CN1274362C - 一种预防和治疗艾滋病药物的制备方法 - Google Patents
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Abstract
一种预防和治疗艾滋病的药物，以金黄色葡萄球菌TSST-1毒素为预防和治疗艾滋病药物的活性组份，其中金黄色葡萄球菌TSST-1毒素分离于在含有氨苄青霉素的培养液中培养后的大肠埃希氏菌(Escherichia coli)XHT CGMCC No.0662菌体中。本发明克服了目前临床常用治疗方法存在的不足，能显著提高CD4/CD8的比值，疗效确切，药物毒副作用小，无过敏反应。
Description
技术领域
本发明涉及生物技术，具体地说是一种从培养的新菌株中获取用于预防和治疗艾滋病药物的制备方法。
背景技术
艾滋病由人类免疫缺陷病毒(HIV)感染而引起，导致被感染者免疫功能的部分或完全丧失，继而发生机会性感染、肿瘤等。HIV侵入人体后主要攻击的是一种带CD4的淋巴细胞(T4淋巴细胞)，这种细胞是免疫系统的基本组成部分，HIV通过大量、不断地复制与释放，导致T4淋巴细胞大量死亡，使人体内T4淋巴细胞明显减少，感染者免疫功能遭到严重破坏，造成免疫缺陷；临床表现为各种机会性感染与肿瘤。HIV一进入人体，这个人就成为HIV感染者，先是处于潜伏期，以后可逐渐发展成艾滋病病人；处于潜伏期的感染者免疫功能没有受到严重破坏，因而没有明显的临床症状。从HIV感染者到艾滋病病人这段时间的长短与感染者的年龄生活医疗条件、心理生理状况、感染病毒的类型等多种因素有关，短则几个月，长则20年以上；当感染者的免疫系统遭到一定程度的破坏(检查发现T4淋巴细胞计数显著下降，CD4/CD8淋巴细胞计数比值＜1等)，可出现一系列临床症状(如发生各种细菌、真菌、病毒感染及肿瘤)，就发展成艾滋病病人；人一旦受到HIV感染将终身携带病毒，因此HIV携带者和艾滋病病人都能传播病毒。
目前尚无可根治HIV感染的药物，也没有证据表明人体会对HIV产生保护性免疫，因此大多数病人会死于反复的继发感染及肿瘤；但早期治疗与预防可延缓病程的发展，提高生活质量；HIV感染者可定期检测T4淋巴细胞计数(正常值为500～1600/微升，T4/T8比值为(1.5～1.7)∶1)，当T4淋巴细胞计数≥200/微升时，可按免疫功能正常情况对感染者进行处理。目前临床上常用的治疗方法有以下三方面：(1)抗病毒治疗：如用叠氮胸苷(AZT)、双脱氧胞苷(DDC)等，目前国际上认为联合用药效果较好，但费用昂贵，一般发展中国家的感染者难以承受。(2)各种机会性感染和肿瘤的处理：由于HIV感染者免疫功能异常，发生感染时往往病情较重，难以控制，加上感染导致肝、肾功能不全，使用药物治疗时还要注意HIV感染者容易出现药物的毒副作用或过敏反应。(3)支持疗法：以提高机体免疫力为主要目的，同时要重视心理治疗和营养疗法。
发明内容
为了克服目前临床常用治疗方法存在的不足，本发明的目的在于提供一种新的大肠埃希氏菌菌株培养物；具有预防和治疗艾滋病功效；其疗效确切，毒副作用小。
为实现上述目的，本发明提供了一种预防和治疗艾滋病的药物是以金黄色葡萄球菌TSST-1毒素作为预防和治疗艾滋病药物的活性组份。
其中还可加入适量的药物辅料；经常采用的药物辅料为右旋糖苷、甘露醇；
所述金黄色葡萄球菌TSST-1毒素分离于大肠埃希氏菌(Escherichia coli)XHT CGMCC No.0662菌体中；
TSST-1毒素的具体制备过程为：首先以大肠埃希氏菌(Escherichia coli)XHT CGMCC No.0662于含有氨苄青霉素的培养液中培养，然后从菌体中分离出工程菌XHT表达的金黄色葡萄球菌TSST-1毒素；
所述分离过程为离心收集菌体，破碎菌体，离心去除菌体碎片，去除菌体碎片的提取液进行透析或超滤后，经阳离子层析柱纯化，用5～200mmol/L PB缓冲液线性梯度洗脱，收集合TSST-1峰的溶液；
所述培养液中氨苄青霉素的浓度为80～120μg/ml；
所述培养液为LB培养液，其PH为6.5～7.5；
本发明中所涉及的大肠埃希氏菌(Escherichia coli)已经于2001年12月10日保藏在中国微生物菌种保藏管理委员会普通微生物中心，保藏号为CGMCC No.0662；菌株代号为XHT。
菌株的情况：从金黄色葡萄球菌的DNA中获得TSST-1基因，以质粒PBV220为载体，以大肠杆菌DH5α为受体菌，自行构造表达TSST-1的工程菌。
菌株CGMCC No.0662的特征：
1.形态特征：为两端钝圆的中等大肠杆菌，宽约0.6μm，长约2～3μm，单独散在，不形成长链条，周围有菌毛。
2.培养特征：为需氧及兼性厌氧菌，在普通LB培养基上生长良好，最适PH7.2～7.4，最适培养增值温度为30℃，诱导表达温度为42℃；普通琼脂培养18～24小时，形成凸起，光滑、湿润，乳白色，边缘整齐的针尖到大头钉帽大小菌落；伊红美蓝琼脂上产生紫黑色带金属光泽的菌落；远滕琼脂上产生黄色菌落。
3.染色特征：革兰氏阴性染色。
4.生理生化特征：能分解葡萄糖、麦芽糖、甘露醇，产酸产气，β-半乳糖苷部分缺失，具有氨苄青霉素抗性，可表达金黄色葡萄球菌TSST-1毒素。
本发明的药物是：通过基因工程的方法，构造出表达金黄色葡萄球菌TSST-1毒素的工程菌种，并从中纯化出TSST-1毒素，制成药物制剂，用于预防和治疗艾兹病的药物。
本发明具有如下优点：克服了目前临床常用治疗方法存在的不足，能显著提高CD4/CD8的比值，疗效确切，毒副作用小，无过敏反应。
具体实施方式
实施例1
接种XHT工程菌于1ml含氨苄青霉素(100μg/ml)的LB培养液中，37℃摇床培养12小时后，转接到300ml含氨苄青霉素(100μg/ml)的LB培养液的三角瓶中，于恒温摇床30℃培养8小时(8～12小时即可)至对数生长期，按5％(按体积百分含量计)接种量，接种于发酵罐中，再于30℃培养12小时，升温至42℃，继续培养6小时(3～6小时均可)。
离心收集菌体，高压匀浆破碎菌体，离心去除菌体碎片，去除菌体碎片后的提取液进行透析，经透析后的样品，上阳离子层析柱(本实施例为羧甲基纤维素层析柱)纯化。依次用5mmol/L PB缓冲液(PH5.5)、30mmol/L PB缓冲液(PH6.0)、45mmol/L PB缓冲液(PH6.0)、200mmol/L PB缓冲液(PH6.8)分步洗脱，收集含TSST-1峰的溶液，经SDS-PAGE，免疫双扩、ELISA等方法进行测定，检测合格(纯度≥95％)后加入5％(按重量百分含量计)的右旋糖苷，喷雾干燥，制得喷雾干粉，分别制成胶囊或片剂。
(1)胶囊中加入适量淀粉，制得胶囊剂，每粒胶囊含TSST-110ng。
(2)片剂(1000片)，分别加入适量的淀粉26g，糊精42g及硬脂酸镁0.7g，TSST-1 10ng及丙烯酸树脂适量(约占总重量的3～5％)制得肠溶片。
实施例2
接种XHT工程菌于1ml含氨苄青霉素(100μg/ml)的LB培养液中，37℃摇床培养12小时后，转接到300ml含氨苄青霉素(100μg/ml)的LB培养液的三角瓶中，于恒温摇床30℃培养8小时至对数生长期，按5％接种量，接种于发酵罐中，再于30℃培养12小时，升温至42℃，继续培养6小时。
离心收集菌体，破碎菌体，离心去除菌体碎片，去除菌体碎片后的提取液在PH5.5的条件下透析，经透析后的样品，上阳离子层析柱纯化；依次用6mmol/L PB缓冲液(PH5.0)、8mmol/L PB缓冲液(PH6.6)、45mmol/L PB缓冲液(PH6.6)、100mmol/L PB缓冲液(PH6.8)分步洗脱，收集含TSST-1峰的溶液，经SDS-PAGE，免疫双扩、ELISA等方法进行测定，检测合格后加入5％的甘露醇，喷雾干燥，制得喷雾干粉，分别制成胶囊或片剂。
(1)胶囊中加入适量淀粉，制得胶囊剂，每粒胶囊含TSST-110ng。
(2)片剂(1000片)，分别加入适量的淀粉26g，糊精42g及硬脂酸镁0.7g，TSST-1 10ng及丙烯酸树脂适量制得肠溶片。
实验例
大多数爱滋病患者在发病阶段呈进行性消瘦，体重减轻，免疫功能下降，T淋巴细胞分布异常，CD4/CD8降低，10例患者服用本品(胶囊)一个月后，T细胞亚群检查的比较。
治疗前及治疗后T细胞亚群检查的比较(X±S)
| n | CD4 | CD8 | CD4/CD8 | |
| 治疗前 | 10 | 22.84±1.57 | 26.00±1.87 | 0.88±0.18 |
| 治疗后 | 10 | 25.19±5.41 | 23.32±5.15 | 1.08士0.22 |
Claims (5)
1.一种预防和治疗艾滋病药物的制备方法，其特征在于以金黄色葡萄球菌TSST-1毒素为预防和治疗艾滋病药物的活性组份；
所述金黄色葡萄球菌TSST-1毒素分离于大肠埃希氏菌Escherichia coli XHT CGMCC No.0662菌体中。
2.按照权利要求1所述的预防和治疗艾滋病药物的制备方法，其特征在于首先以大肠埃希氏菌Escherichia coli XHT CGMCCNo.0662于含有氨苄青霉素的培养液中培养，然后从菌体中分离出工程菌XHT表达的金黄色葡萄球菌TSST-1毒素。
3.按照权利要求2所述的预防和治疗艾滋病药物的制备方法，其特征在于所述培养液中氨苄青霉素的浓度为80～120μg/ml。
4.按照权利要求2所述的预防和治疗艾滋病药物的制备方法，其特征在于所述培养液为LB培养液，PH为6.5～7.5。
5.按照权利要求2所述预防和治疗艾滋病药物的制备方法，其特征在于所述分离过程为离心收集菌体，破碎菌体，离心去除菌体碎片，去除菌体碎片的提取液进行透析或超滤后，经阳离子层析柱纯化，用5～200mmol/L PB缓冲液线性梯度洗脱，收集含TSST-1峰的溶液。
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