CN101801390B - 针对爱泼斯坦-巴尔病毒相关疾病的药剂 - Google Patents
针对爱泼斯坦-巴尔病毒相关疾病的药剂 Download PDFInfo
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Abstract
1-(2-氟-4-硫代-β-D-阿拉伯呋喃糖基)-5-甲基尿嘧啶发挥抗EB病毒活性，且作为EB病毒相关疾病的预防或治疗剂而有效。向TK缺损细胞中分别导入表达EB病毒-TK与人体TK的质粒，以产生分别导入了质粒的两种细胞。使用导入了各质粒的两种细胞，筛选出在导入了表达EB病毒-TK的质粒的细胞中显示细胞毒性，而在导入了人体TK的细胞中不显示毒性的药剂，由此可以筛选出特别发挥抗EB病毒活性的药剂。
Description
技术领域
本发明涉及一种抗爱泼斯坦-巴尔病毒(Epstein-Barr virus)剂、以及针对EB病毒相关疾病的药剂及该药剂的有效筛选法。
背景技术
虽然比率不高，但一般认为EB病毒会引起B淋巴瘤、鼻咽癌、胃癌等各种肿瘤。针对这样的肿瘤，在不适合进行手术的情况下的治疗法，会投予一般的抗癌剂，但这不一定是有效的治疗法。另外，报告有抗病毒剂更昔洛韦(ganciclovir)作为肿瘤治疗药的候选(非专利文献1)，但其效果较弱，尚不实用。
此外，实验室也尝试了使用源自与EB病毒相关的单纯疱疹病毒(herpes simplex virus)的胸苷磷酸化酶(thymidine phosphorylase)(胸苷激酶，thymidine kinase，TK)的基因治疗法，但还不能应用于患者。
另一方面，1-(2-氟-4-硫代-β-D-阿拉伯呋喃糖基)-5-甲基尿嘧啶作为对疱疹病毒等具有较弱的抗病毒活性的化合物而广为人知(非专利文献2、专利文献1以及专利文献2)，但完全不了解该化合物对于EB病毒的抗病毒活性、及对于由EB病毒所引起的肿瘤的效果。
非专利文献1：抗菌物和化学疗法期刊(Antimicrob.AgentsChemother)2001；45(7)：2082-91
非专利文献2：抗病毒药杂志(Antiviral Res.)1998；39(2)129-37
专利文献1：国际公开编号WO91/04982
专利文献2：日本专利特开平10-87687号公报
发明内容
因此，本发明的目的在于找出一种抗EB病毒剂、以及对于EB病毒相关疾病具有显着效果的药剂。
先前，尚未报告找出针对EB病毒相关疾病的药剂的有效筛选方法。因此，本发明者们首先确立有效的筛选法，并尝试了使用该筛选法来找出对于EB病毒相关疾病具有显着效果的药剂。其结果为，利用肿瘤细胞中所存在的源自EB病毒的TK，确立通过该TK而特异性磷酸化后对细胞显示出毒性的药剂的筛选法，并且使用该筛选法对各种化合物进行筛选，结果发现1-(2-氟-4-硫代-β-D-阿拉伯呋喃糖基)-5-甲基尿嘧啶显示出抗EB病毒活性以及对于EB病毒相关疾病的显着效果。
因此，本发明是基于所述见解而完成的，如以下的[1]～[4]所示。
[1]一种抗爱泼斯坦-巴尔(EB)病毒剂，其特征在于：含有1-(2-氟-4-硫代-β-D-阿拉伯呋喃糖基)-5-甲基尿嘧啶、它的盐或者它们的水合物或溶剂合物作为有效成分。
[2]一种EB病毒相关疾病的预防或治疗剂，其特征在于：含有1-(2-氟-4-硫代-β-D-阿拉伯呋喃糖基)-5-甲基尿嘧啶、它的盐或者它们的水合物或溶剂合物作为有效成分。
[3]如所述[2]的预防或治疗剂，其特征在于：EB病毒相关疾病是由EB病毒所引起的肿瘤、或者急性或慢性EB病毒感染症。
[4]一种发挥抗EB病毒活性的药剂的筛选方法，其特征在于：向胸苷激酶(TK)缺损细胞中分别导入表达EB病毒-TK基因与人体TK基因的质粒(plasmid)，以产生分别导入了质粒的两种细胞，使用导入了各质粒的两种细胞，筛选出在导入了表达EB病毒-TK基因的质粒的细胞中显示细胞毒性，而在导入了表达人体TK基因的质粒的细胞中不显示毒性的药剂。
[发明的效果]
本发明的药剂只对表达EB病毒-TK基因的细胞显示细胞毒性，而对表达人体TK基因的细胞不显示毒性，因此可以期待抗EB病毒效果以及对于EB病毒相关疾病的预防及治疗效果、和副作用的减少，因而本发明的药剂作为由EB病毒所引起的疾病，例如EB病毒的急性或慢性感染症，由EB病毒所引起的恶性肿瘤等的预防、治疗药而有用。
另外，本发明的筛选方法可以利用源自EB病毒的TK，来筛选出通过该TK而特异性磷酸化后对细胞显示出毒性的药剂，因此作为筛选出发挥抗EB病毒活性的药剂的方法而有用。
附图说明
图1是示意性地表示本发明的筛选法的概要的图。
图2是表示本发明药剂对于B淋巴球中的EB病毒DNA量的效果的图。
具体实施方式
以下，首先对本发明的筛选方法进行说明，其次对利用该筛选方法所选择出的本发明的药剂进行说明。
(1)本发明的筛选方法
本发明的方法如上所述，涉及如下方法：向TK缺损细胞中分别导入表达EB病毒-TK基因与人体TK基因的质粒，以产生分别导入了质粒的两种细胞，使用导入了各质粒的两种细胞，筛选出在导入了表达EB病毒-TK基因的质粒的细胞中显示细胞毒性，而在导入了表达人体TK基因的质粒的细胞中不显示毒性的药剂。
TK缺损细胞优选TK缺损人体肿瘤细胞，例示包含TK缺损人体骨肉瘤细胞(143B)等。这样的细胞可以从美国菌种保藏中心(American TypeCulture Collection，ATCC)等处购入，所例示的143B细胞注册为ATCCCRL-8303。
表达EB病毒-TK基因或人体TK基因的质粒载体(plasmid vector)可以包含如下的质粒：该质粒如图1所示，具有用于选择的适当的抗生素抗性与对EB病毒-TK或人体TK进行编码的基因，其中对EB病毒-TK或人体TK进行编码的基因在启动子(promoter)的下游以能够表达的状态来连结。
对EB病毒-TK或人体TK进行编码的基因已被克隆(cloning)，它的碱基序列可以使用美国国家生物技术信息中心(National Center forBiotechnology Information，NCBI)的数据库(date base)进行检索。因此，可以基于NCBI的数据库信息，利用常规方法来制备对EB病毒-TK以及人体TK进行编码的基因。
其次，利用常规方法连结以上所制备的TK基因以及具有适当的抗生素抗性且具有例如源自巨细胞病毒(cytomegalovirus，CMV)的启动子与终止子(terminator)的质粒。具体而言，对EB病毒-TK或人体TK进行编码的基因质粒是利用常规方法连结至Promega公司制造的质粒pCI-neo真核表达载体(pCI-neo Mammalian Expression Vector)的启动子的下游的多克隆区域(multicloning region)，以成为能够表达对EB病毒-TK或人体TK进行编码的基因。
将所制备的质粒载体基因导入到所述TK缺损细胞中。基因导入可以根据常规方法(美国国家科学院学报(Proc.Natl.Acad.Sci.USA)1987Nov；84(21)：7413-7)来进行。
使用导入了以所述方式制备的EB病毒-TK与人体TK的各基因的两种细胞，筛选出在导入了EB病毒-TK基因的细胞中显示细胞毒性，而在导入了人体TK基因的细胞中不显示毒性的药剂，由此可以筛选出发挥抗EB病毒活性的药剂。特别是通过求出将被检药剂的细胞生存率抑制为50％的各浓度(CC50)，并求出各浓度的比来作为选择指数(Selectivity Index，SI)，则能够以数值来表示药剂的选择性毒性。
(2)本发明的药剂
本发明药剂的有效成分是1-(2-脱氧-2-氟-4-硫代-β-D-阿拉伯呋喃糖基)-5-甲基尿嘧啶(别名：1-(2-脱氧-2-氟-4-硫代-β-D-阿拉伯呋喃糖基)胸腺嘧啶)。该化合物是公知的化合物，能够以文献中的公知方法或者应用该公知方法的方法来制备(参照非专利文献2、专利文献1或专利文献2等)。该化合物也可以是盐、水合物或溶剂合物的形态。这样的盐可以例示盐酸盐或硫酸盐等酸加成物。另外，水合物或溶剂合物可以例示相对于1分子的所述化合物或它的盐，附着有0.1分子～3.0分子的水或溶剂的水合物或溶剂合物。此外，所述化合物中也可以包含互变异构体等各种异构体。
本发明的药剂作为抗EB病毒剂、EB病毒相关疾病的预防或治疗剂而有效。EB病毒相关疾病可以列举由EB病毒所引起的肿瘤、或者急性或慢性EB病毒感染症，由EB病毒所引起的肿瘤例如可以列举B淋巴瘤、鼻咽癌、胃癌等。
本发明药剂的投予量根据患者的年龄、体重、疾病、患者病情的严重程度、药物的耐受性、投予方法等而有所不同，可以综合这些条件来适当决定，通常是从每天为0.001mg/kg体重～1000mg/kg体重的范围内选择，优选从0.01mg/kg体重～100mg/kg体重的范围内选择，并且一次或分成多次来投予。投予方法可以通过经口、非经口、经肠、局部投予等任一种途径来投予。
制成制剂时，可以使用通常所使用的制剂用载体、赋形剂、其他添加剂。载体可以例示乳糖、高岭土(kaolin)、蔗糖、结晶纤维素(crystalline cellulose)、玉米淀粉(corn starch)、滑石粉(talc)、琼脂、果胶(pectine)、硬脂酸(stearic acid)、硬脂酸镁(magnesium stearate)、卵磷脂(lecithin)、氯化钠等个体状载体，甘油(glycerin)、花生油、聚乙烯吡咯烷酮(polyvinylpyrrolidone)、橄榄油(olive oil)、乙醇 (ethanol)、苯甲醇(benzyl alcohol)、丙二醇(propylene glycol)、水等液状载体。剂型可以采用任意的形态，例如当使用个体状载体时，可以例示片剂、散剂、颗粒剂、胶囊剂、栓剂、口含片剂等，当使用液状载体时，可以例示糖浆(syrup)、乳液、软胶胶囊(softgelatin capsule)、乳膏(cream)、凝胶(gel)、糊剂(paste)、喷剂(spray)、注射剂等。
实施例
以下，列出实施例来具体说明本发明，但明确的是本发明并不限定于该实施例。
实施例
(1)细胞株的建立
将通过EB病毒-TK而受到特异性磷酸化后对细胞显示出毒性的药剂的筛选法的概要示于图1。
首先，基于NCBI的数据库信息来设计引物(primer)，并从B95a细胞(病毒学期刊(J.Virol.)1990；64(2)：700-5)中提取脱氧核糖核酸(Deoxyribonucleic Acid，DNA)，然后通过聚合酶链式反应(Polymerase Chain Reaction，PCR)法将EB病毒的TK基因放大，并将它克隆到表达质粒载体pCI-neo的多克隆区域(pCI-EB-TKneo)。同样地，将人体TK基因也通过PCR法来放大，并进行克隆(pCI-huTKnco)。决定碱基序列后确定所克隆的基因片段是否为目标基因。
接着，利用脂质体转染法(lipofection)(美国国家科学院学报(Proc.Natl.Acad.Sci.USA)1987 Nov；84(21)：7413-7)，将表达EB病毒-TK基因或人体TK基因的质粒载体，即分别为pCI-EB-TKneo或pCI-huTKnco导入到TK缺损人体骨肉瘤细胞(143B)中，并利用新霉素(neomycin)来选择出导入了质粒的细胞。
使用导入了EB病毒-TK基因(143B/EB病毒-TK)与导入了人体TK基因(143B/hu-TK)的这两种细胞，进行在导入了EB病毒-TK基因的细胞中显示毒性，而在导入了人体TK基因的细胞中不显示毒性的药 剂的筛选。
(2)药剂敏感性的决定
143B/EB病毒-TK、143B/hu-TK、143B TK(-)细胞以及EBV持续感染细胞的药剂敏感性是由各药剂的细胞毒性所决定的。即，向加入了100μl的各种浓度的各药剂的96孔平底培养板中添加细胞(143B/EB病毒-TK，143B/hu-TK，143B TK(-)细胞：5×104细胞/100μl，EB病毒持续感染细胞：20×104细胞/100μl)。培养5日后，利用MTT[3-(4，5-二甲基噻唑-2-基)-2，5-二苯基四氮唑溴盐]分析来决定生存细胞数。此外，所测试的药剂的细胞毒性是以将细胞生存率抑制为50％的浓度(CC50)来表示。
(3)药剂的效果
利用MTT分析，来研究过去报告为由EB病毒-TK引起磷酸化的核酸衍生物(叠氮胸苷(azidothymidine，AZT)、5-氟-2′-脱氧尿苷(5-fluoro-2′-deoxyuridine，5FdU)、阿昔洛韦(aciclovir，ACV)、1-β-D-阿拉伯呋喃糖基-5-溴乙烯基尿嘧啶(1-β-D-arabinofuranosyl-5-bromovinyl uracil，BVaraU)、更昔洛韦(GCV)、5-溴乙烯基-2′-脱氧尿苷(5-bromovinyl-2′-deoxyuridine，BVDU))是否对表达EB病毒-TK基因的143B/EB病毒-TK显示选择性毒性。另外，对于作为与本发明的化合物结构类似的核酸衍生物的1-(2-脱氧-2-氟-4-硫代-β-D-阿拉伯呋喃糖基)尿嘧啶(1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl)uracil，FMAU)、1-(C-氰基-2-脱氧-呋喃核糖基)胸腺嘧啶(1-(C-cyano-2-deoxy-ribofuranosyl)thymine，1′-CN-dT)、β-D-2-亚甲基-4-硫代-β-D-赤-戊呋喃糖基)胸腺嘧啶(β-D-2-methylene-4-thio-β-D-erythro-pentofuranosyl)thymine，4′-S-DMDT)、1-(2-脱氧-4-硫代-β-D-阿拉伯呋喃糖基)胸腺嘧啶(1-(2-deoxy-4-thio-β-D-arabinofuranosyl)thymine，4′-S-araT)、1-(2-脱氧-2-氟-4-硫代-β-D-阿拉伯呋喃糖基)胞嘧啶(1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosy)cytosine，4′-S-FMAC)也同样进行了研究。
其结果如表1所示，除本发明的药剂以外，无法找出对143B/EB病毒-TK细胞显示选择性毒性的药剂。另外，对所述核酸衍生物以外的130种核酸衍生物同样进行了筛选，但无法找出显示显着效果的药剂。
(4)本发明药剂的效果
与所述(3)同样，利用MTT分析来查明本发明药剂对于143B/EB病毒-TK细胞以及143B/hu-TK(人体TK)细胞的细胞毒性，结果如表1所示，本发明药剂对于143B/EB病毒-TK细胞显示出最高的选择指数(SI：2700倍或2700倍以上)，但在300μM下对143B/hu-TK细胞完全不显示毒性。
[表1]
表1：各种药剂的细胞毒性效果
(5)本发明药剂对于EB病毒感染癌细胞的效果
利用MTT分析来查明本发明药剂对于作为EB病毒感染癌细胞的NC37 细胞等的细胞毒性效果。其结果如表2所示，在表达EB病毒-TK基因的NC37细胞中，本发明药剂比现有的药剂GCV显示出10倍或10倍以上的效果。但是，在不表达EB病毒-TK基因的细胞中均无效果。
[表2]
表2：对于EB病毒感染癌细胞的细胞毒性效果
(6)对于急性感染的效果
从健康人的血液中分离出B淋巴球。在本发明药剂的存在下使该B淋巴球感染EB病毒，进行2周的培养后。然后，对感染B细胞进行回收、清洗，接着提取DNA。通过实时PCR来对该B淋巴球中的EB病毒DNA量进行定量，并将它作为病毒复制数。将具有代表性的2例(PBMC#1287以及PBMC#5926)的结果示于图2。如图2所示，可以明确本发明药剂使B淋巴球中的EB病毒DNA量下降，且新的感染也受到抑制。
(7)对于慢性活动性EB病毒感染症细胞的效果
慢性活动性EB病毒感染症是EB病毒感染自然杀伤T细胞(NaturalKiller T cells，NKT细胞)而非B细胞的预后不良的感染症。从日本人类科学研究资源库(Human Science Research Resources Bank)购入该慢性感染细胞株KAI3细胞(临床与实验免疫学(Clin.Exp.Immunol.)1999 Mar；115(3)：385-92)，并利用MTT分析来研究本发明药剂的效果。此外，使用GCV来作为对照药剂。其结果如表3所示，本发明药剂与GCV相比，明显地显示出较高的效果。
这样一来，可以明确本发明药剂在所述效果方面，具有与迄今为止所报告的GCV相比优异10倍或10倍以上的效果，并且可以认为本发明药剂只对表达EB病毒-TK基因的细胞显示细胞毒性，且本发明药剂可以不论急性、慢性而排除EBV感染细胞。
[表3]
表3：对于慢性活动性EB病毒感染症细胞的效果
产业上的可利用性
本发明的药剂作为针对由EB病毒所引起的疾病的预防、治疗药而有用，例如EB病毒的急性或慢性感染症，由EB病毒所引起的恶性肿瘤等，且该预防、治疗药的副作用降低。另外，本发明的筛选方法作为筛选特别发挥抗EB病毒活性的药剂的方法而有用。
Claims (3)
1.含有1-(2-脱氧-2-氟-4-硫代-β-D-阿拉伯呋喃糖基)-5-甲基尿嘧啶或它的盐作为有效成分在制备抗爱泼斯坦-巴尔病毒剂中的用途。
2.含有1-(2-脱氧-2-氟-4-硫代-β-D-阿拉伯呋喃糖基)-5-甲基尿嘧啶或它的盐作为有效成分在制备爱泼斯坦-巴尔病毒相关疾病的预防或治疗剂中的用途。
3.根据权利要求2所述的用途，其特征在于：爱泼斯坦-巴尔病毒相关疾病是由爱泼斯坦-巴尔病毒所引起的肿瘤、或者急性或慢性爱泼斯坦-巴尔病毒感染症。
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| WO (1) | WO2009034945A1 (zh) |
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| JP6719369B2 (ja) * | 2016-05-13 | 2020-07-08 | 富士フイルム株式会社 | ２’−フルオロ−５−メチル−４’−チオアラビノウリジンの製造方法及びその一部の工程を含む方法 |
| TWI773520B (zh) * | 2021-09-07 | 2022-08-01 | 博訊生物科技股份有限公司 | 用於藥物篩檢的細胞和藥劑分注裝置及其方法 |
| US11761974B2 (en) | 2021-11-01 | 2023-09-19 | Drsignal Biotechnology Co., Ltd. | Cell and medicament dispensing device for drug screening and method thereof |
| WO2023182460A1 (ja) * | 2022-03-24 | 2023-09-28 | 学校法人 聖マリアンナ医科大学 | 慢性活動性Ｅｐｓｔｅｉｎ－Ｂａｒｒウイルス感染症（ＣＡＥＢＶ）の検出方法 |
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| NZ234534A (en) * | 1989-07-17 | 1994-12-22 | Univ Birmingham | Pyrimidine 4'-thionucleoside derivatives and their preparation; intermediates therefor |
| IE74701B1 (en) * | 1989-10-04 | 1997-07-30 | Univ Birmingham | Further antiviral pyrimidine nucleosides |
| US5587362A (en) * | 1994-01-28 | 1996-12-24 | Univ. Of Ga Research Foundation | L-nucleosides |
| US5808040A (en) * | 1995-01-30 | 1998-09-15 | Yale University | L-nucleosides incorporated into polymeric structure for stabilization of oligonucleotides |
| JPH1087687A (ja) | 1996-04-09 | 1998-04-07 | Yamasa Shoyu Co Ltd | ５−置換−１−（２−デオキシ−２−フルオロ−４−チオ−β−Ｄ−アラビノフラノシル）ウラシル |
| AU2002360697B2 (en) * | 2001-12-20 | 2009-04-23 | Beth Israel Deaconess Medical Center | Treatment of EBV and KHSV infection and associated abnormal cellular proliferation |
| JP4729836B2 (ja) * | 2003-03-28 | 2011-07-20 | Ｔｄｋ株式会社 | 磁気記憶セルおよび磁気メモリデバイスならびに磁気メモリデバイスの製造方法 |
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2008
- 2008-09-08 CA CA2698645A patent/CA2698645A1/en not_active Abandoned
- 2008-09-08 EP EP08830964A patent/EP2189161B1/en not_active Not-in-force
- 2008-09-08 CN CN2008801062690A patent/CN101801390B/zh active Active
- 2008-09-08 JP JP2009532175A patent/JP5326173B2/ja active Active
- 2008-09-08 US US12/677,116 patent/US20100330563A1/en not_active Abandoned
- 2008-09-08 WO PCT/JP2008/066175 patent/WO2009034945A1/ja active Application Filing
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2012
- 2012-04-16 US US13/447,727 patent/US20120225837A1/en not_active Abandoned
Non-Patent Citations (3)
| Title |
|---|
| Gang-Qing Yao,et al.Inhibition of Epstein-Barr Virus Replication by a Novel L-Nucleoside, 2’-Fluoro-5-methyl-β-L-arabinofuranosyluracil.《Biochemical Pharmacology》.1996,第51卷第941-947页. * |
| Haruhiko Machida,et al..Anti-herpesvirus activity profile of 4’-thioarabinofuranosyl purine and uracil nucleosides and activity of 1-β-D-2’-fluoro-4’-thioarabinofuranosyl guanine and 2,6-diaminopurine against clinical isolates of human cytomegalovirus.《Antiviral Research》.1998,第39卷第129–137页. * |
| HaruhikoMachida et al..Anti-herpesvirus activity profile of 4’-thioarabinofuranosyl purine and uracil nucleosides and activity of 1-β-D-2’-fluoro-4’-thioarabinofuranosyl guanine and 2 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101801390A (zh) | 2010-08-11 |
| WO2009034945A1 (ja) | 2009-03-19 |
| JPWO2009034945A1 (ja) | 2010-12-24 |
| EP2189161B1 (en) | 2012-08-08 |
| EP2189161A1 (en) | 2010-05-26 |
| EP2189161A4 (en) | 2011-11-09 |
| US20120225837A1 (en) | 2012-09-06 |
| US20100330563A1 (en) | 2010-12-30 |
| JP5326173B2 (ja) | 2013-10-30 |
| CA2698645A1 (en) | 2009-03-19 |
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