基,由人的15号染色体基因编码,包含119个氨基酸。由于B2M不是通过跨膜结构域锚定在细胞膜上,因此B2M可以从MHC-I复合体上游离下来进入细胞间隙。正常情况下,B2M蛋白以可溶性的单体形式存在,但是在一些病理因素作用下,B2M会发生聚集、沉积。这些病理因素包括衰老、长期的肾功能障碍和炎症等。B2M淀粉样沉积主要存在于骨关节区域,并最终导致严重的关节炎、骨折及腕管综合征。另外,在很多疾病状态下,血清和血浆中B2M的含量均有增加。然而,B2M是否对唐氏综合征和阿尔茨海默病疾病的发生发展产生直接或间接的影响则未见研究报道。
发明内容
本发明人经过深入的研究和创造性的劳动,发现了B2M在唐氏综合征发生发展过程中的作用,本发明人惊奇地发现,阻碍B2M与GluN1结合的封闭肽具有作为防治唐氏综合征或阿尔茨海默病所致认知损伤的药物的潜力。由此提供了下述发明:
本发明的一个方面涉及一种分离的多肽,其为SEQ ID NO:8所示的多肽或SEQ IDNO:8所示多肽的截短片段;优选地,所述截短片段包含SEQ ID NO:11所示的多肽。
EKHNYESAAEAIQAVRDNKLHAFIWDSAVLEFEASQKCDLVTTGELFFRSGFGIGMR(SEQ ID NO:8)
KLHAFIWDSAVLEFEASQ(SEQ ID NO:11)
在本发明的一些实施方式中,所述的分离的多肽,其为SEQ ID NO:11或SEQ IDNOs:14-32中任一序列所示的多肽。
AVRDNKLHAFIWDSAVLEFEASQ(SEQ ID NO:14)
VRDNKLHAFIWDSAVLEFEASQ(SEQ ID NO:15)
RDNKLHAFIWDSAVLEFEASQ(SEQ ID NO:16)
DNKLHAFIWDSAVLEFEASQ(SEQ ID NO:17)
NKLHAFIWDSAVLEFEASQ(SEQ ID NO:18)
KLHAFIWDSAVLEFEASQKCDLV(SEQ ID NO:19)
KLHAFIWDSAVLEFEASQKCDL(SEQ ID NO:20)
KLHAFIWDSAVLEFEASQKCD(SEQ ID NO:21)
KLHAFIWDSAVLEFEASQKC(SEQ ID NO:22)
KLHAFIWDSAVLEFEASQK(SEQ ID NO:23)
RDNKLHAFIWDSAVLEFEASQKCD(SEQ ID NO:24)
RDNKLHAFIWDSAVLEFEASQKC(SEQ ID NO:25)
RDNKLHAFIWDSAVLEFEASQK(SEQ ID NO:26)
DNKLHAFIWDSAVLEFEASQKCD(SEQ ID NO:27)
DNKLHAFIWDSAVLEFEASQKC(SEQ ID NO:28)
DNKLHAFIWDSAVLEFEASQK(SEQ ID NO:29)
NKLHAFIWDSAVLEFEASQKCD(SEQ ID NO:30)
NKLHAFIWDSAVLEFEASQKC(SEQ ID NO:31)
NKLHAFIWDSAVLEFEASQK(SEQ ID NO:32)
本发明的另一方面涉及分离的多核苷酸,其编码本发明中任一项所述的分离的多肽。
本发明的再一方面涉及一种重组表达载体,其包含本发明的分离的多核苷酸。
本发明的再一方面涉及一种转化的细胞,其包含本发明的重组表达载体。
本发明的再一方面涉及一种药物组合物,其包含一种或多种(例如2、3、4或5种)本发明中任一项所述的分离的多肽。
在本发明的一些实施方式中,所述的药物组合物,其还包含一种或多种药学上可接受的辅料。
本发明的再一方面涉及本发明中任一项所述的分离的多肽在制备治疗或预防唐氏综合征、阿尔兹海默病、或者唐氏综合征或阿尔兹海默病所导致的认知损伤的药物中的用途。
本发明的再一方面涉及本发明中任一项所述的分离的多肽在制备如下药物中的用途:
降低人脑中B2M水平的药物、降低人脑中淀粉样前体蛋白水平的药物、抑制人脑中GluN1与B2M结合的药物或者修复人脑中因B2M增加导致的突触损伤的药物。
根据本发明中任一项所述的分离的多肽,其用于治疗或预防唐氏综合征、阿尔兹海默病、或者唐氏综合征或阿尔兹海默病所导致的认知损伤。
根据本发明中任一项所述的分离的多肽,其用于降低人脑中B2M水平、降低人脑中淀粉样前体蛋白水平、抑制人脑中GluN1与B2M结合或者修复人脑中因B2M增加导致的突触损伤。
本发明的再一方面涉及一种治疗或预防唐氏综合征、阿尔兹海默病、或者唐氏综合征或阿尔兹海默病所导致的认知损伤的方法,包括给予有需求的受试者以有效量的本发明中任一项所述的分离的多肽的步骤。
本发明的再一方面涉及一种抑制人脑中GluN1与B2M结合或者修复人脑中因B2M增加导致的突触损伤的方法,包括给予有需求的受试者以有效量的本发明中任一项所述的分离的多肽的步骤。
在本发明的一些实施方式中,所述的治疗或预防唐氏综合征、阿尔兹海默病、或者唐氏综合征或阿尔兹海默病所导致的认知损伤的方法,或者所述的抑制人脑中GluN1与B2M结合或者修复人脑中因B2M增加导致的突触损伤的方法,其中,
本发明中任一项所述的分离的多肽的单次给药剂量为每千克体重0.1-100mg,优选每千克体重5-50mg或5-15mg;
优选地,每3天、每4天、每5天、每6天、每10天、每1周、每2周或每3周给药一次;
优选地,给药方式为静脉滴注或静脉注射。
本发明首次发现唐氏综合征患者脑组织内B2M表达显著升高,B2M增加会损伤突触可塑性和认知功能。进一步地,本发明人发现B2M与GluN1胞外段存在直接的相互作用,使用截短的GluN1氨基酸序列作为封闭肽可以阻碍B2M与GluN1结合,抑制B2M的损伤NMDA受体的功能,体内实验表明封闭肽可以显著抑制脑内B2M与GluN1结合,增强突触可塑性。本发现为唐氏综合征的临床治疗提供了一个潜在的药物靶点以及基于该靶点的新的治疗方式。
在本发明的一些实施方式中,所述GluN1的氨基酸序列如SEQ ID NO:1所示。
大鼠GluN1蛋白的氨基酸序列(N端至C端)如下:
MSTMHLLTFALLFSCSFARAACDPKIVNIGAVLSTRKHEQMFREAVNQANKRHGSWKIQLNATSVTHKPNAIQMALSVCEDLISSQVYAILVSHPPTPNDHFTPTPVSYTAGFYRIPVLGLTTRMSIYSDKSIHLSFLRTVPPYSHQSSVWFEMMRVYNWNHIILLVSDDHEGRAAQKRLETLLEERESKAEKVLQFDPGTKNVTALLMEARELEARVIILSASEDDAAT VYRAAAMLNM TGSGYVWLVGEREISGNALRYAPDGIIGLQLINGKNESAHISDAVGVVAQAVHELLEKENITDPPRGCVGNTNIWKTGPLFKRVLMSSKYADGVTGRVEFNEDGDRKFANYSIMNLQNRKLVQVGIYNGTHVIPNDRKIIWPGGETEKPRGYQMSTRLKIVTIHQEPFVYVKPTMSDGTCKEEFTVNGDPVKKVICTGPNDTSPGSPRHTVPQCCYGFCIDLLIKLARTMNFTYEVHLVADGKFGTQERVNNSNKKEWNGMMGELLSGQADMIVAPLTINNERAQYIEFSKPFKYQGLTILVKKEIPRSTLDSFMQPFQSTLWLLVGLSVHVVAVMLYLLDRFSPFGRFKVNSEEEEEDALTLSSAMWFSWGVLLNSGIGEGAPRSFSARILGMVWAGFAMIIVASYTANLAAFLVLDRPEERITGINDPRLRNPSDKFIYATVKQSSVDIYFRRQVELSTMYRHMEKHNYESAAEAIQAVRDNKLHAFIWDSAVLEFEASQKCDLVTTGELFFRSGFGIGMRKDSPWKQNVSLSILKSHENGFMEDLDKTWVRYQECDSRSNAPATLTFENMAGVFMLVAGGIVAGIFLIFIEIAYKRHKDARRKQMQLAFAAVNVWRKNLQDRKSGRAEPDPKKKATFRAITSTLASSFKRRRSSKDTSTGGGRGALQNQKDTVLPRRAIEREEGQLQ LCSRHRES(SEQ ID NO:1)
在本发明的一些实施方式中,所述GluN1的氨基酸序列如SEQ ID NO:2所示。
人GluN1蛋白的氨基酸序列(N端至C端)如下:
MSTMRLLTLALLFSCSVARAACDPKIVNIGAVLSTRKHEQMFREAVNQANKRHGSWKIQLNATSVTHKPNAIQMALSVCEDLISSQVYAILVSHPPTPNDHFTPTPVSYTAGFYRIPVLGLTTRMSIYSDKSIHLSFLRTVPPYSHQSSVWFEMMRVYSWNHIILLVSDDHEGRAAQKRLETLLEERESKAEKVLQFDPGTKNVTALLMEAKELEARVIILSASEDDAATVYRAAAMLNMTGSGYVWLVGEREISGNALRYAPDGILGLQLINGKNESAHISDAVGVVAQAVHELLEKENITDPPRGCVGNTNIWKTGPLFKRVLMSSKYADGVTGRVEFNEDGDRKFANYSIMNLQNRKLVQVGIYNGTHVIPNDRKIIWPGGETEKPRGYQMSTRLKIVTIHQEPFVYVKPTLSDGTCKEEFTVNGDPVKKVICTGPNDTSPGSPRHTVPQCCYGFCIDLLIKLARTMNFTYEVHLVADGKFGTQERVNNSNKKEWNGMMGELLSGQADMIVAPLTINNERAQYIEFSKPFKYQGLTILVKKEIPRSTLDSFMQPFQSTLWLLVGLSVHVVAVMLYLLDRFSPFGRFKVNSEEEEEDALTLSSAMWFSWGVLLNSGIGEGAPRSFSARILGMVWAGFAMIIVASYTANLAAFLVLDRPEERITGINDPRLRNPSDKFIYATVKQSSVDIYFRRQVELSTMYRHMEKHNYESAAEAIQAVRDNKLHAFIWDSAVLEFEASQKCDLVTTGELFFRSGFGIGMRKDSPWKQNVSLSILKSHENGFMEDLDKTWVRYQECDSRSNAPATLTFENMAGVFMLVAGGIVAGIFLIFIEIAYKRHKDARRKQMQLAFAAVNVWRKNLQDRKSGRAEPDPKKKATFRAITSTLASSFKRRRSSKDTSTGGGRGALQNQKDTVLPRRAIEREEGQLQLCSRHRES(SEQ ID NO:2)
经比对,人GluN1蛋白与大鼠GluN1蛋白的同源性(相似度)为99.25%。
在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所用的细胞培养、分子遗传学、核酸化学、免疫学实验室操作步骤均为相应领域内广泛使用的常规步骤。同时,为了更好地理解本发明,下面提供相关术语的定义和解释。
在本发明中,当提及GluN1的氨基酸序列时,其包括GluN1的全长,还包括其融合蛋白。然而,本领域技术人员理解,在GluN1的氨基酸序列中,可天然产生或人工引入突变或变异(包括但不限于置换,缺失和/或添加),而不影响其生物学功能。在本发明的一个实施方案中,GluN1的氨基酸序列如SEQ ID NO:1所示。在本发明的一个实施方案中,GluN1的氨基酸序列如SEQ ID NO:2所示。
在本发明中,术语“分离的”或“被分离的”指的是,从天然状态下经人工手段获得的。如果自然界中出现某一种“分离”的物质或成分,那么可能是其所处的天然环境发生了改变,或从天然环境下分离出该物质,或二者情况均有发生。例如,某一活体动物体内天然存在某种未被分离的多聚核苷酸或多肽,而从这种天然状态下分离出来的高纯度的相同的多聚核苷酸或多肽即称之为分离的。术语“分离的”或“被分离的”不排除混有人工或合成的物质,也不排除存在不影响物质活性的其它不纯物质。
在本发明中,术语“宿主细胞”指的是导入载体的细胞,包括如下许多细胞类型,如大肠杆菌或枯草菌等原核细胞,如酵母细胞或曲霉菌等真菌细胞,如S2果蝇细胞或Sf9等昆虫细胞,或者如纤维原细胞、CHO细胞、COS细胞、NSO细胞、HeLa细胞、BHK细胞、HEK293细胞,或动物细胞例如人细胞。
在本发明中,术语“载体”指的是,可将抑制某蛋白的多核苷酸插入其中的一种核酸运载工具。举例来说,载体包括:质粒;噬菌粒;柯斯质粒;人工染色体如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC);噬菌体如λ噬菌体或M13噬菌体及动物病毒等。用作载体的动物病毒种类有逆转录酶病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、乳头瘤病毒、乳头多瘤空泡病毒(如SV40)。一种载体可能含有多种控制表达的元件。
术语“疾病和/或病症”是指所述受试者的一种身体状态,该身体状态与本发明所述疾病和/或病症有关。
术语“受试者”可以指患者或者其它接受本发明药物组合物以治疗、预防、减轻和/或缓解本发明所述疾病或病症的动物,特别是哺乳动物,例如人、狗、猴、牛、马等。
如本文中所使用的,术语“药学上可接受的辅料”是指在药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂,其是本领域公知的(参见例如Remington'sPharmaceutical Sciences.Edited by Gennaro AR,19th ed.Pennsylvania:MackPublishing Company,1995),并且包括但不限于:pH调节剂,表面活性剂,佐剂,离子强度增强剂。例如,pH调节剂包括但不限于磷酸盐缓冲液;表面活性剂包括但不限于阳离子,阴离子或者非离子型表面活性剂,例如Tween-80;离子强度增强剂包括但不限于氯化钠。
如本文中所使用的,术语“有效量”是指足以获得或至少部分获得期望的效果的量。例如,预防疾病(例如唐氏综合征或阿尔茨海默病)有效量是指,足以预防,阻止,或延迟疾病(例如唐氏综合征或阿尔茨海默病)的发生的量;治疗疾病有效量是指,足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。测定这样的有效量完全在本领域技术人员的能力范围之内。例如,对于治疗用途有效的量将取决于待治疗的疾病的严重度、患者自己的免疫系统的总体状态、患者的一般情况例如年龄,体重和性别,药物的施用方式,以及同时施用的其他治疗等等。
术语“封闭肽”是指,可以与全长GluN1蛋白竞争性结合B2M,从而抑制B2M结合GluN1损伤突触可塑性的生物学效应。
本发明中,如果没有特别说明,浓度单位μM表示μmol/L,mM表示mmol/L,nM表示nmol/L。
本发明中,提到细胞中的加药量时,如果没有特别说明,一般是指加药后药物的终浓度。
发明的有益效果
本发明提供了新的预防、治疗或改善唐氏综合征或阿尔兹海默病导致的认知功能受损的药物靶点。抑制或阻断β2-微球蛋白活性能够有效地防治唐氏综合征、阿尔兹海默病、或者唐氏综合征或阿尔兹海默病所导致的认知损伤。
附图说明
图1A至图1D:B2M在唐氏胎脑和唐氏小鼠组织中表达水平增加。
其中:
图1A:唐氏患者胎脑组织中B2M表达免疫印迹检测结果。
图1B:Image J分析图1A中B2M表达水平,对照组n=6个人脑组织,唐氏综合征组n=7个人脑组织。数据采用student’s t test进行统计分析。ns,无显著性差异,P>0.05;*P<0.05;**P<0.01;***P<0.001。
图1C:Dp16小鼠脑组织中B2M表达免疫印迹检测结果。
图1D:Image J分析图1C中B2M表达水平,WT组n=6个小鼠脑组织,Dp16组n=6个小鼠脑组织。数据采用student’s t test进行统计分析。ns,无显著性差异,P>0.05;*P<0.05;**P<0.01;***P<0.001。
图2:NMDAR EPSC幅度统计图。在体外条件下,用B2M蛋白(浓度10μg/ml)和ACSF分别孵育WT小鼠脑片两小时,孵育以后进行电生理检测,记录海马区谢弗侧枝环路NMDAREPSC幅度,刺激电极放置于靠近CA3的区域,记录CA1区锥体细胞电流,灌流液中加入50μMPTX和20μM CNQX分别阻断GABAA受体和AMPA受体离子通道,钳制电压为+40mV。记录细胞数量分别为ACSF组n=16,B2M组n=14,数据代表平均值±标准误(SEM),统计学方法为one-way ANOVA,ns,无显著性差异;P>0.05;*P<0.05;**P<0.01;***P<0.001;****P<0.0001。
图3A至图3D:B2M与GluN1胞外环肽段相互结合的免疫共沉淀(co-IP)实验结果。将带有HA标签的B2M质粒分别和GluN1、N端缺失的GluN1、C端缺失的GluN1、GluN1的细胞外环肽段质粒共转染入HEK293T细胞。取等量质量的蛋白裂解液分别与IgG(对照组)、HA抗体以及Protein G beads共孵育过夜进行免疫共沉淀,第二天进行免疫印迹检测并分析。其中:
图3A:用抗HA的抗体免疫沉淀B2M与GluN1。
图3B:用抗HA的抗体免疫沉淀B2M与N端缺失的GluN1。
图3C:用抗HA的抗体免疫沉淀B2M与C端缺失的GluN1。
图3D:用抗HA的抗体免疫沉淀B2M与GluN1胞外环肽段。
图4A:为了进一步确认GluN1细胞外环肽段上与B2M结合的最小区域,将GluN1细胞外环肽段序列截短为3条无重叠序列的短肽的截短示意图。
图4B:通过GST-pull down实验检测GluN1胞外环肽段 L2的GST融合蛋白与B2M结合能力更强。
图4C:为了进一步缩小发挥阻抑效果的氨基酸序列范围,本发明人将GluN1胞外环肽段L2进一步为3条无重叠序列的短肽的节段示意图。
图4D:将上述的3条无重叠序列的短肽在PBS溶液中与Ni-NTA Agarose在4℃预孵育8小时,再加入hB2M蛋白4℃孵育过夜,第二天进行免疫印迹检测并分析。
图4E:将GluN1-P2截短肽与GST-B2M融合蛋白在PBS中4℃旋转预孵育8个小时,再加入800μg转染GluN1质粒的293T细胞裂解液4℃孵育过夜,第二天进行免疫印迹检测并分析。
图5A:NMDAR EPSC幅度统计图。6月龄Dp16小鼠及对照WT小鼠海马脑立体定位注射1μl(1μg/μl)GluN1-P2截短肽或Non-sense肽段(每只小鼠自身大脑左右对照),注射一天后进行电生理记录。记录海马区谢弗侧枝环路NMDAR EPSC幅度,刺激电极放置于靠近CA3的区域,记录CA1区锥体细胞电流,灌流液中加入50μM PTX和20μM CNQX分别阻断GABAA受体和AMPA受体离子通道,钳制电压为+40mV。记录细胞数量分别为WT Scrambled n=14,WTGluN1-P2 n=14,Dp16Scrambled n=15,Dp16 GluN1-P2 n=16,数据代表平均值±标准误(SEM),统计学方法为one-way ANOVA,ns,无显著性差异,P>0.05;*P<0.05;**P<0.01;***P<0.001;****P<0.0001。
图5B:NMDAR EPSC幅度统计图。3月龄C57BL/6小鼠海马脑立体定位注射1μl(1μg/μl)GluN1-P2截短肽或Non-sense肽段(每只小鼠自身大脑左右对照),注射一天后,小鼠切脑片在体外条件下,用B2M蛋白(浓度10μg/ml)和ACSF分别孵育脑片两小时,孵育以后进行电生理记录。记录海马区谢弗侧枝环路NMDAR EPSC幅度,刺激电极放置于靠近CA3的区域,记录CA1区锥体细胞电流,灌流液中加入50μM PTX和20μM CNQX分别阻断GABAA受体和AMPA受体离子通道,钳制电压为+40mV。记录细胞数量分别为WT-ACSF n=15,WT-B2M n=15,WT-B2M Scrambled n=16,WT-B2M GluN1-P2 n=16,数据代表平均值±标准误(SEM),统计学方法为one-way ANOVA,ns,无显著性差异,P>0.05;*P<0.05;**P<0.01;***P<0.001;****P<0.0001。
图5C:脑片CA1区LTP记录分析结果。6月龄Dp16小鼠及对照WT小鼠海马脑立体定位注射1μl(1μg/μl)GluN1-P2截短肽或Non-sense肽段(每只小鼠自身大脑左右对照),注射一天后进行电生理记录。记录脑片数量分别为WT Scrambled n=9,WT GluN1-P2 n=8,Dp16Scrambled n=8,Dp16 GluN1-P2 n=8,数据代表平均值±标准误(SEM),统计学方法为one-way ANOVA,ns,无显著性差异,P>0.05;*P<0.05;**P<0.01;***P<0.001;****P<0.0001。
图5D:图5C中LTP记录结果最后10min fEPSP斜率统计分析结果。每组n值同图5C。
图5E:脑片CA1区LTP记录分析结果。通过脑立体定位注射向8月龄5×FAD小鼠大脑海马内注射1μl(1μg/μl)GluN1-P2截短肽或Non-sense肽段(每只小鼠自身大脑左右对照),注射一天后进行LTP记录。一共注射了5只小鼠,记录脑片数量分别为5×FAD Scrambled n=8,5×FAD GluN1-P2 n=10。数据代表平均值±标准误(SEM),统计学方法为unpaired ttest,ns,无显著性差异,P>0.05;*P<0.05;**P<0.01;***P<0.001。
图5F:图5E中LTP记录结果最后10min fEPSP斜率统计分析结果。每组n值同图5E。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
5×FAD小鼠是阿尔兹海默病疾病的转基因模型小鼠,这种小鼠脑内会表现出阿尔兹海默病特有的β-淀粉样斑病理特征;5×FAD小鼠购买于Jackson Laboratory(Ellsworth,ME,USA),编号034840-JAX。
Dp16小鼠是唐氏综合征模型小鼠,购自美国The Jackson Laboratory,编号013530-JAX。
WT对照小鼠是C57BL/6小鼠,购自厦门大学实验动物中心。
实施例1:B2M在人唐氏胎脑和唐氏小鼠组织中表达水平增加
分别取唐氏综合征患者脑组织和非唐氏综合征样对照人脑组织(从厦门大学附属妇女儿童医院获得,在脑组织样品入库前已获得知情同意书),Dp16小鼠和WT对照小鼠的海马组织,经组织研磨、RIPA蛋白裂解液裂解后提取总蛋白、BCA测浓度制样,然后进行免疫印迹检测(检测抗体来源于Abcam,货号ab75853)。
结果如图1A至图1D所示。
结果表明,相对于对照组,唐氏综合征患者大脑皮层总B2M蛋白显著升高。与对照相比,Dp16小鼠海马组织中的B2M蛋白显著升高。
另外,检测到21号染色体编码的淀粉样前体蛋白(Amyloid Precursor Protein,APP)在唐氏综合征患者和Dp16小鼠脑组织内的表达量显著高于各自对照组的表达量。
实施例2:B2M蛋白孵育损伤NMDA受体功能
在体外条件下,用B2M蛋白(浓度10μg/ml)和人工脑脊液(Artificialcerebrospinal fluid,ACSF)分别孵育WT小鼠脑片两小时,孵育以后进行电生理检测,记录海马区谢弗侧枝环路NMDAR EPSC,刺激电极放置于靠近CA3的区域,记录CA1区锥体细胞电流,电极内液中加入5mM QX-314,灌流液中加入50μM PTX和20μM CNQX分别阻断GABAA受体和AMPA受体离子通道,钳制电压为+40mV。
实验结果如图2所示。
结果显示,相比于对照组,B2M蛋白处理会显著减小海马CA1区锥体神经元NMDAREPSC幅度,说明B2M蛋白处理会损伤海马神经元的NMDA受体功能。
实施例3:GluN1胞外环段与B2M之间存在相互作用
在体外条件下,将HA抗体(Sigma,Cat#H6908)和IgG(对照)抗体(Invitrogen,Cat#02-6102)分别与表达GluN1及其截短蛋白和B2M-HA的蛋白裂解液孵育进行体外免疫共沉淀实验,然后经免疫印迹分析二者之间在体外是否存在直接的相互作用。具体操作如下:
将带有HA标签的B2M质粒分别与GluN1(SEQ ID NO:1)、GluN1C-端胞内段缺失、GluN1 N-端胞外段缺失或者GluN1细胞外环肽段质粒共转染入HEK293T细胞中表达24小时。取等量质量的蛋白裂解液分别与IgG(对照组)、HA抗体以及Protein G magnetic beads(用于与抗体IgG的Fc区域结合,Thermo Fisher Scientific,Cat#88848)共孵育过夜进行免疫共沉淀,第二天进行免疫印迹检测并分析。取免疫共沉淀蛋白裂解液质量的3%作为Input(阳性对照)。
大鼠GluN1 C-端胞内段缺失(与人GluN1 C-端胞内段缺失同源性99.16%)
MSTMHLLTFALLFSCSFARAACDPKIVNIGAVLSTRKHEQMFREAVNQANKRHGSWKIQLNATSVTHKPNAIQMALSVCEDLISSQVYAILVSHPPTPNDHFTPTPVSYTAGFYRIPVLGLTTRMSIYSDKSIHLSFLRTVPPYSHQSSVWFEMMRVYNWNHIILLVSDDHEGRAAQKRLETLLEERESKAEKVLQFDPGTKNVTALLMEARELEARVIILSASEDDAAT VYRAAAMLNM TGSGYVWLVGEREISGNALR YAPDGIIGLQLINGKNESAHISDAVGVVAQAVHELLEKENITDPPRGCVGNTNIWKTGPLFKRVLMSSKYADGVTGRVEFNEDGDRKFANYSIMNLQNRKLVQVGIYNGTHVIPNDRKIIWPGGETEKPRGYQMSTRLKIVTIHQEPFVYVKPTMSDGTCKEEFTVNGDPVKKVICTGPNDTSPGSPRHTVPQCCYGFCIDLLIKLARTMNFTYEVHLVADGKFGTQERVNNSNKKEWNGMMGELLSGQADMIVAPLTINNERAQYIEFSKPFKYQGLTILVKKEIPRSTLDSFMQPFQSTLWLLVGLSVHVVAVMLYLLDRFSPFGRFKVNSEEEEEDALTLSSAMWFSWGVLLNSGIGEGAPRSFSARILGMVWAGFAMIIVASYTANLAAFLVLDRPEERITGINDPRLRNPSDKFIYATVKQSSVDIYFRRQVELSTMYRHMEKHNYESAAEAIQAVRDNKLHAFIWDSAVLEFEASQKCDLVTTGELFFRSGFGIGMRKDSPWKQNVSLSILKSHENGFMEDLDKTWVRYQECDSRSNAPATLTFENMAGVFMLVAGGIVAGIFL IFI(SEQ ID NO:3)
大鼠GluN1 N-端胞外段缺失(与人GluN1 N-端胞外段缺失同源性100%)
STLWLLVGLSVHVVAVMLYLLDRFSPFGRFKVNSEEEEEDALTLSSAMWFSWGVLLNSGIGEGAPRSFSARILGMVWAGFAMIIVASYTANLAAFLVLDRPEERITGINDPRLRNPSDKFIYATVKQSSVDIYFRRQVELSTMYRHMEKHNYESAAEAIQAVRDNKLHAFIWDSAVLEFEASQKCDLVTTGELFFRSGFGIGMRKDSPWKQNVSLSILKSHENGFMEDLDKTWVRYQECDSRSNAPATLTFENMAGVFMLVAGGIVAGIFLIFIEIAYKRHKDARRKQMQLAFAAVNVWRKNLQDRKSGRAEPDPKKKATFRAITSTLASSFKRRRSSKDTSTGGGRGALQNQKDTVLPRRAIEREEGQLQLCSRHRES(SEQ ID NO:4)
大鼠GluN1细胞外环肽段(与人GluN1细胞外环肽段同源性100%)
TANLAAFLVLDRPEERITGINDPRLRNPSDKFIYATVKQSSVDIYFRRQVELSTMYRHMEKHNYESAAEAIQAVRDNKLHAFIWDSAVLEFEASQKCDLVTTGELFFRSGFGIGMRKDSPWKQNVSLSILKSHENGFMEDLDKTWVRYQECDSRSNAPATLTF EN(SEQ ID NO:5)
带有HA标签的B2M蛋白
MSRSVALAVLALLSLSGLEAIQRTPKIQVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEKDEYACRVNHVTLSQPKIVKWDRDMYPYDVPDYA(SEQ ID NO:6)
其中质粒构建、细胞转染和蛋白样品的制备参考下面的方法。
质粒构建:
(1)PCR目的基因片段(例如GluN1 N-端胞外段缺失、GluN1细胞外环肽段、GluN1细胞外环肽段)。(2)将PCR产物和载体(pcDNA3.1(+)/myc-His A)进行双酶切(核酸内切酶分别为EcoR1、Xba1),37℃酶切1小时。(3)将酶切后的载体进行琼脂糖凝胶电泳分离。然后用Gel Green染色,紫外灯下进行切胶回收,使用SanPrep柱式DNA胶回收试剂盒回收纯化酶切后的质粒DNA片段。(4)将退火寡核苷酸双链与酶切回收后的pcDNA3.1(+)/myc-His A载体进行连接,使用T4 DNA Ligase进行连接,22℃连接1小时。(5)将连接产物转化入E.coliDH5α感受态细胞中,冰上30min,42℃热激90s,冰上孵育3min,加无抗生素LB培养基,37℃摇床振荡(250rpm)培养45min,然后将复苏后的E.coli DH5α细菌涂布于含50μg/ml Amp/LB平板上,于37℃培养箱中正置培养30min后,倒置培养12-16小时。(6)挑取单克隆菌落于4-6ml含50μg/ml Amp/LB培养基中37℃摇床上振荡(250rpm)培养12-16小时,然后使用SanPrep柱式质粒DNA小量抽提试剂盒(上海生工生物公司,Cat#HC17KA2946)进行质粒DNA提取。(7)质粒送厦门铂瑞生物科技公司进行测序鉴定。
细胞转染:
使用PEI进行细胞转染。(1)转染前一天,将细胞接种到60mm培养皿中,转染时细胞密度以70-90%为宜;(2)将欲转染的质粒:Opti-MEM:PEI(1:50:5.5,w/v/v),60mm培养皿转染4μg质粒),混匀后,室温静置10min;(3)将混合液逐滴均匀地加入到培养基中,轻轻晃动,于37℃,5%CO2培养箱中继续培养;(4)转染8小时后换为新鲜培养基,继续培养24小时后收集细胞。
蛋白样品制备:
(1)吸去培养皿中的培养基,加入预冷的PBS,摇匀,吸掉PBS,重复三次;(2)加入500μl RIPA 细胞裂解液,用细胞刮刮下细胞,转移到预冷的离心管中,于4℃,1000g离心5min,收集细胞;4℃,涡旋裂解30min;(3)裂解后,4℃,12000g离心10min,所得上清即为所需的蛋白裂解液,将上清转移到新的1.5ml离心管中;(4)采用BCA法测定蛋白浓度,根据所得蛋白浓度进行样品制备。蛋白浓度测定,使用BCA Protein Assay Kit进行蛋白浓度测定。
实验结果如图3A至图3D所示。
结果显示GluN1与B2M存在相互作用(图3A)。
GluN1为三次跨膜蛋白,包括N-端胞外段、C-端胞内段、跨膜结构和胞外环肽段(extracellular loop)。为了检测B2M与GluN1结合的区域,本发明人将GluN1的C-端胞内段和N-端胞外段分别缺失,分别与B2M进行免疫共沉淀实验,结果显示:与对照组相比,B2M与N-端缺失(GluN1-N terminal deletion-myc)(图3B)和C-端缺失的GluN1(GluN1-Cterminal deletion-myc)(图3C)均有相互作用。
N-端缺失和C-端缺失的GluN1包含共同区域细胞外环肽段。为了检测GluN1胞外环肽段是否与B2M结合,对GluN1胞外环肽段与B2M进行免疫共沉淀实验,结果显示GluN1胞外环肽段可以与B2M相互作用(图3D)。
综上,GluN1胞外环段与B2M之间存在相互作用。
实施例4:GluN1截短肽可作为封闭肽,阻碍GluN1与B2M结合,对B2M阻止GluN1发挥
作用产生抑制
为了明确GluN1与B2M发生相互作用的氨基酸序列,如图4A所示,本发明人将GluN1胞外环段序列截短为3个无重叠序列的氨基酸序列,然后合成这些氨基酸序列的GST融合表达蛋白。
大鼠GluN1-S2 loop-L1(与人GluN1-S2 loop-L1同源性100%)
TANLAAFLVLDRPEERITGINDPRLRNPSDKFIYATVKQSSVDIYFRRQVELSTMYRHM(SEQ IDNO:7)
大鼠GluN1-S2 loop-L2(与人GluN1-S2 loop-L2同源性100%)
EKHNYESAAEAIQAVRDNKLHAFIWDSAVLEFEASQKCDLVTTGELFFRSGFGIGMR(SEQ ID NO:8)
大鼠GluN1-S2 loop-L3(与人GluN1-S2 loop-L3同源性100%)
KDSPWKQNVSLSILKSHENGFMEDLDKTWVRYQECDSRSNAPATLTF EN(SEQ ID NO:9)
用上述的3个GluN1胞外环段序列的GST融合蛋白分别与0.5μghB2M蛋白以大约1:1(摩尔比)在4℃条件下共孵育过夜,第二天进行免疫印迹检测。如图4B所示,GluN1-S2loop-L2与B2M相互作用更强。
如图4C所示,在GluN1-S2 loop-L2的基础上,本发明人进一步缩短氨基酸序列以缩小有效结合范围。本发明人将GluN1-S2 loop-L2序列截短为3个无重叠序列的氨基酸序列(具体序列见下面的表1),然后合成这些小肽。其中说明的是,考虑到大鼠GluN1-S2loop-L2与人GluN1-S2 loop-L2同源性100%,表1中的截短片段GluN1-P1、GluN1-P2、GluN1-P3与人GluN1-S2 loop-L2中的相应截短片段的同源性也分别均是100%。
表1
分别将2.5μg上述的3条无重叠序列的短肽在PBS溶液中与Ni beads在4℃预孵育8小时,再加入1μg B2M蛋白4℃孵育过夜。第二天进行免疫印迹分析。如图4D所示,B2M特异性结合GluN1-P2短肽。
为了进一步验证GluN1-P2短肽能不能竞争性结合体内的GluN1。先分别将0.055μg、0.55μg、1.1μg、2.2μg质量梯度的GluN1-P2短肽与GST-B2M融合蛋白(约5μg)在PBS溶液中4℃条件下孵育8个小时。将GluN1质粒(大鼠GluN1与pcDNA3.1的重组质粒)转入293T细胞中,取等量质量的蛋白裂解液加入到上述体系中继续在4℃条件下孵育过夜,第二天进行免疫印迹检测分析。取IP蛋白裂解液质量的0.3%作为Input对照。如图4E所示,随着GluN1-P2短肽的质量增加,其结合B2M的能力越强。
综上,GluN1-P2短肽能够作为封闭肽,阻碍GluN1与B2M结合,使B2M无法抑制NMDA受体功能。
实施例5:GluN1-P2封闭肽阻碍B2M与GluN1结合,进而减少突触损伤
GluN1是NMDA受体的必需亚基,它的功能受损会严重损伤突触可塑性,基于GluN1-P2封闭肽可以阻碍B2M与GluN1结合,因此有必要研究GluN1-P2封闭肽是否能够阻碍B2M损伤NMDA受体功能进而损伤兴奋性突触功能。
6月龄Dp16小鼠及对照WT小鼠海马脑立体定位注射1μl(1μg/μl)GluN1-P2短肽或Non-sense肽段(每只小鼠左侧CA1区注射GluN1-P2短肽,右侧CA1区注射Non-sense肽段),注射一天后进行电生理记录。记录海马区谢弗侧枝环路NMDAR EPSC,刺激电极放置于靠近CA3的区域,记录CA1区锥体细胞电流,电极内液中加入5mM QX-314,灌流液中加入50μM PTX和20μM CNQX分别阻断GABAA受体和AMPA受体离子通道,钳制电压为+40mV。
实验结果如图5A所示。结果显示,在Dp16小鼠中,相对于注射无意义肽组而言,注射GluN1-P2截短肽组NMDA EPSC幅度显著升高,而注射GluN1-P2截短肽对WT小鼠的NMDAEPSC幅度无明显作用,提示GluN1-P2截短肽显著改善Dp16小鼠NMDA受体功能。
3月龄C57BL/6小鼠海马脑立体定位注射1μl(1μg/μl)GluN1-P2截短肽或Non-sense肽段(每只小鼠自身大脑左右对照),注射一天后,小鼠切脑片在体外条件下,用B2M蛋白(浓度10μg/ml)和ACSF分别孵育脑片两小时,孵育以后进行电生理记录。记录海马区谢弗侧枝环路NMDAR EPSC幅度,刺激电极放置于靠近CA3的区域,记录CA1区锥体细胞电流,电极内液中加入5mM QX-314,灌流液中加入50μM PTX和20μM CNQX分别阻断GABAA受体和AMPA受体离子通道,钳制电压为+40mV。
实验结果如图5B所示。结果显示,相对于用ACSF孵育的脑片相比,用B2M孵育的脑片会显著降低WT小鼠的NMDA EPSC幅度,并且注射GluN1-P2截短肽会显著改善B2M孵育后的NMDA EPSC幅度。
6月龄Dp16小鼠及对照WT小鼠海马脑立体定位注射1μl(1μg/μl)GluN1-P2截短肽或Non-sense肽段(每只小鼠左侧CA1区注射GluN1-P2短肽,右侧CA1区注射Non-sense肽段),8月龄5×FAD小鼠进行上述同样操作,注射一天后进行电生理记录。小鼠经麻醉后,快速取出脑组织置于冰冷且氧饱和的人工脑脊液(Artificial cerebrospinal fluid,ACSF)中,随后转至振动切片机进行冠状切片,脑片厚度为400μm。将脑片置于32℃氧饱和的ACSF中孵育1小时,之后转移至室温孵育1小时。将记录电极放置在Schaffer collateral通路的CA1区辐射层,刺激电极放置在CA3区。刺激强度为兴奋性突触后场电位(field excitatorypostsynaptic potential,fEPSP)最大幅度的30%,fEPSP基线稳定记录20分钟后,高频刺激(HFS)诱导LTP(2串刺激,每串刺激包含100个刺激脉冲,每串刺激间隔30秒),持续记录60分钟。
实验结果如图5C至图5F所示。结果显示,在Dp16小鼠中,相对于注射无意义肽组而言,注射GluN1-P2封闭肽组会显著改善Dp16小鼠海马CA1区的LTP,而注射GluN1-P2封闭肽对WT小鼠的LTP无明显作用,提示GluN1-P2封闭肽逆转Dp16小鼠突触损伤。同样,在5×FAD小鼠会看到类似的结果。
综上,GluN1-P2封闭肽阻碍B2M与GluN1结合,进而减少突触损伤。
尽管本发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解。根据已经公开的所有教导,可以对那些细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
SEQUENCE LISTING
<110> 厦门大学
<120> B2M-GluN1封闭肽、其药物组合物及用途
<130> IDC220225
<160> 32
<170> PatentIn version 3.5
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Ile
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<213> Artificial Sequence
<220>
<223> 大鼠GluN1 细胞外环肽段
<400> 5
Thr Ala Asn Leu Ala Ala Phe Leu Val Leu Asp Arg Pro Glu Glu Arg
1 5 10 15
Ile Thr Gly Ile Asn Asp Pro Arg Leu Arg Asn Pro Ser Asp Lys Phe
20 25 30
Ile Tyr Ala Thr Val Lys Gln Ser Ser Val Asp Ile Tyr Phe Arg Arg
35 40 45
Gln Val Glu Leu Ser Thr Met Tyr Arg His Met Glu Lys His Asn Tyr
50 55 60
Glu Ser Ala Ala Glu Ala Ile Gln Ala Val Arg Asp Asn Lys Leu His
65 70 75 80
Ala Phe Ile Trp Asp Ser Ala Val Leu Glu Phe Glu Ala Ser Gln Lys
85 90 95
Cys Asp Leu Val Thr Thr Gly Glu Leu Phe Phe Arg Ser Gly Phe Gly
100 105 110
Ile Gly Met Arg Lys Asp Ser Pro Trp Lys Gln Asn Val Ser Leu Ser
115 120 125
Ile Leu Lys Ser His Glu Asn Gly Phe Met Glu Asp Leu Asp Lys Thr
130 135 140
Trp Val Arg Tyr Gln Glu Cys Asp Ser Arg Ser Asn Ala Pro Ala Thr
145 150 155 160
Leu Thr Phe Glu Asn
165
<210> 6
<211> 128
<212> PRT
<213> Artificial Sequence
<220>
<223> HA-B2M
<400> 6
Met Ser Arg Ser Val Ala Leu Ala Val Leu Ala Leu Leu Ser Leu Ser
1 5 10 15
Gly Leu Glu Ala Ile Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg
20 25 30
His Pro Ala Glu Asn Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser
35 40 45
Gly Phe His Pro Ser Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu
50 55 60
Arg Ile Glu Lys Val Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp
65 70 75 80
Ser Phe Tyr Leu Leu Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp
85 90 95
Glu Tyr Ala Cys Arg Val Asn His Val Thr Leu Ser Gln Pro Lys Ile
100 105 110
Val Lys Trp Asp Arg Asp Met Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
115 120 125
<210> 7
<211> 59
<212> PRT
<213> Artificial Sequence
<220>
<223> GluN1-S2 loop-L1
<400> 7
Thr Ala Asn Leu Ala Ala Phe Leu Val Leu Asp Arg Pro Glu Glu Arg
1 5 10 15
Ile Thr Gly Ile Asn Asp Pro Arg Leu Arg Asn Pro Ser Asp Lys Phe
20 25 30
Ile Tyr Ala Thr Val Lys Gln Ser Ser Val Asp Ile Tyr Phe Arg Arg
35 40 45
Gln Val Glu Leu Ser Thr Met Tyr Arg His Met
50 55
<210> 8
<211> 57
<212> PRT
<213> Artificial Sequence
<220>
<223> GluN1-S2 loop-L2
<400> 8
Glu Lys His Asn Tyr Glu Ser Ala Ala Glu Ala Ile Gln Ala Val Arg
1 5 10 15
Asp Asn Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu Phe
20 25 30
Glu Ala Ser Gln Lys Cys Asp Leu Val Thr Thr Gly Glu Leu Phe Phe
35 40 45
Arg Ser Gly Phe Gly Ile Gly Met Arg
50 55
<210> 9
<211> 49
<212> PRT
<213> Artificial Sequence
<220>
<223> GluN1-S2 loop-L3
<400> 9
Lys Asp Ser Pro Trp Lys Gln Asn Val Ser Leu Ser Ile Leu Lys Ser
1 5 10 15
His Glu Asn Gly Phe Met Glu Asp Leu Asp Lys Thr Trp Val Arg Tyr
20 25 30
Gln Glu Cys Asp Ser Arg Ser Asn Ala Pro Ala Thr Leu Thr Phe Glu
35 40 45
Asn
<210> 10
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> GluN1-P1
<400> 10
Glu Lys His Asn Tyr Glu Ser Ala Ala Glu Ala Ile Gln Ala Val Arg
1 5 10 15
Asp Asn
<210> 11
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> GluN1-P2
<400> 11
Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu Phe Glu Ala
1 5 10 15
Ser Gln
<210> 12
<211> 21
<212> PRT
<213> Artificial Sequence
<220>
<223> GluN1-P3
<400> 12
Lys Cys Asp Leu Val Thr Thr Gly Glu Leu Phe Phe Arg Ser Gly Phe
1 5 10 15
Gly Ile Gly Met Arg
20
<210> 13
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Non-sense
<400> 13
Trp Ser Phe Ala Glu Gln Asp Lys Ala Phe Ile Val His Leu Glu Ala
1 5 10 15
Leu Ser
<210> 14
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 14
Ala Val Arg Asp Asn Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val
1 5 10 15
Leu Glu Phe Glu Ala Ser Gln
20
<210> 15
<211> 22
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 15
Val Arg Asp Asn Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu
1 5 10 15
Glu Phe Glu Ala Ser Gln
20
<210> 16
<211> 21
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 16
Arg Asp Asn Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu
1 5 10 15
Phe Glu Ala Ser Gln
20
<210> 17
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 17
Asp Asn Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu Phe
1 5 10 15
Glu Ala Ser Gln
20
<210> 18
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 18
Asn Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu Phe Glu
1 5 10 15
Ala Ser Gln
<210> 19
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 19
Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu Phe Glu Ala
1 5 10 15
Ser Gln Lys Cys Asp Leu Val
20
<210> 20
<211> 22
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 20
Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu Phe Glu Ala
1 5 10 15
Ser Gln Lys Cys Asp Leu
20
<210> 21
<211> 21
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 21
Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu Phe Glu Ala
1 5 10 15
Ser Gln Lys Cys Asp
20
<210> 22
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 22
Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu Phe Glu Ala
1 5 10 15
Ser Gln Lys Cys
20
<210> 23
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 23
Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu Phe Glu Ala
1 5 10 15
Ser Gln Lys
<210> 24
<211> 24
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 24
Arg Asp Asn Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu
1 5 10 15
Phe Glu Ala Ser Gln Lys Cys Asp
20
<210> 25
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 25
Arg Asp Asn Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu
1 5 10 15
Phe Glu Ala Ser Gln Lys Cys
20
<210> 26
<211> 22
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 26
Arg Asp Asn Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu
1 5 10 15
Phe Glu Ala Ser Gln Lys
20
<210> 27
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 27
Asp Asn Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu Phe
1 5 10 15
Glu Ala Ser Gln Lys Cys Asp
20
<210> 28
<211> 22
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 28
Asp Asn Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu Phe
1 5 10 15
Glu Ala Ser Gln Lys Cys
20
<210> 29
<211> 21
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 29
Asp Asn Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu Phe
1 5 10 15
Glu Ala Ser Gln Lys
20
<210> 30
<211> 22
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 30
Asn Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu Phe Glu
1 5 10 15
Ala Ser Gln Lys Cys Asp
20
<210> 31
<211> 21
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 31
Asn Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu Phe Glu
1 5 10 15
Ala Ser Gln Lys Cys
20
<210> 32
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated fragment
<400> 32
Asn Lys Leu His Ala Phe Ile Trp Asp Ser Ala Val Leu Glu Phe Glu
1 5 10 15
Ala Ser Gln Lys
20
Claims (10)
1.分离的多肽,其为SEQ ID NO:8所示的多肽或SEQ ID NO:8所示多肽的截短片段。
2.根据权利要求1所述的分离的多肽,其中,所述截短片段包含SEQ ID NO:11所示的多肽。
3.根据权利要求1至2中任一权利要求所述的分离的多肽,其为SEQ ID NO:11或SEQ IDNOs:14-32中任一序列所示的多肽。
4.分离的多核苷酸,其编码权利要求1至3中任一权利要求所述的分离的多肽。
5.一种重组表达载体,其包含权利要求4所述的分离的多核苷酸。
6.一种转化的细胞,其包含权利要求5所述的重组表达载体。
7.一种药物组合物,其包含一种或多种权利要求1至3中任一权利要求所述的分离的多肽。
8.根据权利要求7所述的药物组合物,其还包含一种或多种药学上可接受的辅料。
9.权利要求1至3中任一权利要求所述的分离的多肽在制备治疗或预防唐氏综合征、阿尔兹海默病、或者唐氏综合征或阿尔兹海默病所导致的认知损伤的药物中的用途。
10.权利要求1至3中任一权利要求所述的分离的多肽在制备抑制人脑中GluN1与B2M结合的药物或者修复人脑中因B2M增加导致的突触损伤的药物中的用途。
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PCT/CN2023/101626 WO2023246847A1 (zh) | 2022-06-24 | 2023-06-21 | B2M-GluN1封闭肽、其药物组合物及用途 |
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CN104628821B (zh) * | 2015-01-21 | 2017-05-31 | 徐州医学院 | 具有神经保护作用的肽及应用 |
JOP20170004B1 (ar) * | 2016-01-15 | 2022-09-15 | Lilly Co Eli | الأجسام المضادة لببتيد بيتا النشوي مضاد N3pGlu واستخداماته |
US20180126003A1 (en) * | 2016-05-04 | 2018-05-10 | Curevac Ag | New targets for rna therapeutics |
JOP20190247A1 (ar) * | 2017-04-20 | 2019-10-20 | Lilly Co Eli | أجسام بيتا ببتيد النشوانية المضادة لـ N3pGlu واستخداماتها |
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CN109646668B (zh) * | 2019-01-04 | 2019-10-18 | 厦门大学 | 一种多肽用于制备防治阿尔茨海默病药物的用途 |
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