CN1661012A - 小型化抗eb病毒肿瘤多肽及其应用与制备方法 - Google Patents
小型化抗eb病毒肿瘤多肽及其应用与制备方法 Download PDFInfo
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- CN1661012A CN1661012A CN200510020168XA CN200510020168A CN1661012A CN 1661012 A CN1661012 A CN 1661012A CN 200510020168X A CN200510020168X A CN 200510020168XA CN 200510020168 A CN200510020168 A CN 200510020168A CN 1661012 A CN1661012 A CN 1661012A
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Abstract
本发明提供一种小型化抗EB病毒肿瘤多肽的基因、重组质粒和多肽。将编码引导多肽的基因与载有大肠菌素离子通道结构域基因的质粒可操作地连接，将该突变质粒转染入工程菌增菌，经His－tag柱分离纯化获得该多肽。该多肽高效杀灭体内肿瘤细胞，无现用化疗药物的毒副作用。由于大肠菌素离子通道结构域无抗原性，因此该小型化抗EB病毒肿瘤多肽的免疫原性将比全大肠菌素重组抗肿瘤多肽的免疫原性大大降低。
Description
技术领域
本发明涉及一种抗EB病毒肿瘤多肽的基因、重组质粒、多肽及其应用与制备方法。
背景技术
恶性肿瘤是对人类健康的巨大威胁。全世界每年死于恶性肿瘤的患者约有七百万人，其中中国就占了六分之一，恶性肿瘤已是我国第二位的死亡原因。由于其病因、发病机制、临床表现尚未阐明，故防治效果也不理想。现有抗肿瘤药物在肿瘤治疗中占重要地位，虽然对一些肿瘤已取得一定的疗效，但仍存在着对肿瘤细胞选择性差，不良反应多而严重，产生耐药性等缺陷。
近年来肿瘤基础和临床研究取得很大的进展，其中开发新型抗肿瘤药物最重要的努力方向之一就是发展特异杀伤肿瘤细胞的药物。如果能找到一种肿瘤细胞的表面特异性标志物，也就是说这样的表面特异性标志物只有肿瘤细胞才有，而正常细胞没有，那么就可以发展出只攻击肿瘤细胞，不攻击正常细胞的安全型抗肿瘤药物。
寻找肿瘤细胞表面特异性标志物的研究已进行了数十年，然而可供使用的细胞表面特异性标志物发现得并不多，因此该难点已成为开发特异杀伤肿瘤药物的学术/技术瓶颈。
Epstein-Barr病毒(EB病毒)是第一种被确认可在人体引起恶性肿瘤的病毒；其所致的非洲儿童恶性淋巴肉瘤、Hodgkin’s淋巴肉瘤和鼻咽癌以及近来发现部分AIDS病人所患肉瘤的肿瘤细胞表面均带有特异的EB病毒表面抗原。因此，EB病毒表面抗原就可以认为是该类肿瘤细胞的一种特异性标志物。
申请号为200410081446.8的中国专利申请公开了一种抗EB病毒所致肿瘤多肽的基因、重组质粒、多肽及其应用与制备方法，所述多肽具有特异的靶向性，在治疗过程中不会攻击正常细胞，毒性和不良反应远低于传统抗肿瘤药物，与传统抗肿瘤药物相较，肿瘤细胞对其产生耐药性的概率也低得多，同时还可对抗转移过程中的肿瘤细胞。但由于其系全大肠菌素重组，分子量较大，免疫原性也可能较大，因此如患者长期使用，存在着引起不良变态反应的隐患。
发明内容
本发明的一个目的在于提供一种小型化抗EB病毒肿瘤多肽的基因、重组质粒、多肽，该多肽不仅能高效杀灭实体肿瘤及转移的肿瘤细胞而不伤害正常细胞，而且免疫原性大大降低。本发明的再一目的是提供上述重组抗肿瘤多肽的制备方法，此种方法可提高抗肿瘤多肽的纯度并最大程度保存其生物活性。
本发明的技术方案如下：
本发明所述小型化抗EB病毒肿瘤多肽的基因，含有编码大肠菌素离子通道结构域的基因，以及编码以抗EB病毒包膜糖蛋白抗体的CDR区为蓝本而构建的引导多肽的基因。将编码引导多肽的基因与大肠菌素离子通道结构域基因可操作地连接，即获得表达小型化抗EB病毒肿瘤多肽的核苷酸序列。编码引导多肽的基因是以人为选择好的抗EB病毒包膜糖蛋白抗体(ATCC HB-168杂交瘤细胞产生)重链和轻链的诸CDR区，和诸CDR区连接段的基因为蓝本构建而成，如序列表中SEQ ID NO.3或SEQ ID NO.5或SEQ IDNO.7或SEQ ID NO.9或SEQ ID NO.11或SEQ ID NO.13所述的核苷酸序列。大肠菌素离子通道结构域可选自能形成离子通道的大肠菌素E1、Ia、Ib、A、B和N。在本发明的一个优选实施例中，将上述引导多肽的基因与大肠菌素Ia离子通道结构域(SEQID NO.1)的羧基端基因连接而形成如序列表中SEQ ID NO.15、SEQ ID NO.17、SEQ IDNO.19、SEQ ID NO.21、SEQ ID NO.23、SEQ ID NO.25所述的核苷酸序列。在本发明的另一个优选实施例中，将上述引导多肽的基因SEQ ID NO.3与大肠菌素A离子通道结构域(SEQ ID NO.2)的羧基端基因连接而形成如序列表中SEQ ID NO.29所述的核苷酸序列。在本发明的再一个优选实施例中，将上述引导多肽的基因SEQ ID NO.3与大肠菌素Ia离子通道结构域(SEQ ID NO.1)的氨基端基因连接而形成如序列表中SEQ ID NO.27所述的核苷酸序列。
本发明所述重组质粒，是将如上所述的编码引导多肽的核苷酸序列经双链寡聚核苷酸点突变技术插入大肠菌素离子通道结构域的羧基端或氨基端形成。若选用大肠菌素Ia，则将编码引导多肽的核苷酸序列插入Ia离子通道结构域基因的第626位氨基酸后(羧基端)或第451位氨基酸前(氨基端)而形成本发明的诸重组质粒。构建重组质粒的原始质粒(pET-15b，Novagen)装载了大肠菌素Ia离子通道结构域或大肠菌素A离子通道结构域和相应的Immunity蛋白基因，针对引导多肽基因设计了数对引物，其代表序列见实施例1。利用双链寡聚核苷酸点突变技术，按照Strategene公司药箱操作获得重组质粒。
本发明所述小型化抗EB病毒肿瘤多肽，由上述重组质粒表达而成，分子量为25,000～32,000。
本发明的又一方面，提供小型化抗EB病毒肿瘤多肽的新型制备方法。将以抗EB病毒包膜糖蛋白抗体的CDR区为蓝本而构建的引导多肽的基因与载有编码大肠菌素离子通道结构域基因的His-tag质粒可操作地连接获得载有编码重组抗肿瘤多肽的基因，将获得的基因导入到表达系统中进行表达，经His-tag柱(Ni Sepharose High Performance柱)分离纯化而获得本发明所述的小型化抗EB病毒肿瘤多肽。
本发明所述多肽可在制备治疗或预防EB病毒所致肿瘤的药中应用。可以通过将本发明中的多肽添加药学上可接受的载体或赋形剂或可选的其它成分而制成适于临床使用的药物组合物。其机理是：多肽中可与靶肿瘤细胞表面特异性标志物(EB病毒表达在靶肿瘤细胞膜上的EB病毒表面抗原)结合的引导多肽诱导大肠菌素离子通道结构域到达靶肿瘤细胞膜附近，然后大肠菌素离子通道结构域的疏水区段插入靶肿瘤细胞膜中，进而大肠菌素离子通道结构域在靶肿瘤细胞膜上形成离子通道，使靶肿瘤细胞内容物泄漏而致肿瘤细胞死亡，从而达到杀死肿瘤细胞的目的。
本发明所述小型化抗EB病毒肿瘤多肽相较于传统抗肿瘤药物的优点在于，其具有特异的靶向性，因而在治疗过程中不会攻击正常细胞，所以根本无传统抗肿瘤药物的毒副作用。再由于它是在肿瘤细胞膜上直接形成离子通道来杀伤肿瘤细胞，因此与传统抗肿瘤药物相较，肿瘤细胞对其产生耐药性的概率要低得多：1.在抗肿瘤多肽—离子通道造成泄漏而致肿瘤细胞死亡的这一较短时限内，肿瘤细胞较难以利用突变基因—蛋白表达方式来修复抗肿瘤多肽—离子通道在肿瘤细胞膜上造成的几何缺损；2.嵌合在肿瘤细胞基因中的病毒基因是寄生的基因，因而肿瘤细胞内可能缺乏有效的寄生病毒基因反馈机制来及时有效的调整表达在肿瘤细胞膜表面病毒抗原的变异性，这样在一个相对长的时限内，构建的引导多肽总是对该抗原保持着有效的结合效率，所以肿瘤细胞对本发明的抗肿瘤多肽产生耐药性的概率较低。再本发明实施例试验结果证实抗肿瘤多肽可在体液和血液中游动，因此它是对抗转移过程中肿瘤细胞的利器。需要特别说明的是，本发明实施例试验显示，受试环磷酰胺的杀肿瘤细胞效率只有该小型化抗EB病毒肿瘤多肽效率的五十分之一(依据本发明中实施例5结果的最保守估计)，且环磷酰胺的安全性无法与该抗肿瘤多肽相比较。该小型化抗EB病毒肿瘤多肽的分子量(25,000-32,000)只有由全大肠菌素重组的抗EB病毒所致肿瘤多肽分子量(70,000)的40％，加之大肠菌素离子通道结构域本身无抗原性，因此该小型化抗肿瘤多肽的免疫原性将比全大肠菌素重组的抗肿瘤多肽的免疫原性大大降低。
本发明所述方法可得到理想纯度的抗肿瘤多肽(大于95％)并最大程度的保存了它的生物活性，而一般CM柱分离纯化的抗肿瘤多肽纯度较低(约80-90％)。
附图说明
图1是含有引导多肽基因SEQ ID NO.3和大肠菌素Ia离子通道结构域基因SEQ IDNO.1重组质粒pCHCEBCH1的结构示意图。
图2是含有引导多肽基因SEQ ID NO.5和大肠菌素Ia离子通道结构域基因SEQ IDNO.1重组质粒pCHCEBCH2的结构示意图。
图3是含有引导多肽基因SEQ ID NO.7和大肠菌素Ia离子通道结构域基因SEQ IDNO.1重组质粒pCHCEBCH3的结构示意图。
图4是含有引导多肽基因SEQ ID NO.9和大肠菌素Ia离子通道结构域基因SEQ IDNO.1重组质粒pCHCEBCH4的结构示意图。
图5是含有引导多肽基因SEQ ID NO.11和大肠菌素Ia离子通道结构域基因SEQ IDNO.1重组质粒pCHCEBCH5的结构示意图。
图6是含有引导多肽基因SEQ ID NO.13和大肠菌素Ia离子通道结构域基因SEQ IDNO.1重组质粒pCHCEBCH6的结构示意图。
图7是含有引导多肽基因SEQ ID NO.3和大肠菌素Ia离子通道结构域基因SEQ IDNO.1重组质粒pCHCEBCH7的结构示意图。
图8是含有引导多肽基因SEQ ID NO.3和大肠菌素A离子通道结构域基因SEQ IDNO.2的重组质粒pCHCEBCH8的结构示意图。
图9为使用多重荧光染料观察本发明所述小型化抗EB病毒肿瘤多肽对体外培养恶性肿瘤细胞(EB病毒阳性)、恶性肿瘤细胞(EB病毒阴性)和正常人体细胞处理72小时后的杀伤效应图，图中各组结果分别为对照组，抗肿瘤多肽1处理组至抗肿瘤多肽8处理组(分别由pCHCEBCH1质粒-pCHCEBCH8质粒产生)，各实验组的药物用量均为200μg/ml培养液。A：Raji细胞(ATCC CCL-86)，EB病毒阳性的人Burkitt’s淋巴肉瘤细胞；B：ATCC CRL-2230，46岁男性爱滋病人(AIDS)恶性淋巴肉瘤细胞，EB病毒和Kaposi肉瘤病毒(HHV8)均阳性；C：ATCC CRL-1648，EB病毒阴性的人Burkitt’s淋巴肉瘤细胞；D：ECV-304，EB病毒阴性的人静脉内皮细胞。E对照组，F抗肿瘤多肽1处理组，G抗肿瘤多肽2处理组，H抗肿瘤多肽3处理组，I抗肿瘤多肽4处理组，J抗肿瘤多肽5处理组，K抗肿瘤多肽6处理组，L抗肿瘤多肽7处理组，M抗肿瘤多肽8处理组。
图10为本发明所述小型化抗EB病毒肿瘤多肽对裸鼠体内由EB病毒所致人恶性淋巴瘤细胞长出的实体肿瘤的杀伤效应图，图中各组结果分别为对照组，抗肿瘤多肽1组(pCHCEBCH1质粒)和环磷酰胺组，给药途径为每日腹腔注射，各实验组的药物用量：抗肿瘤多肽1组为500μg/鼠/日，环磷酰胺组为100μg/鼠/日。A对照组，给药后第20日，处死鼠后，切开暴露见肿瘤持续长大；B抗肿瘤多肽1组，给药后第20日，处死鼠后，切开暴露无肉眼可见肿瘤团块；C环磷酰胺组，给药后第20日，切开暴露见肿瘤团块，鼠已因环磷酰胺毒性反应死亡。
D～F为各组鼠药物处理20日后取肿瘤标本的光镜观察图，分别为：D对照组肿瘤标本，E抗肿瘤多肽1组肿瘤标本，F环磷酰胺组肿瘤标本，HE染色，100x。
图11为经本发明所述小型化抗EB病毒肿瘤多肽处理20日后的鼠肝、肾、脾的组织切片图，A肝组织切片，B肾组织切片，C脾组织切片，HE染色，100x。
具体实施方式
实施例1 表达抗肿瘤多肽的质粒的构建和重组小型化抗EB病毒肿瘤多肽的制备
原始质粒为装载了大肠菌素Ia离子通道结构域和Immunity蛋白基因的pET-15b商用质粒(质粒大小6.3kb，购自Novagen公司，上述基因由本实验室装载)，经双链寡聚核苷酸点突变技术(QuickChangeTM Kit，Strategene公司)将编码引导多肽的基因(序列表中SEQID NO.3，5，7，9，11和13所述核苷酸序列)插入到大肠菌素Ia通道结构域基因的I626位点后，制备出了抗肿瘤多肽的六种重组质粒pCHCEBCH1至pCHCEBCH6(如图1～6所示)。重组质粒转染入E.coli BL21(DE3)ply S工程菌里制备多肽，获得六种小型化抗EB病毒肿瘤多肽，其氨基酸序列如序列表中SEQ ID NO.16、SEQ ID NO.18、SEQ IDNO.20、SEQ ID NO.22、SEQ ID NO.24、SEQ ID NO.26所述。其中，SEQ ID NO.16所述的抗肿瘤多肽由重组质粒pCHCEBCH1表达(在继后的实施例中称为“重组抗肿瘤多肽1”)，其分子量为30,000；SEQ ID NO.18所述的抗肿瘤多肽由重组质粒pCHCEBCH2表达(在继后的实施例中称为“重组抗肿瘤多肽2”)，其分子量为30,000；SEQ ID NO.20所述的抗肿瘤多肽由重组质粒pCHCEBCH3表达(在继后的实施例中称为“重组抗肿瘤多肽3”)，其分子量为32,000；SEQ ID NO.22所述的抗肿瘤多肽由重组质粒pCHCEBCH4表达(在继后的实施例中称为“重组抗肿瘤多肽4”)，其分子量为30,000；SEQ ID NO.24所述的抗肿瘤多肽由重组质粒pCHCEBCH5表达(在继后的实施例中称为“重组抗肿瘤多肽5”)，其分子量为30,000；SEQ ID NO.26所述的抗肿瘤多肽由重组质粒pCHCEBCH6表达(在继后的实施例中称为“重组抗肿瘤多肽6”)，其分子量为25,000。
突变程序按Strategene QuickChange Site-Directed Mutagenesis Kit(catalog#200518)药箱手册进行：
1、准备点突变反应物
5ul 10x buffer
2ul(10ng)野生型大肠菌素Ia质粒
1ul(125ng)设计的5’-3’寡聚核苷酸引物
1ul(125ng)设计的3’-5’寡聚核苷酸引物
1ul dNTP
双蒸水50ul
1ul pfu
(除质粒，引物和双蒸水外，均为药箱所备试剂)
2、进行PCR扩增，扩增条件：变性95℃，35秒，退火53℃，70秒，延伸68℃，17分共20个循环；
3、加入Dpn1内切酶1ul消化母体DNA链后(37℃，1小时)，取1ul反应物与HMS 174感受态细胞50ul冰孵30分钟，行热冲击42℃，45秒，再置入冰中2分钟；
4、加入NZY培基0.5ml后220rpm，37℃摇菌1小时后，取50-100ul反应物铺板(LB培基加1％琼脂加50ug/ml氨苄青霉素，37℃过夜)；
5、18小时后挑菌，循Qiagene，Gibco等公司的各种商用提取质粒药箱提取质粒均可，测序确定突变成功；
6、将质粒50ng与BL21(DE3)ply S感受态细胞50ul冰孵30分，42℃，90秒热冲击，取50-100ul反应物加入LB培基0.5ml，220rpm，37℃摇菌1小时后铺板(LB培基加1％琼脂加50ug/ml氨苄青霉素)37℃孵育，18小时后挑取菌落；
7、大量增菌，8-16升FB培基，250rpm，37℃，6-8小时；离心沉淀菌体，4℃，6000g，20分钟，取4℃，20mM sodium phosphate，0.5M NaCl，5mM imidazole，2mM EDTA，2mMDTT，pH7.4)50-80ml悬浮菌体，加入0.2M PMSF 250微升后行超声破碎(4℃，400W，2分钟)，高速离心沉淀破碎菌体(4℃，75000g，1.5小时)，取上清加入硫酸链霉素500万单位沉淀DNA，高速离心后(4℃，30000g，10分钟)取上清装入分子量15,000的透析袋于4℃，20mM sodium phosphate缓冲液4升透析过夜后，高速离心后(4℃，30000g，10分钟)将上清上样于His-tag柱(His Trap，Amersham Biosciences)，经20mM sodium phosphate，0.5Mimidazole，pH7.4，4℃线性梯度洗脱后即可得到重组抗肿瘤多肽，经10mM sodiumphosphate，0.2M NaCl，2mM EDTA，pH7.4透析后备用。
下面列出为制备pCHCEBCH1质粒的引导多肽基因所设计的具体双链寡聚核苷酸序列：
pCHCEBCH1
1、5’-3’
gcg aat aag ttc tgg ggt att TCC TTC GGTATG CAT TGG GTG CGT CAG taa ata aaa
tat aag aca ggc
3’-5’
gcc tgt ctt ata ttt tat tta CTG ACG CAC CCA ATG CAT ACC GAA GGA aat acc cca gaa ctt att
cgc
2、5’-3’
ggt atg cat tgg gtg cgt cag GCC CCC GAG AAA GGT CTG GAG TGG GTG GCC taa ata aaa
tat aag aca ggc
3’-5’
gcc tgt ctt ata ttt tat tta GGC CAC CCA CTC CAG ACC TTT CTC GGG GGC ctg acg cac cca
atg cat acc
3、5’-3’
aaa ggt ctg gag tgg gtg gcc GGT CAG GGT TAC TCC TAC CCC TAC ACC taa ata aaa tat aag
aca ggc
3’-5’
gcc tgt ctt ata ttt tat tta GGT GTA GGG GTA GGA GTA ACC CTG ACC ggc cac cca ctc cag
acc ttt
pCHCEBCH2～pCHCEBCH6质粒的引导多肽基因，其双链寡聚核苷酸序列的设计方法同上。
实施例2 表达抗肿瘤多肽的质粒的构建和重组小型化抗EB病毒肿瘤多肽的制备
原始质粒为装载了大肠菌素A离子通道结构域和Immunity蛋白基因的pET-15b商用质粒(质粒大小6.3kb，购自Novagen公司，上述基因由本实验室装载)，经双链寡聚核苷酸点突变技术(QuickChangeTM Kit，Strategene公司)将编码引导多肽的基因(序列表中SEQID NO.3所述核苷酸序列)插入到大肠菌素A离子通道结构域基因的H592位点后，制备出了抗肿瘤多肽的一种重组质粒pCHCEBCH8(如图8所示)。重组质粒转染入E.coli BL21(DE3)ply S工程菌里制备多肽，获得序列表中SEQ ID NO 30所述的小型化抗EB病毒肿瘤多肽(在继后的实施例中称为“重组抗肿瘤多肽8”)，其分子量为30,000。
突变程序按Strategene QuickChange Site-Directed Mutagenesis Kit(catalog#200518)药箱手册进行：
1、准备点突变反应物
5ul 10x buffer
2ul(10ng)野生型大肠菌素Ia质粒
1ul(125ng)设计的5’-3’寡聚核苷酸引物
1ul(125ng)设计的3’-5’寡聚核苷酸引物
1ul dNTP
双蒸水50ul
1ul pfu
(除质粒，引物和双蒸水外，均为药箱所备试剂)
2、进行PCR扩增，扩增条件：变性95℃，35秒，退火53℃，70秒，延伸68℃，17分共20个循环；
3、加入Dpn1内切酶1ul消化母体DNA链后(37℃，1小时)，取1ul反应物与HMS 174感受态细胞50ul冰孵30分钟，行热冲击42℃，45秒，再置入冰中2分钟；
4、加入NZY培基0.5ml后220rpm，37℃摇菌1小时后，取50-100ul反应物铺板(LB培基加1％琼脂加50ug/ml氨苄青霉素，37℃过夜)；
5、18小时后挑菌，循Qiagene，Gibco等公司的各种商用提取质粒药箱提取质粒均可，测序确定突变成功；
6、将质粒50ng与BL21(DE3)plyS感受态细胞50ul冰孵30分，42℃，90秒热冲击，取50-100ul反应物加入LB培基0.5ml，220rpm，37℃摇菌1小时后铺板(LB培基加1％琼脂加50ug/ml氨苄青霉素)37℃孵育，18小时后挑取菌落；
7、大量增菌，8-16升FB培基，250rpm，37℃，6-8小时；离心沉淀菌体，4℃，6000g，20分钟，取4℃，20mM sodium phosphate，0.5M NaCl，5mM imidazole，2mM EDTA，2mMDTT，pH7.4)50-80ml悬浮菌体，加入0.2M PMSF 250微升后行超声破碎(4℃，400W，2分钟)，高速离心沉淀破碎菌体(4℃，75000g，1.5小时)，取上清加入硫酸链霉素500万单位沉淀DNA，高速离心后(4℃，30000g，10分钟)取上清装入分子量15,000的透析袋于4℃，20mM sodium phosphate缓冲液4升透析过夜后，高速离心后(4℃，30000g，10分钟)将上清上样于His-tag柱(His Trap，Amersham Biosciences)，经20mM sodium phosphate，0.5Mimidazole，pH7.4，4℃线性梯度洗脱后即可得到重组抗肿瘤多肽，经10mM sodiumphosphate，0.2M NaCl，2mM EDTA，pH7.4透析后备用。
制备pCHCEBCH8质粒的引导多肽基因所需的双链寡聚核苷酸序列设计方法同实施例1。
实施例3 表达抗肿瘤多肽的质粒的构建和重组小型化抗EB病毒肿瘤多肽的制备
原始质粒为装载了大肠菌素Ia离子通道结构域和Immunity蛋白基因的pET-15b商用质粒(质粒大小6.3kb，购自Novagen公司，上述基因由本实验室装载)，，经双链寡聚核苷酸点突变技术(QuickChangeTM Kit，Strategene公司)将编码引导多肽的基因(序列表中SEQ ID NO.3所述核苷酸序列)插入到大肠菌素Ia离子通道结构域基因的D451位点前，制备出了抗肿瘤多肽的一种重组质粒pCHCEBCH7(如图7所示)。重组质粒转染入E.coliBL21(DE3)ply S工程菌里制备多肽，获得序列表中SEQ ID NO 28所述的小型化抗EB病毒肿瘤多肽(在继后的实施例中称为“重组抗肿瘤多肽7”)，其分子量为30,000。
突变程序按Strategene QuickChange Site-Directed Mutagenesis Kit(catalog#200518)药箱手册进行：
1、准备点突变反应物
5ul 10x buffer
2ul(10ng)野生型大肠菌素Ia质粒
1ul(125ng)设计的5’-3’寡聚核苷酸引物
1ul(125ng)设计的3’-5’寡聚核苷酸引物
1ul dNTP
双蒸水50ul
1ul pfu
(除质粒，引物和双蒸水外，均为药箱所备试剂)
2、进行PCR扩增，扩增条件：变性95℃，35秒，退火53℃，70秒，延伸68℃，17分共20个循环；
3、加入Dpn1内切酶1ul消化母体DNA链后(37℃，1小时)，取1ul反应物与HMS 174感受态细胞50ul冰孵30分钟，行热冲击42℃，45秒，再置入冰中2分钟；
4、加入NZY培基0.5ml后220rpm，37℃摇菌1小时后，取50-100ul反应物铺板(LB培基加1％琼脂加50ug/ml氨苄青霉素，37℃过夜)；
5、18小时后挑菌，循Qiagene，Gibco等公司的各种商用提取质粒药箱提取质粒均可，测序确定突变成功；
6、将质粒50ng与BL21(DE3)plyS感受态细胞50ul冰孵30分，42℃，90秒热冲击，取50-100ul反应物加入LB培基0.5ml，220rpm，37℃摇菌1小时后铺板(LB培基加1％琼脂加50ug/ml氨苄青霉素)37℃孵育，18小时后挑取菌落；
7、大量增菌，8-16升FB培基，250rpm，37℃，6-8小时；离心沉淀菌体，4℃，6000g，20分钟，取4℃，20mM sodium phosphate，0.5M NaCl，5mM imidazole，2mM EDTA，2mMDTT，pH7.4)50-80ml悬浮菌体，加入0.2M PMSF 250微升后行超声破碎(4℃，400W，2分钟)，高速离心沉淀破碎菌体(4℃，75000g，1.5小时)，取上清加入硫酸链霉素500万单位沉淀DNA，高速离心后(4℃，30000g，10分钟)取上清装入分子量15,000的透析袋于4℃，20mM sodium phosphate缓冲液4升透析过夜后，高速离心后(4℃，30000g，10分钟)将上清上样于His-tag柱(HisTrap，Amersham Biosciences)，经20mM sodium phosphate，0.5Mimidazole，pH7.4，4℃线性梯度洗脱后即可得到重组抗肿瘤多肽，经10mM sodiumphosphate，0.2M NaCl，2mM EDTA，pH7.4透析后备用。
制备pCHCEBCH7质粒的引导多肽基因所需的双链寡聚核苷酸序列设计方法同实施例1。
实施例4：重组小型化抗EB病毒肿瘤多肽对EB病毒所致肿瘤细胞及正常细胞体外杀伤作用的多重荧光染色观察
EB病毒阳性及阴性细胞株：为美国ATCC标准细胞株。
细胞培养：取出0.1ml复苏培养的Raji细胞悬浮液，缓缓加入含3ml 1640液体培养基(加10％血清)的培养皿中(稀释比例为1∶30)，混合均匀，放入37℃ CO2培养箱中培养。实验共使用四株细胞，EB病毒阳性细胞株：ATCC CCL-86(Raji细胞，人Burkitt’s恶性淋巴肉瘤细胞)；ATCC CRL-2230，46岁男性爱滋病人(AIDS)恶性淋巴肉瘤细胞株，EB病毒和Kaposi肉瘤病毒(HHV8)均阳性；EB病毒阴性细胞株：ATCC CRL-1648(CA-46，细胞分离自美国型Burkitt’s恶性淋巴肉瘤病人的腹水)；ECV-304人脐静脉内皮细胞(该株细胞源自中国协和医科大学细胞中心)。每株受试细胞分为九个实验组，第一组为加入重组抗肿瘤多肽空白保存液(10mMPB+0.2M NaCI磷酸盐缓冲液(pH7.4))。第二组为加入200μg/ml的重组抗肿瘤多肽1(质粒为pCHCEBCH1)，第三组为加入200μg/ml的重组抗肿瘤多肽2(质粒为pCHCEBCH2)，第四组为加入200μg/ml的重组抗肿瘤多肽3(质粒为pCHCEBCH3)，第五组为加入200μg/ml的重组抗肿瘤多肽4(质粒为pCHCEBCH4)，第六组为加入200μg/ml的重组抗肿瘤多肽5(质粒为pCHCEBCH5)，第七组为加入200μg/ml的重组抗肿瘤多肽6(质粒为pCHCEBCH6)，第八组为加入200μg/ml的重组抗肿瘤多肽7(质粒为pCHCEBCH7)，第九组为加入200μg/ml的重组抗肿瘤多肽8(质粒为pCHCEBCH8)，以上各组保存液均为10mM PB+0.2M NaCI磷酸盐缓冲pH7.4。
细胞在培养24小时后，分别加入上述各组处理物于培养皿中，在加入处理物后的第72小时分别加入50uMol FITC 20ul及50uMol Rodamin-123 20ul两种荧光染料。10分钟后在Olympus IX-71荧光显微镜下观察。EB病毒阴性的各肿瘤细胞株和人正常细胞株被重组抗肿瘤多肽处理后均生长良好，胞体(染为绿色)，胞核(染为淡绿色)及线粒体(染为红色)结构清晰，无细胞肿胀。而EB病毒阳性的各肿瘤细胞株被重组抗肿瘤多肽处理后，绝大多数细胞出现线粒体及胞核结构消失，明显肿胀和坏死，其中以重组抗肿瘤多肽1杀伤效果最为显著，细胞几乎全部死亡。其余各重组抗肿瘤多肽都有一定的杀伤效果，但均不如重组抗肿瘤多肽1有效。实验结果见图9。
EB病毒阴性的肿瘤细胞和正常细胞株生长良好表明本发明所述的重组抗肿瘤多肽并不攻击细胞膜上不带有EB病毒表面抗原的细胞。这提示本发明所述重组抗肿瘤多肽具有理想的靶向性和安全性。
实施例5：重组小型化抗EB病毒肿瘤多肽对EB病毒所致人Burkitt’s恶性淋巴肉瘤细胞种植到裸鼠体内生长出的实体肿瘤的杀伤作用
BALB/C裸体小鼠由四川大学华西动物中心提供，裸鼠喂养按裸鼠饲养要求，水、垫草和饲料均经高温或紫外线灭菌。在相对无菌条件下饲养一周，无异常后进行接种实验。
收集指数生长期的Raji细胞悬液于50毫升离心管中，4℃离心，弃上清后，用1640液体培养基(加小牛血清)重悬细胞，使之达到1.0×107/ml个细胞。在裸鼠右腋处皮下注射Raji细胞悬液0.1ml。
注射Raji细胞悬液后3-4日肿瘤即长到约2×2mm，将荷瘤裸鼠随机分为(A组)重组抗肿瘤多肽空白保存液(10mM PBS+0.2M NaCI磷酸盐缓冲液(pH7.4))为对照组，(B组)重组抗肿瘤多肽1(质粒为pCHCEBCH1)治疗组，500μg/鼠(以25克重计算)/日，(C组)环磷酰胺组，按标准教科书(Cancer，Principles & Practice of Oncology，Editor，V.T.DeVita，Jr.，S.Hellman and S.A.Rosenberg，Lippincott Williams & Wilkins Publisher，2001，6th Edition，p2247-2249，Burkitt’s Lymphoma Treatment)选用环磷酰胺为现用抗肿瘤药物对照组，环磷酰胺100μg/鼠/日(按全国高等医药院校教材“药理学”，第5版，金有豫主编，人民卫生出版社，2002年，“抗恶性肿瘤药”章401页，人体治疗4mg/kμg/日标准剂量换算)，间日给药，同时每日给地塞米松100μg/鼠/日以缓解环磷酰胺毒性；每组10只荷瘤裸鼠。每天观察裸鼠活动情况，并作记录，隔天精确测量肿瘤大小并照相。
给药方式为腹腔注射，每天注射1次，每次0.5ml，连续给药20天。
结果显示：重组抗肿瘤多肽组鼠肿瘤生长明显受到抑制，其中7只裸鼠的瘤块消失，其余3只的瘤块只有对照组和环磷酰胺组鼠瘤块的1/10大小，重组抗肿瘤多肽组鼠所有瘤块重量仅为对照组鼠所有瘤块重量的5-10％左右，所有鼠体重均增加。8只环磷酰胺组鼠在14日实验期中死亡，死亡及未死亡鼠体重均下降，皮下出血，环磷酰胺组鼠所有瘤块重量约为对照组鼠所有瘤块重量的30-50％左右。
重组抗肿瘤多肽在裸鼠体内远比环磷酰胺有效地抑制了Raji细胞所致的实体瘤块生长。却并未表现出环磷酰胺样致死性毒性反应。更重要的是，腹腔给药方式证实重组抗肿瘤多肽是经血液循环到达肿瘤部位来杀灭肿瘤细胞的。
瘤体病理组织学观察：实施例5实验到期后处死动物，取出瘤体于10％福尔马林中固定，石蜡切片，HE染色常规光镜观察。
镜下观对照组鼠的实体肿瘤增殖旺盛；环磷酰胺组鼠的实体肿瘤部分出现坏死，提示经环磷酰胺20日处理后，虽然肉眼观实体肿瘤尺寸未见明显减小，但部分肿瘤细胞已被杀伤；抗肿瘤多肽组鼠标本见缩小的肿瘤细胞团中几乎均为坏死的肿瘤细胞，周边可见淋巴细胞浸润。病理组织学结果提示抗肿瘤多肽几乎杀灭了实体肿瘤中的所有肿瘤细胞，而环磷酰胺对实体肿瘤中的肿瘤细胞表现出的是部分杀灭效应；在20日处理期限中，抗肿瘤多肽的杀灭效果比环磷酰胺的杀灭效果出现得早而且彻底，见附图10。
抗肿瘤多肽的分子量(MW 25,000-32,000)是环磷酰胺分子量(MW 105)的250-320倍，抗肿瘤多肽给药量是环磷酰胺给药量的5倍，因此，若按相同药物分子数量进行比较，在本实施例中本发明的抗肿瘤多肽对所试肿瘤的疗效至少是环磷酰胺对所试肿瘤疗效的50-64倍。
实施例6：体内实体肿瘤消除试验中抗肿瘤多肽对受试鼠内脏毒性的病理观察
实施例5中的受试鼠肝、肾、脾的组织切片显示，经20日抗肿瘤多肽处理后，受试鼠内脏未出现任何形态学异常，见图11。这提示本发明所述小型化抗EB病毒肿瘤多肽具有极好的安全性。
序列表
<110>四川大学
<120>小型化抗EB病毒肿瘤多肽及其应用与制备方法
<160>30
<170>PatentIn Version 3.2
<210>1
<211>528
<212>DNA
<213>Escherichia coli
<220>
<221>misc_feature
<222>(1).....(528)
<223>大肠菌素Ia离子通道结构域基因
<400>1
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gctgagcagt tagccagaga gatggccggg caggctaaag ggaagaaaat acgtaatgtt 120
gaagaggcat taaaaacgta tgaaaagtac cgggctgaca ttaacaaaaa aattaatgca 180
aaagatcgtg cagcgattgc cgcagccctt gagtctgtga agctgtctga tatatcgtct 240
aatctgaaca gattcagtcg gggactggga tatgcaggaa aatttacaag tcttgctgac 300
tggatcactg agtttggtaa ggctgtccgg acagagaact ggcgtcctct ttttgttaaa 360
acagaaacca tcatagcagg caatgccgca acggctcttg tggcactggt cttcagtatt 420
cttaccggaa gcgctttagg cattatcggg tatggtttac tgatggctgt caccggtgcg 480
ctgattgatg aatcgcttgt ggaaaaagcg aataagttct ggggtatt 528
<210>2
<211>612
<212>DNA
<213>Escherichia coli
<220>
<221>misc_feature
<222>(1).....(612)
<223>大肠菌素A离子通道结构域基因
<400>2
gttgcggaaa aagccaaaga tgagcgggag ctgcttgaaa aaaccagtga actgattgct 60
ggtatgggag ataaaatcgg cgagcatctt ggagataaat ataaggcgat agcgaaagat 120
attgcggaca atattaaaaa ttttcagggg aagaccatcc gtagctttga tgatgcaatg 180
gcatcgctga ataaaatcac agccaaccca gccatgaaaa ttaataaggc ggacagagat 240
gctctggtta atgcctggaa acatgttgat gctcaggata tggcgaataa actgggtaat 300
ctcagcaagg cttttaaagt cgccgacgtg gtgatgaagg ttgagaaggt ccgggagaag 360
agcattgagg ggtatgaaac cgggaactgg gggccgctga tgctggaggt ggaatcctgg 420
gtgctcagtg gtatagcttc ctctgttgct ctggggattt tttccgctac attaggagca 480
tatgccttat ctcttggagt tcctgctatt gctgttggta tcgccggtat tctactcgca 540
gcagttgttg gtgcgttaat tgatgataag tttgcagatg ctttgaataa tgaaataatc 600
cgacctgcac at 612
<210>3
<211>84
<212>DNA
<213>人工序列
<220>
<221>CDS
<222>(1).....(84)
<223>编码引导多肽核苷酸序列1
<400>3
tccttcggta tgcattgggt gcgtcaggcc cccgagaaag gtctggagtg ggtggccggt 60
cagggttact cctaccccta cacc 84
<210>4
<211>28
<212>PRT
<213>人工序列
<223>编码引导多肽氨基酸序列1
<400>4
Ser Phe Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu
1 5 10 15
Glu Trp Val Ala Gly Gln Gly Tyr Ser Tyr Pro Tyr Thr
20 25
<210>5
<211>90
<212>DNA
<213>人工序列
<220>
<221>CDS
<222>(1).....(90)
<223>编码引导多肽核苷酸序列2
<400>5
tccttcggta tgcattgggt gcgtcaggcc cccgagaaag gtctggagtg ggtggcctgg 60
ggtaattacc cccattacgc catggattac 90
<210>6
<211>30
<212>PRT
<213>人工序列
<223>编码引导多肽氨基酸序列2
<400>6
Ser Phe Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu
1 5 10 15
Glu Trp Val Ala Trp Gly Asn Tyr Pro His Tyr Ala Met Asp Tyr
20 25 30
<210>7
<211>174
<212>DNA
<213>人工序列
<220>
<221>CDS
<222>(1).....(174)
<223>编码引导多肽核苷酸序列3
<400>7
tccttcggta tgcattgggt gcgtcaggcc cccgagaaag gtctggagtg ggtggcctac 60
atatcctccg gttcctccac cctgcattac gccgataccg tgaaaggttg gtaccagcag 120
aaacccgagc agtcccccaa gctgctgatt tatggtgcct ccaatcgtta tacc 174
<210>8
<211>58
<212>PRT
<213>人工序列
<223>编码引导多肽氨基酸序列3
<400>8
Ser Phe Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu
1 5 10 15
Glu Trp Val Ala Tyr Ile Ser Ser Gly Ser Ser Thr Leu His Tyr
20 25 30
Ala Asp Thr Val Lys Gly Trp Tyr Gln Gln Lys Pro Glu Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Gly Ala Ser Asn Arg Tyr Thr
50 55
<210>9
<211>93
<212>DNA
<213>人工序列
<220>
<221>CDS
<222>(1).....(93)
<223>编码引导多肽核苷酸序列4
<400>9
aaagcctccg agaatgtggt gacctacgtg tcctggtacc agcagaaacc cgagcagtcc 60
cccaaactgc tgatatactc cttcggtatg cat 93
<210>10
<211>31
<212>PRT
<213>人工序列
<223>编码引导多肽氨基酸序列4
<400>10
Lys Ala Ser Glu Asn Val Val Thr Tyr Val Ser Trp Tyr Gln Gln
1 5 10 15
Lys Pro Glu Gln Ser Pro Lys Leu Leu Ile Tyr Ser Phe Gly Met
20 25 30
His
<210>11
<211>111
<212>DNA
<213>人工序列
<220>
<221>CDS
<222>(1).....(111)
<223>编码引导多肽核苷酸序列5
<400>11
aaagcctccg agaatgtggt gacctacgtg tcctggtacc agcagaaacc cgagcagtcc 60
cccaaactgc tgatatactg gggtaattac ccccattacg ccatggatat c 111
<210>12
<211>37
<212>PRT
<213>人工序列
<223>编码引导多肽氨基酸序列5
<400>12
Lys Ala Ser Glu Asn Val Val Thr Tyr Val Ser Trp Tyr Gln Gln
1 5 10 15
Lys Pro Glu Gln Ser Pro Lys Leu Leu Ile Tyr Trp Gly Asn Tyr
20 25 30
Pro His Tyr Ala Met Asp Tyr
35
<210>13
<211>15
<212>DNA
<213>人工序列
<220>
<221>CDS
<222>(1).....(15)
<223>编码引导多肽核苷酸序列6
<400>13
tccttcggta tgcat 15
<210>14
<211>5
<212>PRT
<213>人工序列
<223>编码引导多肽氨基酸序列6
<400>14
Ser Phe Gly Met His
1 5
<210>15
<211>612
<212>DNA
<213>人工序列
<220>
<221>CDS
<222>(1).....(612)
<223>编码多肽核苷酸序列1
<400>15
gacgcaatta atttcacaac agagttcctg aaatcagttt cagaaaaata tggtgcaaaa 60
gctgagcagt tagccagaga gatggccggg caggctaaag ggaagaaaat acgtaatgtt 120
gaagaggcat taaaaacgta tgaaaagtac cgggctgaca ttaacaaaaa aattaatgca 180
aaagatcgtg cagcgattgc cgcagccctt gagtctgtga agctgtctga tatatcgtct 240
aatctgaaca gattcagtcg gggactggga tatgcaggaa aatttacaag tcttgctgac 300
tggatcactg agtttggtaa ggctgtccgg acagagaact ggcgtcctct ttttgttaaa 360
acagaaacca tcatagcagg caatgccgca acggctcttg tggcactggt cttcagtatt 420
cttaccggaa gcgctttagg cattatcggg tatggtttac tgatggctgt caccggtgcg 480
ctgattgatg aatcgcttgt ggaaaaagcg aataagttct ggggtatttc cttcggtatg 540
cattgggtgc gtcaggcccc cgagaaaggt ctggagtggg tggccggtca gggttactcc 600
tacccctaca cc 612
<210>16
<211>204
<212>PRT
<213>人工序列
<223>编码多肽氨基酸序列1
<400>16
Asp Ala Ile Asn Phe Thr Thr Glu Phe Leu Lys Ser Val Ser Glu
1 5 10 15
Lys Tyr Gly Ala Lys Ala Glu Gln Leu Ala Arg Glu Met Ala Gly
20 25 30
Gln Ala Lys Gly Lys Lys Ile Arg Asn Val Glu Glu Ala Leu Lys
35 40 45
Thr Tyr Glu Lys Tyr Arg Ala Asp Ile Asn Lys Lys Ile Asn Ala
50 55 60
Lys Asp Arg Ala Ala Ile Ala Ala Ala Leu Glu Ser Val Lys Leu
65 70 75
Ser Asp Ile Ser Ser Asn Leu Asn Arg Phe Ser Arg Gly Leu Gly
80 85 90
Tyr Ala Gly Lys Phe Thr Ser Leu Ala Asp Trp Ile Thr Glu Phe
95 100 105
Gly Lys Ala Val Arg Thr Glu Asn Trp Arg Pro Leu Phe Val Lys
110 115 120
Thr Glu Thr Ile Ile Ala Gly Asn Ala Ala Thr Ala Lue Val Ala
125 130 135
Leu Val Phe Ser Ile Leu Thr Gly Ser Ala Leu Gly Ile Ile Gly
140 145 150
Tyr Gly Leu Leu Met Ala Val Thr Gly Ala Leu Ile Asp Glu Ser
155 160 165
Leu Val Glu Lys Ala Asn Lys Phe Trp Gly Ile Ser Phe Gly Met
170 175 180
His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val Ala
185 190 195
Gly Gln Gly Tyr Ser Tyr Pro Tyr Thr
200
<210>17
<211>618
<212>DNA
<213>人工序列
<220>
<221>CDS
<222>(1).....(618)
<223>编码多肽核苷酸序列2
<400>17
gacgcaatta atttcacaac agagttcctg aaatcagttt cagaaaaata tggtgcaaaa 60
gctgagcagt tagccagaga gatggccggg caggctaaag ggaagaaaat acgtaatgtt 120
gaagaggcat taaaaacgta tgaaaagtac cgggctgaca ttaacaaaaa aattaatgca 180
aaagatcgtg cagcgattgc cgcagccctt gagtctgtga agctgtctga tatatcgtct 240
aatctgaaca gattcagtcg gggactggga tatgcaggaa aatttacaag tcttgctgac 300
tggatcactg agtttggtaa ggctgtccgg acagagaact ggcgtcctct ttttgttaaa 360
acagaaacca tcatagcagg caatgccgca acggctcttg tggcactggt cttcagtatt 420
cttaccggaa gcgctttagg cattatcggg tatggtttac tgatggctgt caccggtgcg 480
ctgattgatg aatcgcttgt ggaaaaagcg aataagttct ggggtatttc cttcggtatg 540
cattgggtgc gtcaggcccc cgagaaaggt ctggagtggg tggcctgggg taattacccc 600
cattacgcca tggattac 618
<210>18
<211>206
<212>PRT
<213>人工序列
<223>编码多肽氨基酸序列2
<400>18
Asp Ala Ile Asn Phe Thr Thr Glu Phe Leu Lys Ser Val Ser Glu
1 5 10 15
Lys Tyr Gly Ala Lys Ala Glu Gln Leu Ala Arg Glu Met Ala Gly
20 25 30
Gln Ala Lys Gly Lys Lys Ile Arg Asn Val Glu Glu Ala Leu Lys
35 40 45
Thr Tyr Glu Lys Tyr Arg Ala Asp Ile Asn Lys Lys Ile Asn Ala
50 55 60
Lys Asp Arg Ala Ala Ile Ala Ala Ala Leu Glu Ser Val Lys Leu
65 70 75
Ser Asp Ile Ser Ser Asn Leu Asn Arg Phe Ser Arg Gly Leu Gly
80 85 90
Tyr Ala Gly Lys Phe Thr Ser Leu Ala Asp Trp Ile Thr Glu Phe
95 100 105
Gly Lys Ala Val Arg Thr Glu Asn Trp Arg Pro Leu Phe Val Lys
110 115 120
Thr Glu Thr Ile Ile Ala Gly Asn Ala Ala Thr Ala Lue Val Ala
125 130 135
Leu Val Phe Ser Ile Leu Thr Gly Ser Ala Leu Gly Ile Ile Gly
140 145 150
Tyr Gly Leu Leu Met Ala Val Thr Gly Ala Leu Ile Asp Glu Ser
155 160 165
Leu Val Glu Lys Ala Asn Lys Phe Trp Gly Ile Ser Phe Gly Met
170 175 180
His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val Ala
185 190 195
Trp Gly Asn Tyr Pro His Tyr Ala Met Asp Tyr
200 205
<210>19
<211>702
<212>DNA
<213>人工序列
<220>
<221>CDS
<222>(1).....(702)
<223>编码多肽核苷酸序列3
<400>19
gacgcaatta atttcacaac agagttcctg aaatcagttt cagaaaaata tggtgcaaaa 60
gctgagcagt tagccagaga gatggccggg caggctaaag ggaagaaaat acgtaatgtt 120
gaagaggcat taaaaacgta tgaaaagtac cgggctgaca ttaacaaaaa aattaatgca 180
aaagatcgtg cagcgattgc cgcagccctt gagtctgtga agctgtctga tatatcgtct 240
aatctgaaca gattcagtcg gggactggga tatgcaggaa aatttacaag tcttgctgac 300
tggatcactg agtttggtaa ggctgtccgg acagagaact ggcgtcctct ttttgttaaa 360
acagaaacca tcatagcagg caatgccgca acggctcttg tggcactggt cttcagtatt 420
cttaccggaa gcgctttagg cattatcggg tatggtttac tgatggctgt caccggtgcg 480
ctgattgatg aatcgcttgt ggaaaaagcg aataagttct ggggtatttc cttcggtatg 540
cattgggtgc gtcaggcccc cgagaaaggt ctggagtggg tggcctacat atcctccggt 600
tcctccaccc tgcattacgc cgataccgtg aaaggttggt accagcagaa acccgagcag 660
tcccccaagc tgctgattta tggtgcctcc aatcgttata cc 702
<210>20
<211>234
<212>PRT
<213>人工序列
<223>编码多肽氨基酸序列3
<400>20
Asp Ala Ile Asn Phe Thr Thr Glu Phe Leu Lys Ser Val Ser Glu
1 5 10 15
Lys Tyr Gly Ala Lys Ala Glu Gln Leu Ala Arg Glu Met Ala Gly
20 25 30
Gln Ala Lys Gly Lys Lys Ile Arg Asn Val Glu Glu Ala Leu Lys
35 40 45
Thr Tyr Glu Lys Tyr Arg Ala Asp Ile Asn Lys Lys Ile Asn Ala
50 55 60
Lys Asp Arg Ala Ala Ile Ala Ala Ala Leu Glu Ser Val Lys Leu
65 70 75
Ser Asp Ile Ser Ser Asn Leu Asn Arg Phe Ser Arg Gly Leu Gly
80 85 90
Tyr Ala Gly Lys Phe Thr Ser Leu Ala Asp Trp Ile Thr Glu Phe
95 100 105
Gly Lys Ala Val Arg Thr Glu Asn Trp Arg Pro Leu Phe Val Lys
110 115 120
Thr Glu Thr Ile Ile Ala Gly Asn Ala Ala Thr Ala Lue Val Ala
125 130 135
Leu Val Phe Ser Ile Leu Thr Gly Ser Ala Leu Gly Ile Ile Gly
140 145 150
Tyr Gly Leu Leu Met Ala Val Thr Gly Ala Leu Ile Asp Glu Ser
155 160 165
Leu Val Glu Lys Ala Asn Lys Phe Trp Gly Ile Ser Phe Gly Met
170 175 180
His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val Ala
185 190 195
Tyr Ile Ser Ser Gly Ser Ser Thr Leu His Tyr Ala Asp Thr Val
200 205 210
Lys Gly Trp Tyr Gln Gln Lys Pro Glu Gln Ser Pro Lys Leu Leu
215 220 225
Ile Tyr Gly Ala Ser Asn Arg Tyr Thr
230
<210>21
<211>621
<212>DNA
<213>人工序列
<220>
<221>CDS
<222>(1).....(621)
<223>编码多肽核苷酸序列4
<400>21
gacgcaatta atttcacaac agagttcctg aaatcagttt cagaaaaata tggtgcaaaa 60
gctgagcagt tagccagaga gatggccggg caggctaaag ggaagaaaat acgtaatgtt 120
gaagaggcat taaaaacgta tgaaaagtac cgggctgaca ttaacaaaaa aattaatgca 180
aaagatcgtg cagcgattgc cgcagccctt gagtctgtga agctgtctga tatatcgtct 240
aatctgaaca gattcagtcg gggactggga tatgcaggaa aatttacaag tcttgctgac 300
tggatcactg agtttggtaa ggctgtccgg acagagaact ggcgtcctct ttttgttaaa 360
acagaaacca tcatagcagg caatgccgca acggctcttg tggcactggt cttcagtatt 420
cttaccggaa gcgctttagg cattatcggg tatggtttac tgatggctgt caccggtgcg 480
ctgattgatg aatcgcttgt ggaaaaagcg aataagttct ggggtattaa agcctccgag 540
aatgtggtga cctacgtgtc ctggtaccag cagaaacccg agcagtcccc caaactgctg 600
atatactcct tcggtatgca t 621
<210>22
<211>207
<212>PRT
<213>人工序列
<223>编码多肽氨基酸序列4
<400>22
Asp Ala Ile Asn Phe Thr Thr Glu Phe Leu Lys Ser Val Ser Glu
1 5 10 15
Lys Tyr Gly Ala Lys Ala Glu Gln Leu Ala Arg Glu Met Ala Gly
20 25 30
Gln Ala Lys Gly Lys Lys Ile Arg Asn Val Glu Glu Ala Leu Lys
35 40 45
Thr Tyr Glu Lys Tyr Arg Ala Asp Ile Asn Lys Lys Ile Asn Ala
50 55 60
Lys Asp Arg Ala Ala Ile Ala Ala Ala Leu Glu Ser Val Lys Leu
65 70 75
Ser Asp Ile Ser Ser Asn Leu Asn Arg Phe Ser Arg Gly Leu Gly
80 85 90
Tyr Ala Gly Lys Phe Thr Ser Leu Ala Asp Trp Ile Thr Glu Phe
95 100 105
Gly Lys Ala Val Arg Thr Glu Asn Trp Arg Pro Leu Phe Val Lys
110 115 120
Thr Glu Thr Ile Ile Ala Gly Asn Ala Ala Thr Ala Lue Val Ala
125 130 135
Leu Val Phe Ser Ile Leu Thr Gly Ser Ala Leu Gly Ile Ile Gly
140 145 150
Tyr Gly Leu Leu Met Ala Val Thr Gly Ala Leu Ile Asp Glu Ser
155 160 165
Leu Val Glu Lys Ala Asn Lys Phe Trp Gly Ile Lys Ala Ser Glu
170 175 180
Asn Val Val Thr Tyr Val Ser Trp Tyr Gln Gln Lys Pro Glu Gln
185 190 195
Ser Pro Lys Leu Leu Ile Tyr Ser Phe Gly Met His
200 205
<210>23
<211>639
<212>DNA
<213>人工序列
<220>
<221>CDS
<222>(1).....(639)
<223>编码多肽核苷酸序列5
<400>23
gacgcaatta atttcacaac agagttcctg aaatcagttt cagaaaaata tggtgcaaaa 60
gctgagcagt tagccagaga gatggccggg caggctaaag ggaagaaaat acgtaatgtt 120
gaagaggcat taaaaacgta tgaaaagtac cgggctgaca ttaacaaaaa aattaatgca 180
aaagatcgtg cagcgattgc cgcagccctt gagtctgtga agctgtctga tatatcgtct 240
aatctgaaca gattcagtcg gggactggga tatgcaggaa aatttacaag tcttgctgac 300
tggatcactg agtttggtaa ggctgtccgg acagagaact ggcgtcctct ttttgttaaa 360
acagaaacca tcatagcagg caatgccgca acggctcttg tggcactggt cttcagtatt 420
cttaccggaa gcgctttagg cattatcggg tatggtttac tgatggctgt caccggtgcg 480
ctgattgatg aatcgcttgt ggaaaaagcg aataagttct ggggtattaa agcctccgag 540
aatgtggtga cctacgtgtc ctggtaccag cagaaacccg agcagtcccc caaactgctg 600
atatactggg gtaattaccc ccattacgcc atggattac 639
<210>24
<211>213
<212>PRT
<213>人工序列
<223>编码多肽氨基酸序列5
<400> 24
Asp Ala Ile Asn Phe Thr Thr Glu Phe Leu Lys Ser Val Ser Glu
1 5 10 15
Lys Tyr Gly Ala Lys Ala Glu Gln Leu Ala Arg Glu Met Ala Gly
20 25 30
Gln Ala Lys Gly Lys Lys Ile Arg Asn Val Glu Glu Ala Leu Lys
35 40 45
Thr Tyr Glu Lys Tyr Arg Ala Asp Ile Asn Lys Lys Ile Asn Ala
50 55 60
Lys Asp Arg Ala Ala Ile Ala Ala Ala Leu Glu Ser Val Lys Leu
65 70 75
Ser Asp Ile Ser Ser Asn Leu Asn Arg Phe Ser Arg Gly Leu Gly
80 85 90
Tyr Ala Gly Lys Phe Thr Ser Leu Ala Asp Trp Ile Thr Glu Phe
95 100 105
Gly Lys Ala Val Arg Thr Glu Asn Trp Arg Pro Leu Phe Val Lys
110 115 120
Thr Glu Thr Ile Ile Ala Gly Asn Ala Ala Thr Ala Lue Val Ala
125 130 135
Leu Val Phe Ser Ile Leu Thr Gly Ser Ala Leu Gly Ile Ile Gly
140 145 150
Tyr Gly Leu Leu Met Ala Val Thr Gly Ala Leu Ile Asp Glu Ser
155 160 165
Leu Val Glu Lys Ala Asn Lys Phe Trp Gly Ile Lys Ala Ser Glu
170 175 180
Asn Val Val Thr Tyr Val Ser Trp Tyr Gln Gln Lys Pro Glu Gln
185 190 195
Ser Pro Lys Leu Leu Ile Tyr Trp Gly Asn Tyr Pro His Tyr Ala
200 205 210
Met Asp Tyr
<210>25
<211>543
<212>DNA
<213>人工序列
<220>
<221>CDS
<222>(1).....(543)
<223>编码多肽核苷酸序列6
<400>25
gacgcaatta atttcacaac agagttcctg aaatcagttt cagaaaaata tggtgcaaaa 60
gctgagcagt tagccagaga gatggccggg caggctaaag ggaagaaaat acgtaatgtt 120
gaagaggcat taaaaacgta tgaaaagtac cgggctgaca ttaacaaaaa aattaatgca 180
aaagatcgtg cagcgattgc cgcagccctt gagtctgtga agctgtctga tatatcgtct 240
aatctgaaca gattcagtcg gggactggga tatgcaggaa aatttacaag tcttgctgac 300
tggatcactg agtttggtaa ggctgtccgg acagagaact ggcgtcctct ttttgttaaa 360
acagaaacca tcatagcagg caatgccgca acggctcttg tggcactggt cttcagtatt 420
cttaccggaa gcgctttagg cattatcggg tatggtttac tgatggctgt caccggtgcg 480
ctgattgatg aatcgcttgt ggaaaaagcg aataagttct ggggtattct ggggtatttc 540
cat 543
<210>26
<211>181
<212>PRT
<213>人工序列
<223>编码多肽氨基酸序列6
<400>26
Asp Ala Ile Asn Phe Thr Thr Glu Phe Leu Lys Ser Val Ser Glu
1 5 10 15
Lys Tyr Gly Ala Lys Ala Glu Gln Leu Ala Arg Glu Met Ala Gly
20 25 30
Gln Ala Lys Gly Lys Lys Ile Arg Asn Val Glu Glu Ala Leu Lys
35 40 45
Thr Tyr Glu Lys Tyr Arg Ala Asp Ile Asn Lys Lys Ile Asn Ala
50 55 60
Lys Asp Arg Ala Ala Ile Ala Ala Ala Leu Glu Ser Val Lys Leu
65 70 75
Ser Asp Ile Ser Ser Asn Leu Asn Arg Phe Ser Arg Gly Leu Gly
80 85 90
Tyr Ala Gly Lys Phe Thr Ser Leu Ala Asp Trp Ile Thr Glu Phe
95 100 105
Gly Lys Ala Val Arg Thr Glu Asn Trp Arg Pro Leu Phe Val Lys
110 115 120
Thr Glu Thr Ile Ile Ala Gly Asn Ala Ala Thr Ala Lue Val Ala
125 130 135
Leu Val Phe Ser Ile Leu Thr Gly Ser Ala Leu Gly Ile Ile Gly
140 145 150
Tyr Gly Leu Leu Met Ala Val Thr Gly Ala Leu Ile Asp Glu Ser
155 160 165
Leu Val Glu Lys Ala Asn Lys Phe Trp Gly Ile Ser Phe Gly Met
170 175 180
His
<210>27
<211>612
<212>DNA
<213>人工序列
<220>
<221>CDS
<222>(1).....(612)
<223>编码多肽核苷酸序列7
<400>27
tccttcggta tgcattgggt gcgtcaggcc cccgagaaag gtctggagtg ggtggccggt 60
cagggttact cctaccccta caccgacgca attaatttca caacagagtt cctgaaatca 120
gtttcagaaa aatatggtgc aaaagctgag cagttagcca gagagatggc cgggcaggct 180
aaagggaaga aaatacgtaa tgttgaagag gcattaaaaa cgtatgaaaa gtaccgggct 240
gacattaaca aaaaaattaa tgcaaaagat cgtgcagcga ttgccgcagc ccttgagtct 300
gtgaagctgt ctgatatatc gtctaatctg aacagattca gtcggggact gggatatgca 360
ggaaaattta caagtcttgc tgactggatc actgagtttg gtaaggctgt ccggacagag 420
aactggcgtc ctctttttgt taaaacagaa accatcatag caggcaatgc cgcaacggct 480
cttgtggcac tggtcttcag tattcttacc ggaagcgctt taggcattat cgggtatggt 540
ttactgatgg ctgtcaccgg tgcgctgatt gatgaatcgc ttgtggaaaa agcgaataag 600
ttctggggta tt 612
<210>28
<211>204
<212>PRT
<213>人工序列
<223>编码多肽氨基酸序列7
<400>28
Ser Phe Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu
1 5 10 15
Glu Trp Val Ala Gly Gln Gly Tyr Ser Tyr Pro Tyr Thr Asp Ala
20 25 30
Ile Asn Phe Thr Thr Glu Phe Leu Lys Ser Val Ser Glu Lys Tyr
35 40 45
Gly Ala Lys Ala Glu Gln Leu Ala Arg Glu Met Ala Gly Gln Ala
50 55 60
Lys Gly Lys Lys Ile Arg Asn Val Glu Glu Ala Leu Lys Thr Tyr
65 70 75
Glu Lys Tyr Arg Ala Asp Ile Asn Lys Lys Ile Asn Ala Lys Asp
80 85 90
Arg Ala Ala Ile Ala Ala Ala Leu Glu Ser Val Lys Leu Ser Asp
95 100 105
Ile Ser Ser Asn Leu Asn Arg Phe Ser Arg Gly Leu Gly Tyr Ala
110 115 120
Gly Lys Phe Thr Ser Leu Ala Asp Trp Ile Thr Glu Phe Gly Lys
125 130 135
Ala Val Arg Thr Glu Asn Trp Arg Pro Leu Phe Val Lys Thr Glu
140 145 150
Thr Ile Ile Ala Gly Asn Ala Ala Thr Ala Lue Val Ala Leu Val
155 160 165
Phe Ser Ile Leu Thr Gly Ser Ala Leu Gly Ile Ile Gly Tyr Gly
170 175 180
Leu Leu Met Ala Val Thr Gly Ala Leu Ile Asp Glu Ser Leu Val
185 190 195
Glu Lys Ala Asn Lys Phe Trp Gly Ile
200
<210>29
<211>696
<212>DNA
<213>人工序列
<220>
<221>CDS
<222>(1).....(696)
<223>编码多肽核苷酸序列8
<400>29
gttgcggaaa aagccaaaga tgagcgggag ctgcttgaaa aaaccagtga actgattgct 60
ggtatgggag ataaaatcgg cgagcatctt ggagataaat ataaggcgat agcgaaagat 120
attgcggaca atattaaaaa ttttcagggg aagaccatcc gtagctttga tgatgcaatg 180
gcatcgctga ataaaatcac agccaaccca gccatgaaaa ttaataaggc ggacagagat 240
gctctggtta atgcctggaa acatgttgat gctcaggata tggcgaataa actgggtaat 300
ctcagcaagg cttttaaagt cgccgacgtg gtgatgaagg ttgagaaggt ccgggagaag 360
agcattgagg ggtatgaaac cgggaactgg gggccgctga tgctggaggt ggaatcctgg 420
gtgctcagtg gtatagcttc ctctgttgct ctggggattt tttccgctac attaggagca 480
tatgccttat ctcttggagt tcctgctatt gctgttggta tcgccggtat tctactcgca 540
gcagttgttg gtgcgttaat tgatgataag tttgcagatg ctttgaataa tgaaataatc 600
cgacctgcac attccttcgg tatgcattgg gtgcgtcagg cccccgagaa aggtctggag 660
tgggtggccg gtcagggtta ctcctacccc tacacc 696
<210>30
<211>232
<212>PRT
<213>人工序列
<223>编码多肽氨基酸序列8
<400>30
Val Ala Glu Lys Ala Lys Asp Glu Arg Glu Leu Leu Glu Lys Thr
1 5 10 15
Ser Glu Leu Ile Ala Gly Met Gly Asp Lys Ile Gly Glu His Leu
20 25 30
Gly Asp Lys Tyr Lys Ala Ile Ala Lys Asp Ile Ala Asp Asn Ile
35 40 45
Lys Asn Phe Gln Gly Lys Thr Ile Arg Ser Phe Asp Asp Ala Met
50 55 60
Ala Ser Leu Asn Lys Ile Thr Ala Asn Pro Ala Met Lys Ile Asn
65 70 75
Lys Ala Asp Arg Asp Ala Leu Val Asn Ala Trp Lys His Val Asp
80 85 90
Ala Gln Asp Met Ala Asn Lys Leu Gly Asn Leu Ser Lys Ala Phe
95 100 105
Lys Val Ala Asp Val Val Met Lys Val Glu Lys Val Arg Glu Lys
110 115 120
Ser Ile Glu Gly Tyr Glu Thr Gly Asn Trp Gly Pro Leu Met Leu
125 130 135
Glu Val Glu Ser Trp Val Leu Ser Gly Ile Ala Ser Ser Val Ala
140 145 150
Leu Gly Ile Phe Ser Ala Thr Leu Gly Ala Tyr Ala Leu Ser Leu
155 160 165
Gly Val Pro Ala Ile Ala Val Gly Ile Ala Gly Ile Leu Leu Ala
170 175 180
Ala Val Val Gly Ala Leu Ile Asp Asp Lys Phe Ala Asp Ala Leu
185 190 195
Asn Asn Glu Ile Ile Arg Pro Ala His Ser Phe Gly Met His Trp
200 205 210
Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val Ala Gly Gln
215 220 225
Gly Tyr Ser Tyr Pro Tyr Thr
230
Claims (21)
1、一种编码小型化抗EB病毒肿瘤多肽的基因， 其特征在于其含有编码大肠菌素离子通道结构域的基因，以及编码以抗EB病毒包膜糖蛋白抗体的CDR区为蓝本而构建的引导多肽的基因。
2、根据权利要求1所述的小型化抗EB病毒肿瘤多肽的基因，其特征在于它具有序列表中SEQ ID NO.15所述的核苷酸序列。
3、根据权利要求1所述的小型化抗EB病毒肿瘤多肽的基因，其特征在于它具有序列表中SEQ ID NO.17所述的核苷酸序列。
4、根据权利要求1所述的小型化抗EB病毒肿瘤多肽的基因，其特征在于它具有序列表中SEQ ID NO.19所述的核苷酸序列。
5、根据权利要求1所述的小型化抗EB病毒肿瘤多肽的基因，其特征在于它具有序列表中SEQ ID NO.21所述的核苷酸序列。
6、根据权利要求1所述的小型化抗EB病毒肿瘤多肽的基因，其特征在于它具有序列表中SEQ ID NO.23所述的核苷酸序列。
7、根据权利要求1所述的小型化抗EB病毒肿瘤多肽的基因，其特征在于它具有序列表中SEQ ID NO.25所述的核苷酸序列。
8、根据权利要求1所述的小型化抗EB病毒肿瘤多肽的基因，其特征在于它具有序列表中SEQ ID NO.27所述的核苷酸序列。
9、根据权利要求1所述的小型化抗EB病毒肿瘤多肽的基因，其特征在于它具有序列表中SEQ ID NO.29所述的核苷酸序列。
10、一种小型化抗EB病毒肿瘤多肽的重组质粒，其特征在于它含有权利要求1所述的基因。
11、一种小型化抗EB病毒肿瘤多肽，其特征在于它由权利要求10所述的重组质粒表达而成，分子量为25,000～32,000。
12、根据权利要求11所述的小型化抗EB病毒肿瘤多肽，其特征在于它具有序列表中SEQ ID NO.16所述的氨基酸序列，其分子量为30,000。
13、根据权利要求11所述的小型化抗EB病毒肿瘤多肽，其特征在于它具有序列表中SEQ ID NO.18所述的氨基酸序列，其分子量为30,000。
14、根据权利要求11所述的小型化抗EB病毒肿瘤多肽，其特征在于它具有序列表中SEQ ID NO.20所述的氨基酸序列，其分子量为32,000。
15、根据权利要求11所述的小型化抗EB病毒肿瘤多肽，其特征在于它具有序列表中SEQ ID NO.22所述的氨基酸序列，其分子量为30,000。
16、根据权利要求11所述的小型化抗EB病毒肿瘤多肽，其特征在于它具有序列表中SEQ ID NO.24所述的氨基酸序列，其分子量为30,000。
17、根据权利要求11所述的小型化抗EB病毒肿瘤多肽，其特征在于它具有序列表中SEQ ID NO.26所述的氨基酸序列，其分子量为25,000。
18、根据权利要求11所述的小型化抗EB病毒肿瘤多肽，其特征在于它具有序列表中SEQ ID NO.28所述的氨基酸序列，其分子量为30,000。
19、根据权利要求11所述的小型化抗EB病毒肿瘤多肽，其特征在于它具有序列表中SEQ ID NO.30所述的氨基酸序列，其分子量为30,000。
20、小型化抗EB病毒肿瘤多肽在制备治疗或预防EB病毒所致肿瘤的药中的应用。
21、一种小型化抗EB病毒肿瘤多肽的制备方法，其特征在于包括以下步骤：
将以抗EB病毒包膜糖蛋白抗体的CDR区为蓝本而构建的引导多肽的基因与载有编码大肠菌素离子通道结构域基因的His-tag质粒可操作地连接获得载有编码重组抗肿瘤多肽的基因，将获得的基因导入到表达系统中进行表达，经His-tag柱分离纯化而获得本发明的抗肿瘤多肽。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510020168XA CN1314806C (zh) | 2005-01-14 | 2005-01-14 | 小型化抗eb病毒肿瘤多肽及其应用与制备方法 |
| US11/333,487 US20060193867A1 (en) | 2004-12-10 | 2006-01-17 | Antiviral bifunctional molecules, methods of construction and methods of treating virus-induced cancer therewith |
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| CNB200510020168XA CN1314806C (zh) | 2005-01-14 | 2005-01-14 | 小型化抗eb病毒肿瘤多肽及其应用与制备方法 |
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| CN1661012A true CN1661012A (zh) | 2005-08-31 |
| CN1314806C CN1314806C (zh) | 2007-05-09 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006103494A3 (en) * | 2004-12-10 | 2006-12-07 | West China Hospital Sichuan Univ | Antiviral bifunctional molecules, methods of construction and methods of treating virus-induced cancer therewith |
| WO2007083175A1 (en) * | 2006-01-17 | 2007-07-26 | West China Hospital, Sichuan University | Antiviral bifunctional molecules, methods of construction and methods of treating virus-induced cancer therewith |
| CN106532101A (zh) * | 2016-12-03 | 2017-03-22 | 合肥国轩高科动力能源有限公司 | 一种去除轧辊表面粘滞物料的溶液及其制备方法 |
| CN110172513A (zh) * | 2019-05-30 | 2019-08-27 | 浙江自贸区锐赛生物医药科技有限公司 | 突变型免疫多肽临床入组的筛选方法 |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2691539C (en) * | 2007-06-21 | 2014-08-26 | Angelica Therapeutics, Inc. | Modified toxins |
| US8470314B2 (en) * | 2008-02-29 | 2013-06-25 | Angelica Therapeutics, Inc. | Modified toxins |
| CN102101888B (zh) | 2009-12-17 | 2013-03-20 | 畿晋庆三联（北京）生物技术有限公司 | 一种新型抗eb病毒所致肿瘤多肽及其应用与制备方法 |
| US9200251B1 (en) | 2011-03-31 | 2015-12-01 | David Gordon Bermudes | Bacterial methionine analogue and methionine synthesis inhibitor anticancer, antiinfective and coronary heart disease protective microcins and methods of treatment therewith |
| JP2016519651A (ja) | 2013-03-15 | 2016-07-07 | アンジェリカ セラピューティックス，インク． | 改質された毒素 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL82627A0 (en) * | 1986-05-28 | 1987-11-30 | Univ Toronto | Bacteriocins and compositions thereof in anti-viral treatment |
| CN1396178A (zh) * | 2002-06-17 | 2003-02-12 | 成都阳辉生物科技有限责任公司 | 抗乙肝病毒等包膜病毒感染的工程多肽及其制备方法 |
| CN1482242A (zh) * | 2002-06-17 | 2004-03-17 | 成都阳辉生物科技有限责任公司 | 一种重组抗包膜病毒多肽及其制备方法 |
-
2005
- 2005-01-14 CN CNB200510020168XA patent/CN1314806C/zh not_active Expired - Fee Related
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2006
- 2006-01-17 US US11/333,487 patent/US20060193867A1/en not_active Abandoned
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006103494A3 (en) * | 2004-12-10 | 2006-12-07 | West China Hospital Sichuan Univ | Antiviral bifunctional molecules, methods of construction and methods of treating virus-induced cancer therewith |
| WO2007083175A1 (en) * | 2006-01-17 | 2007-07-26 | West China Hospital, Sichuan University | Antiviral bifunctional molecules, methods of construction and methods of treating virus-induced cancer therewith |
| CN106532101A (zh) * | 2016-12-03 | 2017-03-22 | 合肥国轩高科动力能源有限公司 | 一种去除轧辊表面粘滞物料的溶液及其制备方法 |
| CN110172513A (zh) * | 2019-05-30 | 2019-08-27 | 浙江自贸区锐赛生物医药科技有限公司 | 突变型免疫多肽临床入组的筛选方法 |
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| Publication number | Publication date |
|---|---|
| US20060193867A1 (en) | 2006-08-31 |
| CN1314806C (zh) | 2007-05-09 |
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