CN110357968A - 抗肿瘤融合蛋白及其制法和应用 - Google Patents
抗肿瘤融合蛋白及其制法和应用 Download PDFInfo
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Abstract
本发明提供了一种抗肿瘤融合蛋白及其制法和应用。具体地,本发明提供了一种包括GnRH蛋白元件、PEA蛋白的跨膜转运区和P53蛋白元件的融合蛋白,所述融合蛋白可以高效地将p53蛋白输送到细胞核并高效引发肿瘤细胞凋亡。本发明还提供了编码所述融合蛋白的核苷酸、生产所述融合蛋白的方法以及包含所述融合蛋白的药物组合物。
Description
技术领域
本发明涉及生物医药领域,更具体地涉及一种抗肿瘤融合蛋白及其制法和应用。
背景技术
免疫毒素是一组人工构建的具有特异性细胞杀伤能力的杂合分子,由毒性部分、载体部分和靶向部分三部分组成。毒性部分可以是植物、动物、微生物来源的细胞毒素,靶向部分可以是单克隆抗体或细胞因子。免疫毒素与其他抗肿瘤药物相比,具有毒性强和特异性高的优点,在肿瘤治疗中显示出巨大的应用前景。
冻干重组人促黄体激素释放激素-绿脓杆菌外毒素A融合蛋白(lyophilizedrecombinant human luteinizing hormone releasing hormone-exotoxin ofpseudomonas aeruginosa fusion protein,简称LHRH-PE40)是长春基因工程药物研究生产的一种对肿瘤细胞有特异性杀伤作用的重组毒素。其生产方法为首先采用基因工程的方法将编码绿脓杆菌外毒素A基因的受体结合区(I区)切除,置换成LHRH基因,再将LHRH-PE40重组基因克隆于质粒中,通过工程发酵表达出LHRH-PE40融合蛋白。
LHRH-PE40中发挥细胞毒作用的是绿脓杆菌外毒素A(exotoxin A ofpseudomonas aeruginosa,PEA)。绿脓杆菌外毒素A是绿脓杆菌中毒力最强的一种毒素,能阻断细胞蛋白质的合成并引起细胞的凋亡。LHRH-PE40中的导向物为人促黄体激素释放激素(human luteinizing hormone releasing hormone,LHRH),通过与其在肿瘤细胞表面的I型受体结合而靶向性地把PEA导入到肿瘤细胞中发挥抗肿瘤作用。
LHRH的受体有两型,即I型和II型。LHRH与I型受体的亲和力很高。人体正常情况下,I型受体主要存在于垂体前叶,垂体外组织如性腺、胎盘和脑组织也含有一定量的I型受体,其它重要器官均不表达I型LHRH受体。然而某些肿瘤细胞表面由于受体异化则分布着大量的LHRH I型受体,包括生殖系统恶性肿瘤、黑色素瘤、胃癌、肝癌、胰腺癌、肠癌、肺癌等。由于I型LHRH受体在肿瘤细胞中普遍高表达,而在正常组织中只呈局限性分布,因此LHRH是设计重组靶向毒素所需的理想导向物。
LHRH的II型受体广泛存在于人体各组织中。LHRH与II型受体的亲和力很低。但在很高剂量的情况下,LHRH可以和II型受体发生低亲和力结合,从而使LHRH-PE40产生广泛的细胞毒作用。这是LHRH-PE40重组毒素对动物产生毒性作用的理论基础。LHRH-PE40不能透过血脑屏障,因此不会对垂体产生毒性作用。
尽管以LHRH-PE40为代表的免疫毒素显示出良好的应用前景,但其仍存在免疫原性和非特异的细胞毒性等问题,阻碍了免疫毒素在临床上的应用。因此,本领域迫切需要开发特异性好、细胞毒性低的新的免疫毒素。
发明内容
本发明的目的在于提供一种抗肿瘤融合蛋白及其制法和应用。
在本发明的第一方面,提供了一种抗肿瘤融合蛋白,所述的抗肿瘤融合蛋白具有式I所述结构:
D-A-B-C-E (I)
其中,
A为GnRH蛋白元件;
B为PEA蛋白的跨膜转运区或为无;
C为P53蛋白元件;
E为TAT蛋白元件或为无;
D为任选的信号肽和/或前导肽序列;
并且,B和E不同时为无;
其中,“-”表示连接上述各元件的肽键。
在另一优选例中,所述的抗肿瘤融合蛋白具有式II所述结构:
D-A-C-E (II)
其中,
A为GnRH蛋白元件;
C为P53蛋白元件;
E为TAT蛋白元件;
D为任选的信号肽和/或前导肽序列;
其中,“-”表示连接上述各元件的肽键。
在另一优选例中,所述的抗肿瘤融合蛋白
在另一优选例中,所述的TAT为HIV-I编码的一段富含碱性氨基酸的短肽。
在另一优选例中,所述的TAT蛋白来源于人或非人哺乳动物。
在另一优选例中,所述的TAT蛋白包括野生型和突变型。
在另一优选例中,所述的TAT蛋白包括全长的、成熟形式的P53,或其活性片段。
在另一优选例中,所述的TAT蛋白的序列如SEQ ID NO.:5中第405-416位所示。
在另一优选例中,所述的抗肿瘤融合蛋白的
在另一优选例中,所述的抗肿瘤融合蛋白选自下组:
(A)具有SEQ ID NO.:5所示氨基酸序列的多肽;
(B)具有与SEQ ID NO.:5所示氨基酸序列≥80%同源性(优选地,≥90%的同源性;等优选地≥95%的同源性;最优选地,≥97%的同源性,如98%以上,99%以上)的多肽,且所述多肽具有抑制肿瘤细胞生长的活性;
(C)将SEQ ID NO:5所示氨基酸序列经过1-10个氨基酸残基的取代、缺失或添加而形成的,且保留抑制肿瘤细胞生长活性的衍生多肽。
在另一优选例中,所述的抗肿瘤融合蛋白具有式II所述结构:
D-A-B-C (II)
其中,
A为GnRH蛋白元件;
B为PEA蛋白的跨膜转运区;
C为P53蛋白元件;
D为任选的信号肽和/或前导肽序列;
“-”表示连接上述各元件的肽键。
在另一优选例中,所述的GnRH蛋白来源于人或非人哺乳动物。
在另一优选例中,所述的GnRH蛋白包括野生型和突变型。
在另一优选例中,所述的GnRH蛋白包括全长的、成熟形式的GnRH,或其活性片段。
在另一优选例中,所述的GnRH蛋白包括II型GnRH蛋白和I型GnRH蛋白。
在另一优选例中,所述的GnRH蛋白为II型GnRH蛋白。
在另一优选例中,所述的GnRH蛋白的序列如SEQ ID NO.:2中第1-10位所示。
在另一优选例中,所述的P53蛋白来源于人或非人哺乳动物。
在另一优选例中,所述的P53蛋白包括野生型和突变型。
在另一优选例中,所述的P53蛋白包括全长的、成熟形式的P53,或其活性片段。
在另一优选例中,所述的P53蛋白的序列如SEQ ID NO.:2中第128-520位所示。
在另一优选例中,所述PEA蛋白的跨膜转运区来源于绿脓杆菌。
在另一优选例中,所述PEA蛋白的跨膜转运区的长度为100-120氨基酸,较佳地为100-115个氨基酸。
在另一优选例中,所述PEA蛋白的跨膜转运区的序列如SEQ ID NO.:2中第13-127位所示。
在另一优选例中,所述的抗肿瘤融合蛋白是由细菌,较佳地由大肠杆菌表达的重组蛋白。
在另一优选例中,所述的抗肿瘤融合蛋白是不经糖基化修饰的蛋白。
在另一优选例中,所述的抗肿瘤融合蛋白选自下组:
(A)具有SEQ ID NO.:2所示氨基酸序列的多肽;
(B)具有与SEQ ID NO.:2所示氨基酸序列≥80%同源性(优选地,≥90%的同源性;等优选地≥95%的同源性;最优选地,≥97%的同源性,如98%以上,99%以上)的多肽,且所述多肽具有抑制肿瘤细胞生长的活性;
(C)将SEQ ID NO:2所示氨基酸序列经过1-10个氨基酸残基的取代、缺失或添加而形成的,且保留抑制肿瘤细胞生长活性的衍生多肽。
在另一优选例中,所述的肿瘤细胞为表达GnRHR的肿瘤细胞,较佳地为表达I型GnRHR的肿瘤细胞。
在另一优选例中,所述的肿瘤细胞为表达II型GnRHR的肿瘤细胞。
在另一优选例中,所述抗肿瘤融合蛋白的氨基酸序列如SEQ ID NO:2所示。
在另一优选例中,所述抗肿瘤融合蛋白含有6xHis纯化标签。
在另一优选例中,所述抗肿瘤融合蛋白能够抑制肿瘤细胞生长和/或诱导肿瘤细胞的凋亡
在本发明的第二方面,提供了一种分离的多核苷酸,所述的多核苷酸编码本发明第一方面所述的抗肿瘤融合蛋白。
在另一优选例中,所述多核苷酸的序列如SEQ ID NO.:1所示。
在本发明的第三方面,提供了一种载体,所述载体含有本发明第二方面所述的多核苷酸。
在另一优选例中,所述的载体包括质粒、病毒载体。
在另一优选例中,所述的病毒载体包括:慢病毒载体、腺病毒载体、黄热病毒载体。
在另一优选例中,所述的载体包括表达载体。
在本发明的第四方面,提供了一种宿主细胞,所述宿主细胞含有本发明第三方面所述的载体或基因组中整合有本发明第二方面所述的多核苷酸。
在另一优选例中,所述宿主细胞包括原核细胞和真核细胞。
在另一优选例中,所述宿主细胞为细菌,较佳地为大肠杆菌。
在本发明的第五方面,提供了一种生产抗肿瘤融合蛋白的方法,包括步骤:
(a)在适合表达条件下,培养本发明第四方面所述的宿主细胞,从而表达本发明第一方面所述的抗肿瘤融合蛋白;
(b)分离纯化出步骤(a)中所表达的抗肿瘤融合蛋白。
在本发明的第六方面,提供了一种药物组合物,所述药物组合物含有本发明第一方面所述的抗肿瘤融合蛋白,以及药学上可接受的载体或赋形剂。
在本发明的第七方面,提供了一种本发明第一方面所述抗肿瘤融合蛋白的用途,用于制备治疗或预防肿瘤的药物。
在另一优选例中,所述的肿瘤为表达GnRH的肿瘤。
在另一优选例中,所述肿瘤选自下组:乳腺癌,肺癌,大肠癌,胰腺癌,卵巢癌,前列腺癌,肾癌,肝癌,脑癌,黑色素瘤,多发性骨髓瘤,头颈部肿瘤。
在本发明的第八方面,提供了一种体外非治疗性的抑制肿瘤细胞的方法,包括步骤:在本发明第一方面所述的抗肿瘤融合蛋白存在的条件下,培养所述肿瘤细胞。
在本发明的第九方面,提供了一种治疗肿瘤的方法,包括步骤:给需要的对象施用本发明第一方面所述的抗肿瘤融合蛋白。
在另一优选例中,所述的抗肿瘤融合蛋白以单体、二聚体和/或四聚体形式施用,较佳地所述的抗肿瘤融合蛋白以四聚体形式施用。
在另一优选例中,所述的对象是人。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1显示了诱导表达的本发明融合蛋白的SDS-PAGE电泳图。其中,第一泳道为Marker,第二泳道为加诱导剂前的样品,第三泳道为加诱导剂后的全菌蛋白样品,第四泳道为加诱导剂后的可溶表达组份,第五泳道为加诱导剂后的包涵体表达组份。
图2显示了GnRH+PII+P53对Ishikawa细胞的杀伤效果。
图3显示了PEA分子结构示意图。
具体实施方式
本发明人经过广泛而深入地研究,首次意外地发现一种高效地将p53蛋白输送到细胞核并高效引发细胞凋亡的融合蛋白。该融合蛋白不仅可以高效地表达,不易降解,而且高效地形成多聚体(尤其是四聚体)。此外,实验结果还表明,本发明的融合蛋白(单体或多聚体)可以极其高效地穿过细胞膜进入到胞内,并高效快速地进入细胞核,从而极其高效地诱导非正常细胞(如肿瘤细胞)的凋亡。在此基础上完成了本发明。
融合蛋白
如本文所用,术语“活性成分”是指本发明所述的抗肿瘤融合蛋白。
如本文所用,术语“本发明的融合蛋白”、“融合蛋白”、“抗肿瘤融合蛋白”可互换使用,是指本发明第一方面所述的融合蛋白。
在一优选例中,所述的融合蛋白具有GnRH+PII+P53结构,序列如SEQ ID NO.:2所示。
在另一优选例中,所述的融合蛋白具有GnRH+P53+TAT结构,,序列SEQ ID NO.:5所示(QHWSYGLRPGHMEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGPDEAPRMPEAAPRVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNYMCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVHVCACPGRDRRTEEENLRKKGEPHHELPPGSTKRALSNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAGKEPGGSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSDGRKKRRQRRRPQ),其中第1-10为GnRH,第12-404位为P53,第405-416位为TAT。
本发明的两种融合蛋白可以混合后共同使用。
药物组合物
由于本发明所述的融合蛋白具有优异的对肿瘤细胞生长的抑制活性,因此本发明所述的融合蛋白以及含有本发明所述的融合蛋白为主要活性成分的药物组合物可用于(a)预防或抑制肿瘤生长、转移或肿瘤细胞增长、迁移,或(b)诱导人肿瘤细胞凋亡。
本发明的药物组合物包含安全有效量范围内的本发明所述的融合蛋白及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:融合蛋白的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明所述的融合蛋白/剂,更佳地,含有10-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份之间以及各组份和本发明所述活性成分能相互掺和,而不明显降低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、橄榄油等)、多元醇(如丙二醇、甘油、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
施用方法
本发明所述的融合蛋白或其药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、和肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性成分与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、和硅酸;(b)粘合剂,例如,羟甲基纤维素、明胶、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明所述的融合蛋白可以单独给药,或者与其他药学上可接受的化合物(或肿瘤抑制剂)联合给药。
所述其他药学上可接受的化合物包含选自下组的抗肿瘤药物:烷化剂、抗代谢物、叶酸类似物、嘧啶类似物、嘌呤类似物、长春花碱类、表鬼臼毒素(epipodophyllotoxin)、抗生素、L-天冬酞胺酶、拓扑异构酶抑制剂、干扰素、铂配位复合物、大黄素取代的脲、甲基肼衍生物、肾上腺皮质抑制剂、肾上腺皮质类固醇、孕激素、雌激素、抗雌激素、雄激素、抗雄激素以及或促性腺激素-释放激素类似物。
优选地,所述抗肿瘤药物选自下组的物质:5-氟尿嘧啶(5-FU)、甲酰四氢叶酸、伊立替康、奥沙利铂、卡培他滨、紫杉醇、多西紫杉醇、或其组合。
使用药物组合物时,是将安全有效量的本发明所述的融合蛋白适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选20~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
PEA
PEA是由613个氨基酸构成的单链毒素蛋白,分子量66kD。它由三个结构功能区构成:I区、II区和III区。I区在PEA分子的N端,呈反向平行的β结构。I区又分为Ia区和Ib区,这两部分在DNA序列上是分离的,但在三维结构中紧靠在一起。Ia区含第1-252位氨基酸,负责与靶细胞表面受体结合-细胞结合功能;Ib区含365-399位氨基酸,此区的大部(第365-380位氨基酸)缺失并不影响PEA的生物学活性。II区为中央区,包括第253-364位氨基酸,有6个连续的α螺旋,它负责跨膜转位功能,当II区缺失时,尽管其细胞结合功能和ADP核糖基化活性尚存,但细胞毒性丧失,说明II区为毒素转位功能所必需。III区包括400-613位氨基酸,它有两个功能:其一是催化EF-2的ADP核糖基化作用;其二是它的C末端特异氨基酸序列介导毒素片断进行入内质网,此特异系列是由(Arg609 Glu610 Asp611 Leu612 Lys613即REDLK)五个氨基酸残基片段构成,它的缺失,使PE的细胞毒性丧失,而将其进行序列调整,能够明显增进毒素的ADP核糖基化效率。下表1显示PE分子结构与功能关系。
表1:PE分子结构与功能关系
PEA分子的结构如图3所示。
GnRH
GnRH是由Schally等于1971年从动物体内分离纯化,阐明其结构后又人工合成的,并以此获得了1976年的Nobel奖。GnRH为一个不含游离氨基酸与羧基的十肽,其分子结构为:P-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2,其中第4-6位氨基酸形成β转折,呈发夹形,适合与受体结合,第2和3位对生物活性很重要,第6位对维持发夹构象起重要作用,第1位与第4-10位氨基酸均参与受体结合,若置换以上氨基酸残基可导致活力丧失或呈几何级增强。
天然GnRH在体内很容易被蛋白水解酶降解,故其半衰期仅4-8min。其水解酶肽酶的主要作用部位是Gly6-Leu7和Pro9-Gly10-NH2。为寻求高效且持久的GnRH类似物,通过对其肽链结构中氨基酸的拾取或替换,已合成3000多种GnRH类似物。由于合成的GnRH半衰期长,作用更强,所以比天然的GnRH更适于病人的治疗。合成长效的GnRH激动剂的要求是稳定分子结构,使之不易被酶水解,增加与循环中的蛋白和胞膜的结合及提高对GnRH受体的亲和力。如6位为D-氨基酸的类似物和取代Gly10酰胺基。这种GnRH激动剂不仅耐蛋白酶水解作用较大,而且对受体有较高的亲和力。若在第6位引入庞大的疏水基团可进一步增加与受体的亲和力。这样的置换稳定了释放激素类似物的“活性”构型,提高了与循环中蛋白的结合,从而延长半衰期。
正常人的性腺激素释放激素(GnRH)受体主要存在于垂体前叶,垂体外组织如性腺胎盘组织中有少量GnRH受体分布,虽然在重要器官如肝、肾、心及骨骼肌中也可以检测出一定水平的GnRH受体的mRNA。但使用受体定量分析的方法—放射配体分析法(RLA)检测这些器官组织,则只能获得阴性结果。
目前的研究表明,GnRH基本上可以分成两种,即
GnRHⅠ,一级结构如下:
pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2
GnRHⅡ,一级结构如下:
pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2
其相应的受体也分为两种即Ⅰ型GnRH受体和Ⅱ型GnRH受体。两型GnRH受体的主要区别是:
1基因存在位置不同:Ⅰ型GnRH受体基因存在于8号染色体上,Ⅱ型GnRH受体基因存在于20号染色体上。
2基因转录方向不同:Ⅰ型GnRH受体基因转录方向是正义方向进行的,而Ⅱ型GnRH受体基因转录方向是反义方向进行的,因此造成RNA剪切和终止位点的差异也有很大区别。
3氨基酸组成不同:Ⅱ型GnRH受体基因外显子2和3所表达的氨基酸与Ⅰ型受体的相同部位氨基酸同源性分别为45%和41%。
4分子结构不同:Ⅱ型GnRH受体结构上有一个C末端胞浆区尾部。而Ⅰ型GnRH受体则无。
5与配基结合的选择性不同:在功能细胞上进行的配基结合特异性试验表明两种受体有明确的配基选择性,Ⅱ型受体对Ⅱ型GnRH的反应能力非常高,而对I型GnRH的反应能力则很低,二者相差420余倍。
6在组织中分布不同:利用RT-PCR检测,GnRHRⅠ的mRNA主要分布在垂体中和少数生殖系统组织中,而GnRHRⅡ的mRNA则广泛分布在几乎所有的器官组织中。Ⅱ型GnRH受体在人组织中广泛而丰富的存在的意义至今尚不十分清楚。
7不同配基与不同受体结合后所产生的信号不同。
P53
Wtp53(wild-type p53)是迄今为止发现的最有效的肿瘤抑制因子。研究如何应用wtp53治疗肿瘤已成为肿瘤研究领域中的热点,由于p53蛋白半衰期短暂,且属于非分泌型蛋白,细胞膜上不存在p53受体或配体,使p53蛋白很难突破细胞膜而进入细胞内发挥作用。
目前,国内外的研究大多集中在通过载体(如病毒载体AAV)将p53基因导入细胞内,但导入的载体存在不安全性因素,因此如何使p53蛋白进入细胞内发挥作用,且既不影响p53蛋白的生物活性,又避免导入的载体的不安全性是应用p53治疗肿瘤必须解决的问题。
p53基因定位于人染色体17p13,全长约20kb,由11个外显子和10个内含子组成,转录成2.5kbmRNA,编码393个氨基酸的蛋白质,相对分子质量为53×103。该蛋白是一种核结合蛋白,含有3个主要功能区:1)N-末端转录激活区,可激活转录,介导蛋白间相互作用,这一区域还可和p53负调控因子结合;2)中央DNA核心结合区,这一区域具有特异性结合DNA功能,并且是肿瘤细胞突变热点区域;3)C-末端非专一DNA结合区,包括核定位信号区和核输出信号区
P53蛋白是一种磷酸化蛋白,在细胞中易水解,半衰期只有大约30分钟,在正常细胞的细胞核中几乎检测不到。但当细胞受到外界因素刺激,如低氧、紫外照射或某些药物作用而导致DNA损伤时,p53蛋白一方面作为转录因子,通过反式激活对细胞增殖起抑制作用;另一方面,p53蛋白可直接同DNA复制机制中的成分相互作用,抑制DNA的复制,保证了遗传的稳定性。具体地,P53具有以下功能:
P53对细胞周期调控
P53能有效防止细胞恶性转化,监视基因组的完整性,识别各种可能引发肿瘤的异常情况,被称为“基因卫士”。DNA的各种损伤均可通过特异性的翻译后修饰来调节p53功能,主要包括磷酸化和乙酰化,病毒编码的蛋白、细胞内蛋白和转录抑制物等调节物也可影响其功能。P53通过与不同的协同分子相互作用,诱导激活不同的靶基因,对细胞周期进行调控,使细胞周期停顿于特定的检查点。
细胞周期G1期停顿
P53通过上调p21基因,与p21相互调节,在DNA损伤所致的G1/S期停顿过程中起重要调控作用。
P53的另一种阻滞细胞周期G1期停滞通过非转录机制进行。CDK激酶(CDK-activating kinase,CAK)即周期蛋白依赖性蛋白激酶,能与细胞周期蛋白结合并活化,使靶蛋白磷酸化、调控细胞周期进程。
细胞周期S期停顿
P21waf1可与增殖细胞核抗原(PCNA),一种参与真核细胞复制的蛋白质结合,而抑制PCNA的活性。PCNA只存在与增殖细胞及肿瘤细胞内,p21waf1与PCNA结合,形成的复合物阻止DNA复制的延伸,影响细胞周期的进展。在DNA复制过程中,PCNA与复制因子C(replication factor C,RFC)共同识别引物-模板连接(primer template junction),促进聚合酶δ(polδ)加载,PCNA也可与聚合酶ε(polε)结合,PCNA-RFC-polδ复合物使DNA在其形成的环中滑行,使DNA前导链连续合成,加快DNA复制延伸阶段进展。P21waf1与PCNA直接结合导致PCNA-RFC-polδ复合物快速从DNA复制叉上解离,使PCNA细胞增殖的启动作用减弱,从而阻止DNA的复制合成。此外,p53蛋白还可以直接与PCNA作用,抑制DNA的复制,阻止细胞分裂。
细胞周期G2期停顿
在细胞周期S期时,p21waf1在核内消失,而在细胞周期G2期的后期,p21waf1又再次进入核内,短暂停留。与p53通过非转录机制阻滞G1期停滞类似,p21waf1也能与cyclin A及B复合物结合。P21waf1可阻止蛋白底物cdk2被CAK活化,或直接抑制cdk2活性,使细胞无法度过检验点,干扰细胞周期的进展。P21waf1还能与cdk2/cyclinA形成复合物,p21waf1-cdk2/cyclinA复合物可阻断底物与cdk2/cyclinA的相互作用。另外,当cdk2与p21waf1形成复合物后,cdk2正向调节cdk1/cyclin B复合物的激活作用减弱,使细胞无法进入有丝分裂期。
P53与细胞凋亡
P53可通过两种机制诱导肿瘤细胞生长抑制,促进细胞凋亡。一方面作为转录因子,p53在细胞核中诱导Bax、Bcl-2和p53调节凋亡的诱导蛋白等转录诱发凋亡。Bax是启动凋亡的必需信号,Bax启动子上存在p53的结合位点,p53识别结合位点直接作用于Bax基因,p53通过诱导Bax转录诱发细胞凋亡
P53蛋白的另一种促进细胞凋亡的机制是直接在细胞质中锚定至线粒体,诱导线粒体依赖性细胞凋亡。研究表明,p53线粒体锚定作用主要通过E3连接酶鼠双微体2(murinedouble minute 2,mdm2)起作用。P53作为重要的抑癌基因可通过多种途径调控肿瘤的发生和发展,而mdm2基因在同p53的相互作用中,一方面介导了p53的降解,抑制p53转录激活,下调其肿瘤生长抑制活性;另一方面由p53诱导产生的mdm2又可以稳定p53蛋白的作用
促进细胞自我吞噬
细胞调控损伤的自噬调节剂(damage-regulated autophagy modulator,DRAM)主要参与细胞的自我吞噬作用。DRAM内含有p53结合序列,是新发现的p53下游靶基因。DRAM在细胞营养缺乏时,能激活细胞自我吞噬功能,分解长效蛋白质,以稳定细胞的形态和维持细胞基本生命状态。DRAM在细胞受到刺激时,则诱导细胞凋亡。研究发现,当p53缺失而仅表达DRAM时,DRAM对细胞的杀伤作用仅为原有杀伤作用的2%~4%,而当DRAM与p53共转染时,其杀伤能力大大提高。因此得出结论,DRAM的诱导细胞程序性死亡的作用是依赖于p53发挥的,DRAM可依赖p53蛋白诱导细胞自噬性死亡。
血管生成抑制作用
肿瘤发展到一定程度后,通过自分泌途径可以形成促血管生成因子,促进新生血管生成,有利于肿瘤快速生长,这种现象的产生是血小板凝集素-1(thrombospondin-1TSP-1)基因表达水平下降的结果。TSP-1是血管生成强有力的抑制因子,p53对TSP-1基因表达有上调作用,能激活内源性的TSP-1基因,正性调节TSP-1的启动子序列。研究还发现,p53可激活a(Ⅱ)胶原脯氨酰-4-羟化酶(a2PH)转录,致使全长胶原合成以及分泌,并产生抗血管生成抑素,在基质水平诱导蛋白质水解,增加胶原源性抗血管生成胶原的合成及分解。P53通过刺激抑制血管生成基因的表达,抑制肿瘤血管形成。同时,研究表明,p53与血管内皮生长因子(VEGF)间也有明显的关联性,p53突变后能上调VEGF,增加微血管数量促使肿瘤血管生成。
DNA修复
P53蛋白在DNA修复过程中起重要作用,主要表现在:若DNA损伤,p53蛋白阻止DNA复制,为DNA修复争取时间,若修复失败,p53蛋白则激活诱导细胞凋亡机制,促使细胞程序性死亡,以维持机体的稳定性。P53也可以于DNA修复因子如RPA、PCNA等基因相互作用,直接参与DNA的损伤修复过程。同时p53又可以和核酸切除修复基因(Nucleotide ExcisionRepair,NER)的组成成分相互作用,使NER也聚集于此,进行核苷酸修复。
P53具有多种与DNA相互作用方式的能力,这使得p53可以直接参与DNA修复,如与DNA修复因子相结合,或通过p53蛋白-蛋白相互作用直接参与DNA修复,这些能力对p53与损伤DNA结合具有重要意义。在DNA损伤因子作用下,p53的C-端探测到损伤的DNA,与其结合形成p53-DNA复合物。P53与损伤DNA结合后起转录因子作用,与序列特异的DNA结合,通过反式激活靶基因,参与并增强DNA修复。
抑制肿瘤细胞运动
细胞迁移有赖于细胞丝状伪足的形成以及细胞外基质的完整性被破坏,细胞骨架和其结合蛋白是这一过程的物质基础。P53蛋白可负性调节细胞的铺展及纤维黏连蛋白的形成。Ras(P21)蛋白位于细胞膜内侧,它在传递细胞生长分化信号方面起重要作用。Ras可调节Ras同族基因家族成员A(Rashomolog gene fami ly member A,RhoA)的作用。一方面,Ras可使RhoA的膜锚定;另一方面,Ras促进p190Rho GTPase激活蛋白(Rho GAP)酪氨酸磷酸化,促进RhoA-GTP水解成无活性的RhoA-GDP,致使RhoA活性降低。P53是Ras促进Rho GAP磷酸化作用的必需因子,与RhoA的膜锚定作用无关。P53缺失后,由于p190Rho GAP磷酸化降低,降低了RhoA GTP载入,从而大大促进了细胞的运动能力。
TAT
人类免疫缺陷病毒Ⅰ型(HIV-Ⅰ)是获得性免疫缺陷综合征(AIDS)的病原体。Tat是由HIV-Ⅰ编码的一段富含碱性氨基酸的短肽,其序列为YGRKKRRQRRR(SEQ ID NO.:5第405-416位),是其编码的6个调控蛋白中的一个很重要的调控蛋白,而Tat转导结构域的核心区就是由这11个氨基酸残基所组成。作为新发现的一种蛋白转导结构域,Tat蛋白能高效地介导与其共价连接的DNA、多肽、蛋白质等分子进入几乎所有的组织和细胞,甚至可以通过血脑屏障,转导效率高且对细胞几乎没有损伤,并且能保持蛋白的生物活性。Tat融合蛋白系统被认为是一种很有前途的高效运载工具,在基础医学研究和临床治疗方面都有着非常广阔的应用前景。
Tat蛋白的转导作用
Tat蛋白可以引导多种多肽和蛋白质进入几乎所有的靶细胞,这即是Tat蛋白的转导作用(transduction),又称为内化作用(internalization)。Tat蛋白的转导作用主要依赖于多肽或蛋白质的浓度,而不同于一般的通道、受体、内吞作用的的入胞方式。由于具有这一功能,Tat可被用来作为介导外源蛋白通过细胞膜的运载工具,因此日益受到人们的重视。
Tat蛋白以小窝途径介导外源物质进入细胞
小窝(caveolae)是细胞膜上很小的凹陷,大约50-70nm。Eguchi对Tat蛋白介导的外源基因转导进行了制菌霉素试验,制菌霉素能够抑制外源物质以小窝途径进入细胞,研究发现Tat介导的外源蛋白转导受到了抑制,因此得出结论Tat通过破坏细胞质膜,以小窝的方式进入细胞。这种方式操作简单,不受外界因素如温度的影响,也不受其他体内环境的影响,不产生毒性,可直接应用与体内的细胞。这种方法的诱导效果明显高于其他转染方法,速度快,转导效率高,在转导过程中保留了蛋白的生物活性。用另一种抑制小窝途径的药物fillipin使小窝的一个必需成分小窝蛋白-1在细胞表面重新分布,影响小窝途径后,发现Tat介导的外源蛋白输送受到了抑制,证明Tat蛋白是通过小窝途径穿膜的。
融合蛋白的制备
生物技术的发展为重组人溶菌酶的生产提供了有效途径,一种典型的生产抗肿瘤融合蛋白的方法,包括步骤:
(a)在适合表达条件下,培养本发明第四方面所述的宿主细胞,从而表达本发明第一方面所述的抗肿瘤融合蛋白;
(b)分离纯化出步骤(a)中所表达的抗肿瘤融合蛋白。
在另一优选例中,所述宿主细胞为细菌,较佳地为大肠杆菌。
在另一优选例中,本发明提供的GnRH+PII+P53的制备方法包括下列几个方面:
1)以GnRH+PII+P53氨基酸序列为基础,通过序列的结构优化以及密码子的简并性全基因合成了GnRH+PII+P53的编码基因,获得了该基因在大肠杆菌中的高表达;
2)在1)的基础上在GnRH+PII+P53编码序列前加入ULP1的识别位点98AA的SUMO,保证融合蛋白在经过ULP1的酶解后能够获得和GnRH+PII+P53理论设计一样的N端残基序列;
3)在2)的基础上,加入了一段有利于表达和纯化的序列,最终通过NdeI和HindIII克隆到表达载体pET21中得到表达构建pET21-6xhis-SUMO-GnRH+PII+P53,命名为pET220-GnRH+PII+P53;
4)表达载体pET220-GnRH+PII+P53转入大肠杆菌菌株BL21(DE3)RP plus中,得到工程菌;
5)工程菌在IPTG的诱导下表达融合蛋白6xhis-SUMO-GnRH+PII+P53,融合蛋白以包涵体形式表达;
6)融合表达的6xhis-SUMO-GnRH+PII+P53经过裂菌、包涵体溶解、金属螯合纯化等步骤得到纯化的融合蛋白;
7)融合蛋白通过滴加到到复性液中进行复性;
8)复性后的融合蛋白经过透析,酶切,亲和等层析步骤得到GnRH+PII+P53粗品;
9)GnRH+PII+P53粗品通过分子筛精制纯化,最终得到纯度大于95%的GnRH+PII+P53,在SDS-PAGE电泳上显示为单一条带,在分子筛上表现为四聚体的蛋白;
10)步骤9)中所获得GnRH+PII+P53纯品通过ISHIKAWA细胞检测生物学活性,在蛋白终浓度为0.5μg/ml以上时,>95%的细胞通过凋亡途径崩解。
本发明的主要优点包括:
(a)本发明融合蛋白不易降解,可以自然高效地形成四聚体。
(b)本发明的融合蛋白(四聚体)可以高效的进入靶细胞,并快速地进入细胞核区域,诱导已突变细胞(如肿瘤细胞)凋亡。
(c)本发明融合蛋白因P53的使用,动物实验未见毒性。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实施例1
编码本发明GnRH+PII+P53基因序列的优化设计和全基因合成
根据设计的GnRH+PII+P53氨基酸序列,通过基因软件分析,充分考虑了稀有密码子以及基因的二级结构,以及同义密码子的使用,最终得到优选的GnRH+PII+P53编码核酸序列如SEQ ID NO.:1所示,具体核酸序列为:
CAGCATTGGTCTTACGGTCTGAGACCTGGACATATGGCTGAAGAAGGTGGAAGTCTGGCTGCATTGACTGCTCATCAAGCTTGTCATCTACCTTTAGAGACTTTCACAAGACACAGACAGCCTAGAGGATGGGAACAACTGGAACAGTGTGGTTACCCAGTACAAAGACTAGTAGCTCTGTACCTGGCAGCTAGATTGTCTTGGAACCAGGTTGATCAGGTTATCAGAAACGCACTGGCAAGTCCTGGATCTGGTGGAGACTTAGGAGAAGCAATTAGAGAACAACCTGAGCAGGCAAGACTAGCATTGACACTGGCAGCCGCCGAATCTGAGAGATTTGTAAGACAGGGTACAGGAAACGATGAGGCTGGAGCTGCTAATATGGAAGAACCTCAAAGTGATCCTAGTGTTGAGCCACCACTATCACAGGAGACATTCTCCGATTTGTGGAAACTTCTTCCTGAGAATAACGTCCTTTCCCCTCTTCCATCCCAGGCTATGGATGATCTTATGCTGTCCCCAGATGATATTGAGCAATGGTTTACCGAGGACCCAGGACCAGATGAGGCACCAAGAATGCCAGAAGCCGCTCCTAGAGTCGCACCAGCTCCTGCTGCTCCAACACCAGCTGCTCCTGCACCAGCCCCATCTTGGCCATTGTCTTCTAGTGTTCCATCTCAGAAGACTTATCAAGGTTCTTATGGATTCAGACTTGGATTCTTGCATTCAGGAACAGCTAAGTCAGTTACTTGTACTTATAGTCCAGCTTTGAATAAGATGTTCTGTCAATTAGCTAAGACTTGTCCAGTCCAATTGTGGGTAGATAGTACTCCTCCACCTGGTACTAGAGTTAGAGCTATGGCCATCTACAAGCAAAGTCAACACATGACGGAGGTTGTCAGACGTTGTCCACATCATGAGAGATGTTCTGATTCCGATGGTCTAGCCCCTCCACAACATTTGATTAGAGTGGAAGGTAACCTAAGGGTGGAATATTTGGACGACCGTAACACTTTCCGTCACTCCGTTGTTGTGCCATATGAGCCTCCTGAAGTTGGTTCAGATTGTACCACTATTCACTACAACTATATGTGTAACTCCTCCTGTATGGGGGGTATGAACAGGCGTCCTATCTTGACTATTATAACGCTTGAGGACTCCTCCGGTAATTTGTTGGGCAGGAATTCATTTGAGGTGCACGTCTGTGCCTGTCCCGGTAGGGACAGGCGTACCGAAGAAGAGAATTTGCGTAAGAAAGGTGAACCCCATCATGAATTACCCCCCGGTTCTACCAAAAGGGCCTTATCAAATAATACCTCTTCCTCACCCCAACCCAAGAAGAAACCCTTAGACGGTGAATACTTTACGTTGCAAATACGTGGGCGTGAACGTTTTGAGATGTTTCGTGAGCTTAATGAAGCCTTAGAATTGAAAGACGCCCAAGCCGGGAAAGAACCCGGCGGCTCAAGGGCCCACTCTTCTCACTTAAAGTCTAAGAAAGGCCAAAGTACCTCACGTCACAAGAAATTAATGTTTAAAACCGAAGGCCCCGACTCAGAC(SEQ ID NO.:1);
GnRH+PII+P53蛋白序列如SEQ ID NO.:2所示,具体蛋白序列为:
QHWSYGLRPGHMAEEGGSLAALTAHQACHLPLETFTRHRQPRGWEQLEQCGYPVQRLVALYLAARLSWNQVDQVIRNALASPGSGGDLGEAIREQPEQARLALTLAAAESERFVRQGTGNDEAGAANMEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGPDEAPRMPEAAPRVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNYMCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVHVCACPGRDRRTEEENLRKKGEPHHELPPGSTKRALSNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAGKEPGGSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD(SEQ ID NO.:2)
在优化后的序列N端加入限制性内切酶NdeI位点和有利于表达和纯化的序列以及ulp1识别序列sumo的编码序列,在C端加入限制性内切酶Hind III位点,得到的序列如SEQID NO.:3所示,具体核酸序列为:
CATATGAGCGATAAAATTATTCACCTGACTGACGACAGTTTTGACACGGATGTACTCAAAGCGGACGGGGCGATCCTCGTCGATTTCTGGGCAGAGGGTTCTGGTTCTGGCCATGGTACCGGCAGCAGCCATCATCATCATCATCATGGCAGCGGTCTGGTGCCGCGTGGCAGCGCGAGCATGAGCGATAGCGAGGTGAACCAGGAAGCGAAGCCGGAGGTCAAGCCGGAGGTCAAGCCGGAGACGCACATCAACCTGAAGGTCAGCGATGGCAGCTCTGAGATTTTCTTCAAGATCAAGAAGACCACGCCGCTGCGTCGTCTGATGGAGGCGTTCGCTAAGCGTCAAGGCAAGGAGATGGACAGCCTTCGCTTCCTGTACGATGGCATCCGCATTCAAGCTGATCAGACTCCGGAGGACCTGGATATGGAGGACAACGACATCATCGAAGCTCATCGTGAGCAGATCGGAGGCCAGCATTGGTCTTACGGTCTGAGACCTGGACATATGGCTGAAGAAGGTGGAAGTCTGGCTGCATTGACTGCTCATCAAGCTTGTCATCTACCTTTAGAGACTTTCACAAGACACAGACAGCCTAGAGGATGGGAACAACTGGAACAGTGTGGTTACCCAGTACAAAGACTAGTAGCTCTGTACCTGGCAGCTAGATTGTCTTGGAACCAGGTTGATCAGGTTATCAGAAACGCACTGGCAAGTCCTGGATCTGGTGGAGACTTAGGAGAAGCAATTAGAGAACAACCTGAGCAGGCAAGACTAGCATTGACACTGGCAGCCGCCGAATCTGAGAGATTTGTAAGACAGGGTACAGGAAACGATGAGGCTGGAGCTGCTAATATGGAAGAACCTCAAAGTGATCCTAGTGTTGAGCCACCACTATCACAGGAGACATTCTCCGATTTGTGGAAACTTCTTCCTGAGAATAACGTCCTTTCCCCTCTTCCATCCCAGGCTATGGATGATCTTATGCTGTCCCCAGATGATATTGAGCAATGGTTTACCGAGGACCCAGGACCAGATGAGGCACCAAGAATGCCAGAAGCCGCTCCTAGAGTCGCACCAGCTCCTGCTGCTCCAACACCAGCTGCTCCTGCACCAGCCCCATCTTGGCCATTGTCTTCTAGTGTTCCATCTCAGAAGACTTATCAAGGTTCTTATGGATTCAGACTTGGATTCTTGCATTCAGGAACAGCTAAGTCAGTTACTTGTACTTATAGTCCAGCTTTGAATAAGATGTTCTGTCAATTAGCTAAGACTTGTCCAGTCCAATTGTGGGTAGATAGTACTCCTCCACCTGGTACTAGAGTTAGAGCTATGGCCATCTACAAGCAAAGTCAACACATGACGGAGGTTGTCAGACGTTGTCCACATCATGAGAGATGTTCTGATTCCGATGGTCTAGCCCCTCCACAACATTTGATTAGAGTGGAAGGTAACCTAAGGGTGGAATATTTGGACGACCGTAACACTTTCCGTCACTCCGTTGTTGTGCCATATGAGCCTCCTGAAGTTGGTTCAGATTGTACCACTATTCACTACAACTATATGTGTAACTCCTCCTGTATGGGGGGTATGAACAGGCGTCCTATCTTGACTATTATAACGCTTGAGGACTCCTCCGGTAATTTGTTGGGCAGGAATTCATTTGAGGTGCACGTCTGTGCCTGTCCCGGTAGGGACAGGCGTACCGAAGAAGAGAATTTGCGTAAGAAAGGTGAACCCCATCATGAATTACCCCCCGGTTCTACCAAAAGGGCCTTATCAAATAATACCTCTTCCTCACCCCAACCCAAGAAGAAACCCTTAGACGGTGAATACTTTACGTTGCAAATACGTGGGCGTGAACGTTTTGAGATGTTTCGTGAGCTTAATGAAGCCTTAGAATTGAAAGACGCCCAAGCCGGGAAAGAACCCGGCGGCTCAAGGGCCCACTCTTCTCACTTAAAGTCTAAGAAAGGCCAAAGTACCTCACGTCACAAGAAATTAATGTTTAAAACCGAAGGCCCCGACTCAGACTAAGCTT(SEQ ID NO.:3);
通过商业化基因合成公司上海生工生物工程有限公司全基因合成该序列,并克隆到PUC19载体中,经测序验证后命名为PUC19-GnRH+PII+P53。
实施例2
表达GnRH+PII+P53的载体构建
GnRH+PII+P53在大肠杆菌中表达的优先表达载体为PET21,将Pet21和PUC19-GnRH+PII+P53用限制性内切酶Nde I和Hind III做双酶切,酶切产物用琼脂糖凝胶电泳分离后切胶回收,再用T4连接酶连接,连接产物转化到大肠杆菌DH5α中。挑出阳性克隆,抽出其中的质粒,经过测序验证无误后命名为pET220-GnRH+PII+P53。
pET220-GnRH+PII+P53蛋白序列如SEQ ID NO.:4所示,具体蛋白序列为:
MSDKIIHLTDDSFDTDVLKADGAILVDFWAEGSGSGHGTGSSHHHHHHGSGLVPRGSASMSDSEVNQEAKPEVKPEVKPETHINLKVSDGSSEIFFKIKKTTPLRRLMEAFAKRQGKEMDSLRFLYDGIRIQADQTPEDLDMEDNDIIEAHREQIGGQHWSYGLRPGHMAEEGGSLAALTAHQACHLPLETFTRHRQPRGWEQLEQCGYPVQRLVALYLAARLSWNQVDQVIRNALASPGSGGDLGEAIREQPEQARLALTLAAAESERFVRQGTGNDEAGAANMEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGPDEAPRMPEAAPRVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNYMCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVHVCACPGRDRRTEEENLRKKGEPHHELPPGSTKRALSNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAGKEPGGSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD(SEQ ID NO.:4)
实施例3
表达GnRH+PII+P53蛋白的工程菌构建及诱导表达分析
将质粒pET220-GnRH+PII+P53转化到大肠杆菌宿主BL21 Codon Plus(DE3)RP中,离心后取细菌涂布在含100μg/ml的氨苄青霉素的LB平板上,37℃培养过夜,在LB平板上挑单克隆培养,经过菌落PCR鉴定,得到单克隆转化子pET220-GnRH+PII+P53/BL21 CodonPlus(DE3)RP得到的单克隆转化子pET220-GnRH+PII+P53/BL21 Codon Plus(DE3)RP接种于3ml的含100μg/ml的氨苄青霉素的LB培养液中,37℃培养过夜;按2%的接种量取过夜培养的大肠杆菌接种到新鲜的LB培养液中37℃培养,当细菌密度OD600值达到0.6-1.0之间时,加入终浓度为0.5mM的IPTG诱导融合蛋白表达,继续培养3.5小时后,收集菌体。通过SDS-PAGE分析蛋白表达情况。
结果如图1所示,融合蛋白以包涵体形式表达,融合蛋白表达量占细菌总蛋白的25%左右。
实施例4
GnRH+PII+P53蛋白的发酵生产与分离纯化
1、发酵生产
将pET220-GnRH+PII+P53/BL21 Codon Plus(DE3)RP接种于LB培养基中37℃培养过夜,第二天按2%的接种量接入新鲜的TB(甘油5克/升,蛋白胨12克/升,酵母膏24克/升,K2HPO4 12.54克/升,KH2PO42.31克/升)发酵液体培养液中,37℃培养到细菌OD600值达到1,加入终浓度为0.5mM的IPTG诱导融合蛋白表达,继续培养4小时后收集菌体。
2、包涵体获取
融合蛋白以包涵体形式表达,为了获得包涵体,用PBS按1:10的比例重悬菌体,设置匀浆压力为750pa,匀浆两次,15000g的离心条件下离心收集沉淀部分;绝大部分包涵体蛋白在收集的沉淀部分中。
3、融合蛋白的溶解和纯化
包涵体按1:20的比例用溶液1(20Mm Tris-HCL,500mM NaCl,20mM Imidazole,8MUrea 20mM 2-Mercaptoethanol pH8.0)充分溶解,15000g的离心条件下离心20分钟,取上清组分做进一步的纯化
上清组分通过NI2+metal chelating chromatography在变性条件下纯化得纯的融合蛋白,融合蛋白处在含8M Urea的变性溶液中,加入终浓度为5mM的DTT处理融合蛋白,室温下搅拌过夜
4、变性蛋白的重折叠(蛋白复性)
经过处理的变性蛋白通过滴加到复性液中(复性液配方为100mM Tris-HCL,500mMNaCl,0.5M Arginine,1%triton X-100,10%glycerol,1mM EDTA,1mM GSH,0.5mM GSSGpH8.0)滴加完后4℃冰箱中放置48-72小时,充分复性
5、复性后蛋白的回收
充分复性的蛋白溶液装入透析袋对缓冲液(20Mm Tris.CL,Ph8.5)透析,每次透析4小时,总共透析3次;透析后,用阴离子柱Q回收目的蛋白
6、融合蛋白肠ULP1酶切
阴离子柱Q回收的融合蛋白中加入20IU/mg融合蛋白的ULP1酶,加入磁力搅拌子缓慢搅拌,保证充分酶切,酶切条件:4℃,16-24小时
7、酶切后纯化
经过酶切后的融合蛋白溶液,主要为二种成分:融合表达标签蛋白和GnRH+PII+P53,以及少量未酶切的完整融合蛋白,其中融合表达标签蛋白和完整融合蛋白都含有6xHis纯化标签,通过NI2+metal chelating chromatography可以结合这两部分蛋白,GnRH+PII+P53不能结合到NI2+metal chelating柱而存在于流穿部分中
8、GnRH+PII+P53的肝素亲和层析浓缩、分子筛精制
用购自GE healthcare的肝素亲和填料装填的层析柱亲和浓缩存在于(步骤7)流穿部分的GnRH+PII+P53,浓缩后的GnRH+PII+P53通过SUPERDEX 200精制,精制后的蛋白溶液无菌过滤后供后续实验使用。
实施例5
GnRH+PII+P53对不同肿瘤细胞的杀伤效果测定
用实施例4制得的GnRH+PII+P53融合蛋白处理下表2中的各细胞,测定IC50值。
结果如表2所示,GnRH+PII+P53对正常细胞没有杀伤效果IC50>100μg/ml,GnRH+PII+P53对多种肿瘤细胞均具有较好的杀伤效果,IC50基本均小于5μg/ml。
表2 GnRH+PII+P53对不同肿瘤细胞的杀伤效果
实施例6
GnRH+PII+P53对Ishikawa细胞的杀伤效果测定
以实施例4制得的GnRH+PII+P53融合蛋白Slg001为例,说明其对Ishikawa细胞的杀伤效果,检测结果如图2所示,高浓度细胞致死,无正常细胞,仅可见培养基中大量颗粒碎片。具体如下:
Ishikawa细胞Slg001处理72小时后,20μg/ml Slg001处理的孔板中培养基呈现红色,显微观察可见大量颗粒状细胞碎片,10μg/ml Slg001处理的孔板中培养基呈现浅红色,显微观察可见部分细胞和细胞碎片,低浓度Slg001处理的细胞则和对照组差异不大;
随着处理时间延长至8天,不同与对照组细胞,0.4-20μg/ml Slg001处理的细胞都有不同程度的细胞碎片出现。空白对照组培养基在5%CO2下呈黄色,pH为6.0,而20μg/mlSlg001处理的细胞在8天后培养基呈紫红色,pH在8.0左右。
实施例7
GnRH+PII+P53对接种舌鳞癌CAL-27的荷瘤鼠静脉给药有效性试验
对3组接种了CAL-27荷瘤鼠静脉施用实施例4制得的GnRH+PII+P53融合蛋白,隔天给药,共给药五次,剂量分别是250μg/kg、500μg/kg、1000μg/kg、2000μg/kg、4000μg/kg,观察荷瘤鼠是否有毒性反应,药物是否有效。结果是,未见毒性反应,前4针未见瘤体增大,第5针后测定抑瘤率达72%。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 颜, 浩为
侯, 天全
<120> 抗肿瘤融合蛋白及其制法和应用
<130> P2016-0672
<160> 5
<170> PatentIn version 3.5
<210> 1
<211> 1560
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 1
cagcattggt cttacggtct gagacctgga catatggctg aagaaggtgg aagtctggct 60
gcattgactg ctcatcaagc ttgtcatcta cctttagaga ctttcacaag acacagacag 120
cctagaggat gggaacaact ggaacagtgt ggttacccag tacaaagact agtagctctg 180
tacctggcag ctagattgtc ttggaaccag gttgatcagg ttatcagaaa cgcactggca 240
agtcctggat ctggtggaga cttaggagaa gcaattagag aacaacctga gcaggcaaga 300
ctagcattga cactggcagc cgccgaatct gagagatttg taagacaggg tacaggaaac 360
gatgaggctg gagctgctaa tatggaagaa cctcaaagtg atcctagtgt tgagccacca 420
ctatcacagg agacattctc cgatttgtgg aaacttcttc ctgagaataa cgtcctttcc 480
cctcttccat cccaggctat ggatgatctt atgctgtccc cagatgatat tgagcaatgg 540
tttaccgagg acccaggacc agatgaggca ccaagaatgc cagaagccgc tcctagagtc 600
gcaccagctc ctgctgctcc aacaccagct gctcctgcac cagccccatc ttggccattg 660
tcttctagtg ttccatctca gaagacttat caaggttctt atggattcag acttggattc 720
ttgcattcag gaacagctaa gtcagttact tgtacttata gtccagcttt gaataagatg 780
ttctgtcaat tagctaagac ttgtccagtc caattgtggg tagatagtac tcctccacct 840
ggtactagag ttagagctat ggccatctac aagcaaagtc aacacatgac ggaggttgtc 900
agacgttgtc cacatcatga gagatgttct gattccgatg gtctagcccc tccacaacat 960
ttgattagag tggaaggtaa cctaagggtg gaatatttgg acgaccgtaa cactttccgt 1020
cactccgttg ttgtgccata tgagcctcct gaagttggtt cagattgtac cactattcac 1080
tacaactata tgtgtaactc ctcctgtatg gggggtatga acaggcgtcc tatcttgact 1140
attataacgc ttgaggactc ctccggtaat ttgttgggca ggaattcatt tgaggtgcac 1200
gtctgtgcct gtcccggtag ggacaggcgt accgaagaag agaatttgcg taagaaaggt 1260
gaaccccatc atgaattacc ccccggttct accaaaaggg ccttatcaaa taatacctct 1320
tcctcacccc aacccaagaa gaaaccctta gacggtgaat actttacgtt gcaaatacgt 1380
gggcgtgaac gttttgagat gtttcgtgag cttaatgaag ccttagaatt gaaagacgcc 1440
caagccggga aagaacccgg cggctcaagg gcccactctt ctcacttaaa gtctaagaaa 1500
ggccaaagta cctcacgtca caagaaatta atgtttaaaa ccgaaggccc cgactcagac 1560
<210> 2
<211> 520
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Gln His Trp Ser Tyr Gly Leu Arg Pro Gly His Met Ala Glu Glu Gly
1 5 10 15
Gly Ser Leu Ala Ala Leu Thr Ala His Gln Ala Cys His Leu Pro Leu
20 25 30
Glu Thr Phe Thr Arg His Arg Gln Pro Arg Gly Trp Glu Gln Leu Glu
35 40 45
Gln Cys Gly Tyr Pro Val Gln Arg Leu Val Ala Leu Tyr Leu Ala Ala
50 55 60
Arg Leu Ser Trp Asn Gln Val Asp Gln Val Ile Arg Asn Ala Leu Ala
65 70 75 80
Ser Pro Gly Ser Gly Gly Asp Leu Gly Glu Ala Ile Arg Glu Gln Pro
85 90 95
Glu Gln Ala Arg Leu Ala Leu Thr Leu Ala Ala Ala Glu Ser Glu Arg
100 105 110
Phe Val Arg Gln Gly Thr Gly Asn Asp Glu Ala Gly Ala Ala Asn Met
115 120 125
Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln Glu
130 135 140
Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu Ser
145 150 155 160
Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp Asp
165 170 175
Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro Arg
180 185 190
Met Pro Glu Ala Ala Pro Arg Val Ala Pro Ala Pro Ala Ala Pro Thr
195 200 205
Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser Val
210 215 220
Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly Phe
225 230 235 240
Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro Ala
245 250 255
Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln Leu
260 265 270
Trp Val Asp Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met Ala
275 280 285
Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys Pro
290 295 300
His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln His
305 310 315 320
Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg
325 330 335
Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu Val
340 345 350
Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser Ser
355 360 365
Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu
370 375 380
Glu Asp Ser Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val His
385 390 395 400
Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu
405 410 415
Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr Lys
420 425 430
Arg Ala Leu Ser Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys
435 440 445
Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu Arg
450 455 460
Phe Glu Met Phe Arg Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp Ala
465 470 475 480
Gln Ala Gly Lys Glu Pro Gly Gly Ser Arg Ala His Ser Ser His Leu
485 490 495
Lys Ser Lys Lys Gly Gln Ser Thr Ser Arg His Lys Lys Leu Met Phe
500 505 510
Lys Thr Glu Gly Pro Asp Ser Asp
515 520
<210> 3
<211> 2041
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 3
catatgagcg ataaaattat tcacctgact gacgacagtt ttgacacgga tgtactcaaa 60
gcggacgggg cgatcctcgt cgatttctgg gcagagggtt ctggttctgg ccatggtacc 120
ggcagcagcc atcatcatca tcatcatggc agcggtctgg tgccgcgtgg cagcgcgagc 180
atgagcgata gcgaggtgaa ccaggaagcg aagccggagg tcaagccgga ggtcaagccg 240
gagacgcaca tcaacctgaa ggtcagcgat ggcagctctg agattttctt caagatcaag 300
aagaccacgc cgctgcgtcg tctgatggag gcgttcgcta agcgtcaagg caaggagatg 360
gacagccttc gcttcctgta cgatggcatc cgcattcaag ctgatcagac tccggaggac 420
ctggatatgg aggacaacga catcatcgaa gctcatcgtg agcagatcgg aggccagcat 480
tggtcttacg gtctgagacc tggacatatg gctgaagaag gtggaagtct ggctgcattg 540
actgctcatc aagcttgtca tctaccttta gagactttca caagacacag acagcctaga 600
ggatgggaac aactggaaca gtgtggttac ccagtacaaa gactagtagc tctgtacctg 660
gcagctagat tgtcttggaa ccaggttgat caggttatca gaaacgcact ggcaagtcct 720
ggatctggtg gagacttagg agaagcaatt agagaacaac ctgagcaggc aagactagca 780
ttgacactgg cagccgccga atctgagaga tttgtaagac agggtacagg aaacgatgag 840
gctggagctg ctaatatgga agaacctcaa agtgatccta gtgttgagcc accactatca 900
caggagacat tctccgattt gtggaaactt cttcctgaga ataacgtcct ttcccctctt 960
ccatcccagg ctatggatga tcttatgctg tccccagatg atattgagca atggtttacc 1020
gaggacccag gaccagatga ggcaccaaga atgccagaag ccgctcctag agtcgcacca 1080
gctcctgctg ctccaacacc agctgctcct gcaccagccc catcttggcc attgtcttct 1140
agtgttccat ctcagaagac ttatcaaggt tcttatggat tcagacttgg attcttgcat 1200
tcaggaacag ctaagtcagt tacttgtact tatagtccag ctttgaataa gatgttctgt 1260
caattagcta agacttgtcc agtccaattg tgggtagata gtactcctcc acctggtact 1320
agagttagag ctatggccat ctacaagcaa agtcaacaca tgacggaggt tgtcagacgt 1380
tgtccacatc atgagagatg ttctgattcc gatggtctag cccctccaca acatttgatt 1440
agagtggaag gtaacctaag ggtggaatat ttggacgacc gtaacacttt ccgtcactcc 1500
gttgttgtgc catatgagcc tcctgaagtt ggttcagatt gtaccactat tcactacaac 1560
tatatgtgta actcctcctg tatggggggt atgaacaggc gtcctatctt gactattata 1620
acgcttgagg actcctccgg taatttgttg ggcaggaatt catttgaggt gcacgtctgt 1680
gcctgtcccg gtagggacag gcgtaccgaa gaagagaatt tgcgtaagaa aggtgaaccc 1740
catcatgaat taccccccgg ttctaccaaa agggccttat caaataatac ctcttcctca 1800
ccccaaccca agaagaaacc cttagacggt gaatacttta cgttgcaaat acgtgggcgt 1860
gaacgttttg agatgtttcg tgagcttaat gaagccttag aattgaaaga cgcccaagcc 1920
gggaaagaac ccggcggctc aagggcccac tcttctcact taaagtctaa gaaaggccaa 1980
agtacctcac gtcacaagaa attaatgttt aaaaccgaag gccccgactc agactaagct 2040
t 2041
<210> 4
<211> 677
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Met Ser Asp Lys Ile Ile His Leu Thr Asp Asp Ser Phe Asp Thr Asp
1 5 10 15
Val Leu Lys Ala Asp Gly Ala Ile Leu Val Asp Phe Trp Ala Glu Gly
20 25 30
Ser Gly Ser Gly His Gly Thr Gly Ser Ser His His His His His His
35 40 45
Gly Ser Gly Leu Val Pro Arg Gly Ser Ala Ser Met Ser Asp Ser Glu
50 55 60
Val Asn Gln Glu Ala Lys Pro Glu Val Lys Pro Glu Val Lys Pro Glu
65 70 75 80
Thr His Ile Asn Leu Lys Val Ser Asp Gly Ser Ser Glu Ile Phe Phe
85 90 95
Lys Ile Lys Lys Thr Thr Pro Leu Arg Arg Leu Met Glu Ala Phe Ala
100 105 110
Lys Arg Gln Gly Lys Glu Met Asp Ser Leu Arg Phe Leu Tyr Asp Gly
115 120 125
Ile Arg Ile Gln Ala Asp Gln Thr Pro Glu Asp Leu Asp Met Glu Asp
130 135 140
Asn Asp Ile Ile Glu Ala His Arg Glu Gln Ile Gly Gly Gln His Trp
145 150 155 160
Ser Tyr Gly Leu Arg Pro Gly His Met Ala Glu Glu Gly Gly Ser Leu
165 170 175
Ala Ala Leu Thr Ala His Gln Ala Cys His Leu Pro Leu Glu Thr Phe
180 185 190
Thr Arg His Arg Gln Pro Arg Gly Trp Glu Gln Leu Glu Gln Cys Gly
195 200 205
Tyr Pro Val Gln Arg Leu Val Ala Leu Tyr Leu Ala Ala Arg Leu Ser
210 215 220
Trp Asn Gln Val Asp Gln Val Ile Arg Asn Ala Leu Ala Ser Pro Gly
225 230 235 240
Ser Gly Gly Asp Leu Gly Glu Ala Ile Arg Glu Gln Pro Glu Gln Ala
245 250 255
Arg Leu Ala Leu Thr Leu Ala Ala Ala Glu Ser Glu Arg Phe Val Arg
260 265 270
Gln Gly Thr Gly Asn Asp Glu Ala Gly Ala Ala Asn Met Glu Glu Pro
275 280 285
Gln Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln Glu Thr Phe Ser
290 295 300
Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu Ser Pro Leu Pro
305 310 315 320
Ser Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp Asp Ile Glu Gln
325 330 335
Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro Arg Met Pro Glu
340 345 350
Ala Ala Pro Arg Val Ala Pro Ala Pro Ala Ala Pro Thr Pro Ala Ala
355 360 365
Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser Val Pro Ser Gln
370 375 380
Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly Phe Leu His Ser
385 390 395 400
Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro Ala Leu Asn Lys
405 410 415
Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln Leu Trp Val Asp
420 425 430
Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met Ala Ile Tyr Lys
435 440 445
Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys Pro His His Glu
450 455 460
Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln His Leu Ile Arg
465 470 475 480
Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg Asn Thr Phe
485 490 495
Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp
500 505 510
Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser Ser Cys Met Gly
515 520 525
Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser
530 535 540
Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val His Val Cys Ala
545 550 555 560
Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu Arg Lys Lys
565 570 575
Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr Lys Arg Ala Leu
580 585 590
Ser Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys Pro Leu Asp
595 600 605
Gly Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu Arg Phe Glu Met
610 615 620
Phe Arg Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp Ala Gln Ala Gly
625 630 635 640
Lys Glu Pro Gly Gly Ser Arg Ala His Ser Ser His Leu Lys Ser Lys
645 650 655
Lys Gly Gln Ser Thr Ser Arg His Lys Lys Leu Met Phe Lys Thr Glu
660 665 670
Gly Pro Asp Ser Asp
675
<210> 5
<211> 416
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Gln His Trp Ser Tyr Gly Leu Arg Pro Gly His Met Glu Glu Pro Gln
1 5 10 15
Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln Glu Thr Phe Ser Asp
20 25 30
Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu Ser Pro Leu Pro Ser
35 40 45
Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp Asp Ile Glu Gln Trp
50 55 60
Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro Arg Met Pro Glu Ala
65 70 75 80
Ala Pro Arg Val Ala Pro Ala Pro Ala Ala Pro Thr Pro Ala Ala Pro
85 90 95
Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser Val Pro Ser Gln Lys
100 105 110
Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly Phe Leu His Ser Gly
115 120 125
Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro Ala Leu Asn Lys Met
130 135 140
Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln Leu Trp Val Asp Ser
145 150 155 160
Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met Ala Ile Tyr Lys Gln
165 170 175
Ser Gln His Met Thr Glu Val Val Arg Arg Cys Pro His His Glu Arg
180 185 190
Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln His Leu Ile Arg Val
195 200 205
Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg Asn Thr Phe Arg
210 215 220
His Ser Val Val Val Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp Cys
225 230 235 240
Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser Ser Cys Met Gly Gly
245 250 255
Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser Ser
260 265 270
Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val His Val Cys Ala Cys
275 280 285
Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu Arg Lys Lys Gly
290 295 300
Glu Pro His His Glu Leu Pro Pro Gly Ser Thr Lys Arg Ala Leu Ser
305 310 315 320
Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys Pro Leu Asp Gly
325 330 335
Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu Arg Phe Glu Met Phe
340 345 350
Arg Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp Ala Gln Ala Gly Lys
355 360 365
Glu Pro Gly Gly Ser Arg Ala His Ser Ser His Leu Lys Ser Lys Lys
370 375 380
Gly Gln Ser Thr Ser Arg His Lys Lys Leu Met Phe Lys Thr Glu Gly
385 390 395 400
Pro Asp Ser Asp Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Pro Gln
405 410 415
Claims (10)
1.一种抗肿瘤融合蛋白,其特征在于,所述的融合蛋白具有式I所述结构:
D-A-B-C-E (I)
其中,
A为GnRH蛋白元件;
B为PEA蛋白的跨膜转运区或为无;
C为P53蛋白元件;
E为TAT蛋白元件或为无;
D为任选的信号肽和/或前导肽序列;
并且,B和E不同时为无;
其中,“-”表示连接上述各元件的肽键。
2.如权利要求1所述的融合蛋白,其特征在于,所述的融合蛋白具有式II所述结构:
D-A-B-C (II)
其中,
A为GnRH蛋白元件;
B为PEA蛋白的跨膜转运区;
C为P53蛋白元件;
D为任选的信号肽和/或前导肽序列;
“-”表示连接上述各元件的肽键。
3.如权利要求1所述的融合蛋白,其特征在于,所述的GnRH蛋白包括II型GnRH蛋白和I型GnRH蛋白。
4.如权利要求1所述的融合蛋白,其特征在于,所述的融合蛋白是由细菌,较佳地由大肠杆菌表达的重组蛋白。
5.一种分离的多核苷酸,其特征在于,所述的多核苷酸编码权利要求1所述的融合蛋白。
6.一种载体,其特征在于,所述载体含有权利要求5所述的多核苷酸。
7.一种宿主细胞,其特征在于,所述宿主细胞含有权利要求6所述的载体或基因组中整合有权利要求5所述的多核苷酸。
8.一种生产抗肿瘤融合蛋白的方法,其特征在于,包括步骤:
(a)在适合表达条件下,培养权利要求7所述的宿主细胞,从而表达权利要求1所述的融合蛋白;
(b)分离纯化出步骤(a)中所表达的抗肿瘤融合蛋白。
9.一种药物组合物,其特征在于,所述药物组合物含有权利要求1所述的融合蛋白,以及药学上可接受的载体或赋形剂。
10.一种权利要求1所述的抗肿瘤融合蛋白的用途,其特征在于,用于制备治疗或预防肿瘤的药物。
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