CN114685400B - 一种阿立哌唑关键基团衍生物、免疫原、抗阿立哌唑特异性抗体及其制备方法与应用 - Google Patents
一种阿立哌唑关键基团衍生物、免疫原、抗阿立哌唑特异性抗体及其制备方法与应用 Download PDFInfo
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- CN114685400B CN114685400B CN202011557554.3A CN202011557554A CN114685400B CN 114685400 B CN114685400 B CN 114685400B CN 202011557554 A CN202011557554 A CN 202011557554A CN 114685400 B CN114685400 B CN 114685400B
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Abstract
本发明公开了一种阿立哌唑关键基团衍生物、免疫原、抗阿立哌唑特异性抗体及其制备方法与应用。首先将新型阿立哌唑关键基团衍生物与经过基因工程改造得到的重组人血清白蛋白偶联制得阿立哌唑人工抗原,再用阿立哌唑人工抗原免疫实验动物获得抗阿立哌唑特异性抗体,经ELISA检测表明该特异性抗体的特异性强、灵敏度高,干扰实验显示该特异性抗体与100种常见药物无任何交叉反应;将抗阿立哌唑特异性抗体应用于制备阿立哌唑检测试剂,包括阿立哌唑均相酶免疫检测试剂与阿立哌唑胶乳增强免疫比浊检测试剂,所述检测试剂可以实现在全自动生化分析仪上对阿立哌唑的高通量、快速化检测。
Description
技术领域
本发明涉及一种阿立哌唑关键基团衍生物、免疫原、抗阿立哌唑特异性抗体及其制备方法与应用,属于生物医学检测技术领域。
背景技术
阿立哌唑(Aripiprazole)为二氢喹啉酮类化合物,是一种非典型性抗精神病药物,它具有部分激动多巴胺(D2)受体与五-羟色胺(5-HT1A)受体、拮抗五-羟色胺(5-HT2A)受体的作用。临床主要用于治疗精神分裂症、双相障碍、癫痫性精神障碍。其分子式为:C23H27N3O2Cl2,相对分子量为:448.39。
阿立哌唑口服后吸收良好,在3~5h内达到血浆浓度的峰值,与其活性代谢产物脱氢阿立哌唑的平均消除半衰期分别为75h和94h,二者均在14d内达稳态浓度。由于阿立哌唑在体内吸收、分布、代谢及排泄过程的不同,以及遗传因素、合并用药及服药依从性等因素的影响,所以需要监测其血药浓度作为调整给药方案的客观依据。儿童、青少年、孕期妇女、患有阿尔茨海默病性痴呆的老年患者、癫痫性精神障碍患者应及时监测血清中的阿立哌唑水平并调整治疗剂量。CYP2D6基因型会对阿立哌唑的血药浓度产生很大影响,因此,阿立哌唑用于临床时应注意及时监测血药浓度,避免个体化差异而导致药物毒性或药效不明显。在与CYP2D6抑制剂、CYP3A4抑制剂或CYP3A4诱导剂同服时,应及时监测血药浓度,调整阿立哌唑的剂量。此外,由于阿立哌唑在临床上会引起患者的一些不良反应,如:恶心、呕吐、体位性低血压、窦性心动过速、焦虑、失眠、激越、思睡、头痛、静坐不能、肌张力障碍、震颤和恶性综合征等。因此应定期监测药物的血药浓度,及时发现,及时处理,确保用药安全。
阿立哌唑的血药浓度检测方法有多种,包括反相高效液相色谱法(RP-HPLC)、液相色谱-二极管阵列法(LC-DAD)、液相串联质谱法(LC-MS/MS)等。反相高效液相色谱法(RP-HPLC)与液相色谱-二极管阵列法(LC-DAD)前处理复杂,要求目标分析物在色谱上被完全分离,因此分析时间较长,且检测限低,不能满足临床研究的要求。高效液相串联质谱法(LC-MS/MS)检测灵敏度高,快速,但结构复杂,维护成本高,需经过专门培训的技术人员操作,不易在基层医疗机构普及。
因此,目前市面上缺乏线性范围宽、灵敏度高、准确度高、精密度高,检测时间短,样品处理简单,仪器自动化程度高,可多样本连续检测的阿立哌唑检测产品。
发明内容
为了克服现有技术的不足,本发明的第一个目的在于提供一种阿立哌唑关键基团衍生物,该衍生物为新合成的化合物,自然界中不存在。
本发明的第一个目的采用以下技术方案实现:一种阿立哌唑关键基团衍生物,其结构式如式Ⅰ所示:
式Ⅰ。
本发明的第二个目的在于提供一种如上所述的阿立哌唑关键基团衍生物的合成方法,该合成方法不同于常规合成方法,具有良好的合成效果,显著提高了阿立哌唑关键基团衍生物的合成效率。
本发明的第二个目的采用以下技术方案实现:一种如上述结构式Ⅰ所示的阿立哌唑关键基团衍生物的合成方法,反应过程如下式所示:
;
具体的,反应过程包括以下步骤:
(A1)化合物2的合成:
将化合物1 (5 g, 22 mmol)与5-溴戊酸甲酯(4.3 g, 22 mmol)共同溶解于在含有K2CO3 (3g, 22 mmol)的二甲基甲酰胺(50 ml)中制成混合溶液,将此混合溶液在80℃下搅拌20小时;将反应后的混合溶液用乙酸乙酯稀释,再用碳酸氢钠溶液和浓盐水洗涤,并用硫酸钠进行干燥,蒸发溶剂后得到化合物2。
(A2)阿立哌唑关键基团衍生物的合成:
将化合物2 (4 g,12 mmol)溶解于甲醇(50 ml)中,然后添加LiOH (0.6 g,15mmol)制成反应溶液,然后将此反应溶液在室温下搅拌过夜,然后进行减压蒸发浓缩,将浓缩得到的残留物通过硅胶色谱柱纯化,最终得到阿立哌唑关键基团衍生物。
本发明的第三个目的在于提供一种阿立哌唑免疫原。
本发明的第三个目的采用以下技术方案实现:一种阿立哌唑免疫原,所述阿立哌唑免疫原由上述结构式Ⅰ所示的阿立哌唑关键基团衍生物与载体蛋白连接而成,其结构式如式Ⅱ所示:
式Ⅱ;
其中,载体蛋白为重组人血清白蛋白,进一步地,所述重组人血清白蛋白的氨基酸序列如序列表SEQ ID NO:1所示。
重组人血清白蛋白的氨基酸序列(SEQ ID NO:1)具体如下:
MKWVTFISLKFLFSSAYSRGVFRRDAHKSEVAHRFKDLGEKNFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCKADESAENCDKSLHTLFGDKLCTVATKRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRKVRPEVDVMCTAFHDNEETFLKKYLYEIARRKPYFYAPELLFFAKRYKAAFTECCQAADKAKCLLPKLDELRDEGKASKAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTKLTKVHTECCHGDLLECADDRAKLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENKEMPADLPSLAADFVESKDVCKNYAEAKDVFKGMFLYEYARRHPDYSVVLLKRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEKPQNLIKQNCELFEQLGEYKFQNALKVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRKPCAEDYLSVVLNQLCVLHEKTPVSDRVTKKCTESLVNRRPCFSALEVDETYVPKEFNAKTFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFKAFVEKCCKADDKETCFAEEGKKLVAASQKALGL
本发明的第四个目的在于提供一种如上所述的阿立哌唑免疫原的制备方法。
本发明的第四个目的采用以下技术方案实现:一种如上所述的阿立哌唑免疫原的制备方法,包括以下步骤:
(B1)载体蛋白溶液的制备:将上述的重组人血清白蛋白溶解于磷酸盐缓冲液中,得到载体蛋白溶液;
(B2)阿立哌唑关键基团衍生物溶液的制备:将上述结构式Ⅰ所示的阿立哌唑关键基团衍生物与二甲基甲酰胺、乙醇、磷酸钾缓冲液、1-乙基-3-(-3-二甲氨丙基)碳二亚胺和N-羟基硫代琥珀酰亚胺混合,搅拌溶解,得到阿立哌唑关键基团衍生物溶液;
(B3)阿立哌唑免疫原的合成:将步骤(B2)得到的阿立哌唑关键基团衍生物溶液加入到步骤(B1)得到的载体蛋白溶液中,搅拌反应,经透析纯化,得到阿立哌唑免疫原。
具体的,所述阿立哌唑免疫原的制备方法,包括以下步骤:
(b1)载体蛋白溶液的制备:将重组人血清白蛋白溶解于0.35mol/L的磷酸钾缓冲液(pH=8.5)中,重组人血清白蛋白的终浓度为5.0mg/mL,得到载体蛋白溶液;
(b2)阿立哌唑关键基团衍生物溶液的制备:将250.0mg上述的阿立哌唑关键基团衍生物、7.5mL二甲基甲酰胺、7.5mL乙醇、15.0mL的磷酸钾缓冲液(10.0mmol/L,pH=8.0)、150.0mg 1-乙基-3-(-3-二甲氨丙基)碳二亚胺、90.0mg N-羟基硫代琥珀酰亚胺混合,搅拌溶解反应3小时,得到阿立哌唑关键基团衍生物溶液;
(b3)阿立哌唑免疫原的合成:将步骤(b2)得到的阿立哌唑关键基团衍生物溶液逐滴加入到步骤(b1)得到的载体蛋白溶液中,并在-4℃下搅拌过夜,经透析纯化,得到阿立哌唑免疫原。
本发明的第五个目的在于提供一种抗阿立哌唑特异性抗体。
本发明的第五个目的采用以下技术方案实现:一种抗阿立哌唑特异性抗体,所述抗阿立哌唑特异性抗体为使用上述的阿立哌唑免疫原对实验动物进行注射后所得到的特异性抗体,所述的实验动物为兔子、山羊、绵羊、小鼠、大鼠、豚鼠或马中的一种。
本发明的第六个目的在于提供一种如上所述的抗阿立哌唑特异性抗体的制备方法。
本发明的第六个目的采用以下技术方案实现:一种如上所述的抗阿立哌唑特异性抗体的制备方法,包含以下步骤:
(C1)将上述的阿立哌唑免疫原用磷酸盐缓冲液稀释,得到阿立哌唑人工抗原溶液,然后将阿立哌唑人工抗原溶液与等量弗氏完全佐剂混合,对上述的实验动物进行多点注射;
(C2)3-6周后,再用相同的阿立哌唑人工抗原溶液与等量弗氏不完全佐剂混合,对上述实验动物进行多点注射,之后每隔3-6周注射一次,共计注射3-10次;
(C3)对步骤(C2)中完成注射的实验动物取血,分离纯化,得到抗阿立哌唑特异性抗体。
具体的,所述抗阿立哌唑特异性抗体的制备方法,包含以下步骤:
(c1)将上述的阿立哌唑免疫原用0.15mol/L磷酸钠缓冲液(pH=7.0)稀释至终浓度为3.5mg/mL,得到人工抗原溶液,然后将3.0mL人工抗原溶液与等量弗氏完全佐剂混合,对实验动物兔子进行多点注射;
(c2)4周后,再用3.0mL相同的人工抗原溶液与等量弗氏不完全佐剂对上述实验动物兔子进行多点注射,之后每隔5周注射一次,共计注射6次;
(c3)对步骤(c2)完成注射的实验动物兔子取血,分离纯化,得到抗阿立哌唑特异性抗体。
本发明的第七个目的在于提供一种如上所述的抗阿立哌唑特异性抗体的应用。
本发明的第七个目的采用以下技术方案实现:一种如上所述的抗阿立哌唑特异性抗体的应用,将所述抗阿立哌唑特异性抗体用于制备阿立哌唑检测试剂,所述阿立哌唑检测试剂包括阿立哌唑均相酶免疫检测试剂与阿立哌唑胶乳增强免疫比浊检测试剂。
优选地,上述的抗阿立哌唑特异性抗体的应用,所述阿立哌唑均相酶免疫检测试剂,由R1试剂与R2试剂组成,所述R1试剂包含上述的抗阿立哌唑特异性抗体与R1缓冲液,所述R2试剂包含阿立哌唑葡萄糖-6-磷酸脱氢酶标记偶联物与R2缓冲液;
所述的R1缓冲液含有酶底物、辅酶、牛血清白蛋白及Tris缓冲液,所述的酶底物为葡萄糖-6-磷酸,所述的辅酶为氧化型烟酰胺腺嘌呤二核苷酸;
所述的阿立哌唑葡萄糖-6-磷酸脱氢酶标记偶联物由上述结构式Ⅰ所示的阿立哌唑关键基团衍生物与葡萄糖-6-磷酸脱氢酶偶联而成;其结构式如式Ⅲ所示:
式Ⅲ;
所述的R2缓冲液为含有牛血清白蛋白的Tris缓冲液。
具体的,所述阿立哌唑均相酶免疫检测试剂的制备方法,包含以下步骤:
(D1)将250.0mg牛血清白蛋白、250.0mg葡萄糖-6-磷酸及50.0mg氧化型烟酰胺腺嘌呤二核苷酸依次加入250mL Tris缓冲液(50mmol/L,pH=8.5)中搅拌溶解制成R1缓冲液,再将抗阿立哌唑特异性抗体以1∶1000的体积比加入到上述R1缓冲液中混匀,再用1.0 mol/L的盐酸调节pH至7.6,制成R1试剂;
(D2)将250.0mg牛血清白蛋白加入250mL Tris缓冲液(100mmol/L,pH=8.7)中搅拌溶解制成R2缓冲液,再将阿立哌唑葡萄糖-6-磷酸脱氢酶标记偶联物以1∶1000的体积比加入到上述R2缓冲液中混匀,再用1.0 mol/L的盐酸调节pH至8.0,制成R2试剂。
所述的阿立哌唑葡萄糖-6-磷酸脱氢酶标记偶联物的制备方法,包含以下步骤:
(E1)称取20.0 mg活力单位为200KU的葡萄糖-6-磷酸脱氢酶,在室温条件下溶解于50.0mL磷酸钠(100mmol/L,pH=8.0)缓冲液中,然后加入150.0 mg还原态的烟酰胺腺嘌呤二核苷酸、75.0 mg葡萄糖-6-磷酸以及0.75 mL卡必醇,再逐滴加入2.5 mL二甲基亚砜,搅拌溶解,得到葡萄糖-6-磷酸脱氢酶溶液;
(E2)在无水状态下称取15.0 mg上述结构式Ⅰ所示的阿立哌唑关键基团衍生物,溶解于500.0 µL二甲基甲酰胺中,将上述溶液温度降到0℃后加入4.5 µL三丁胺、2.5 µL氯甲酸异丁酯、3.5 µL N,N′-二环己基碳二亚胺,0℃下搅拌45分钟,得到阿立哌唑关键基团衍生物激活液;
(E3)将阿立哌唑关键基团衍生物激活液逐滴加入到葡萄糖-6-磷酸脱氢酶溶液中,-4℃搅拌反应12小时,反应结束后经G-25凝胶层析柱纯化得到阿立哌唑葡萄糖-6-磷酸脱氢酶标记偶联物。
优选地,上述的抗阿立哌唑特异性抗体的应用,所述阿立哌唑胶乳增强免疫比浊检测试剂,由L1试剂与L2试剂组成;
所述L1试剂由上述的抗阿立哌唑特异性抗体、pH=8.0的缓冲液、牛血清白蛋白、氯化钠、吐温-20、丙三醇、乙二胺四乙酸、促凝剂以及防腐剂组成;
所述L2试剂由阿立哌唑-牛血清白蛋白复合体包被的聚苯乙烯胶乳颗粒、pH=8.0的缓冲液、牛血清白蛋白、氯化钠、吐温-20、丙三醇、乙二胺四乙酸以及防腐剂组成;
所述的阿立哌唑-牛血清白蛋白复合体由上述结构式Ⅰ所示的阿立哌唑关键基团衍生物与牛血清白蛋白偶联而成,其结构式如式Ⅳ所示:
式Ⅳ;
所述的聚苯乙烯胶乳颗粒直径范围为50-250nm;
所述的缓冲液为磷酸盐缓冲液、甘氨酸缓冲液、MES缓冲液、硼酸盐缓冲液、Tris-HCl缓冲液或巴比妥缓冲液中的一种;
所述促凝剂为PEG-4000、PEG-6000、PEG-8000或硫酸葡聚糖钠中的一种;
所述防腐剂为叠氮钠、硫柳汞、苯酚或乙基汞硫代硫酸钠中的一种。
具体的,所述阿立哌唑胶乳增强免疫比浊检测试剂的制备方法,包含以下步骤:
(F1)将5.0mL的抗阿立哌唑特异性抗体溶解于250.0mL磷酸钾缓冲液(50.0 mmol/L pH=8.0)中,然后添加100.0mg牛血清白蛋白、25.0mg氯化钠、250.0μL吐温-20、250.0μL丙三醇、100.0μL的乙二胺四乙酸、150.0μL的PEG-4000以及5.0mg叠氮钠,搅拌均匀,调节pH=7.3,制成L1试剂;
(F2)将1.5mg表面带有羧基的直径为125nm的聚苯乙烯胶乳颗粒加入15.0mL的MES缓冲液(50.0mmol/L,pH=7.0)中,然后加入5.0mg碳二亚胺,在25℃下反应3小时,制成胶乳颗粒溶液,再将1.2mg阿立哌唑-牛血清白蛋白复合体用7.5mL的硼酸盐缓冲液(50.0mmol/L,pH=9.2)稀释后,立即加入到上述胶乳颗粒溶液中,在41℃下反应18小时,然后加入3.0mL的甘氨酸缓冲液(100.0mmol/L,pH=8.0)搅拌3小时,反应终止后离心去除上清液,再将沉淀物用20.0mL的Tris-HCl缓冲液(50.0mmol/L,pH=8.0)洗涤3次,再用50.0mL的甘氨酸缓冲液(50.0mmol/L,pH=8.6)稀释成胶乳悬浊液,最后加入质量分数为100.0mg牛血清白蛋白、25.0mg氯化钠、250.0μL吐温-20、250.0μL丙三醇、100.0μL的乙二胺四乙酸以及5.0mg叠氮钠,搅拌均匀,制成L2试剂。
所述的阿立哌唑-牛血清白蛋白复合体的制备方法,包含以下步骤:
将10.0mg牛血清白蛋白用7.5mL的磷酸钠缓冲液(100.0mmol/L,pH=7.5)稀释,然后加入100.0mg上述结构式Ⅰ所示的阿立哌唑关键基团衍生物,再加入50.0mg的1-乙基-3-(3-二甲基氨基丙基)碳二亚胺,在0℃下反应10 小时,再用100.0mL磷酸盐缓冲液(100.0mmol/L,pH=7.5)在-4℃下透析12小时,得到阿立哌唑-牛血清白蛋白复合体。
相比现有技术,本发明的有益效果在于:
1、本发明设计的阿立哌唑关键基团衍生物及其合成方法均为针对性的新设计与研究,在现有技术中并不存在;
2、本发明使用经过基因工程改造得到的重组人血清白蛋白与阿立哌唑关键基团衍生物偶联得到阿立哌唑免疫原,偶联效率高,显著提高阿立哌唑免疫原的免疫原性。使用本发明的阿立哌唑免疫原制备得到的抗阿立哌唑特异性抗体的特异性强、灵敏度高,并且与100种常见药物无任何交叉反应,因此能够用于制备具有较高的准确性、精密度、灵敏度和特异性的阿立哌唑检测试剂。
、本发明的两种阿立哌唑检测试剂可以实现在全自动生化分析仪上对阿立哌唑高通量、快速化的检测,能同时测定多个样品,具有操作简便、灵敏度高、特异性强、结果准确等优点,还能有效降低阿立哌唑检测成本,有利于临床推广使用。
附图说明
图1为实施例4 阿立哌唑的ELISA检测标准曲线;
图2为实施例8阿立哌唑均相酶免疫检测试剂校准曲线;
图3为实施例10阿立哌唑胶乳增强免疫比浊检测试剂校准曲线。
具体实施方式
下面结合附图以及具体实施方式,对本发明做进一步描述,这些附图均为简化的示意图,仅以示意方式说明本发明的基本结构,因此其仅显示与本发明有关的构成。除非特别指明,以下实施例中所用的试剂、仪器、设备、耗材均可从正规渠道商购买获得。
实施例1:阿立哌唑关键基团衍生物的合成
通过以下合成路线合成阿立哌唑关键基团衍生物:
;
具体的合成步骤如下:
(1)化合物2的合成:
将化合物1 (5 g, 22 mmol)与5-溴戊酸甲酯(4.3 g, 22 mmol)共同溶解于在含有K2CO3 (3g, 22 mmol)的二甲基甲酰胺(50 ml)中制成混合溶液,将此混合溶液在80℃下搅拌20小时;将反应后的混合溶液用乙酸乙酯稀释,再用碳酸氢钠溶液和浓盐水洗涤,并用硫酸钠进行干燥。蒸发溶剂后得到4g白色泡沫状的化合物2。
(2)阿立哌唑关键基团衍生物的合成:
将化合物2 (4 g,12 mmol)溶解于甲醇(50 ml)中,然后添加LiOH (0.6 g,15mmol)制成反应溶液,然后将此反应溶液在室温下搅拌过夜,然后进行减压蒸发浓缩,将浓缩得到的残留物通过硅胶色谱柱纯化最终得到3.5 g阿立哌唑关键基团衍生物。
实施例2:阿立哌唑免疫原的制备
阿立哌唑免疫原的制备方法具体步骤如下:
(1)载体蛋白溶液的制备:将重组人血清白蛋白溶解于0.35mol/L的磷酸钾缓冲液(pH=8.5)中,重组人血清白蛋白的终浓度为5.0mg/mL,得到载体蛋白溶液;
(2)阿立哌唑关键基团衍生物溶液的制备:将250.0mg上述的阿立哌唑关键基团衍生物、7.5mL二甲基甲酰胺、7.5mL乙醇、15.0mL的磷酸钾缓冲液(10.0mmol/L,pH=8.0)、150.0mg 1-乙基-3-(-3-二甲氨丙基)碳二亚胺、90.0mg N-羟基硫代琥珀酰亚胺混合,搅拌溶解反应3小时,得到阿立哌唑关键基团衍生物溶液;
(3)阿立哌唑免疫原的合成:将步骤(2)得到的阿立哌唑关键基团衍生物溶液逐滴加入到步骤(1)得到的载体蛋白溶液中,并在-4℃下搅拌过夜,经透析纯化,得到阿立哌唑免疫原。
实施例3:抗阿立哌唑特异性抗体的制备
抗阿立哌唑特异性抗体的制备方法具体步骤如下:
(1)将上述的阿立哌唑免疫原用0.15mol/L磷酸钠缓冲液(pH=7.0)稀释至终浓度为3.5mg/mL,得到人工抗原溶液,然后将3.0mL人工抗原溶液与等量弗氏完全佐剂混合,对实验动物兔子进行多点注射;
(2)4周后,再用3.0mL相同的人工抗原溶液与等量弗氏不完全佐剂对上述实验动物兔子进行多点注射,之后每隔5周注射一次,共计注射6次;
(3)对步骤(2)完成注射的实验动物兔子取血,分离纯化,得到抗阿立哌唑特异性抗体。
实施例4:ELISA法检验抗阿立哌唑特异性抗体的性能
1.阿立哌唑的ELISA检测标准曲线的建立:
(1)标准品的制备:
将阿立哌唑纯品粉末(购于Sigma公司) 溶解于甲醇溶液,制备成1mg/mL的储存液。用ELISA缓冲液将储存液依次稀释为1600.00ng/mL、800.00ng/mL、400.00ng/mL、200.00ng/mL、100.00ng/mL、0.00ng/mL的标准溶液。其中,ELISA缓冲液由50.0mmol/L的Tris缓冲液,质量分数为1.5%的NaCl以及体积分数为0.25%的BSA配制而成。
(2)利用阿立哌唑的ELISA检验方法制备标准曲线:
用磷酸钾缓冲液(50.0mmol/L,pH=8.0)将实施例3中所制备的抗阿立哌唑特异性抗体稀释成1 : 10000的终浓度溶液,100μL/孔包被在96孔酶联板上,4℃放置18小时;用磷酸钾缓冲液将包被有抗阿立哌唑特异性抗体的96孔酶联板洗涤3次后,加入200μL/孔的体积分数0.5%的BSA溶液,4℃下放置12小时。然后用磷酸钾缓冲液洗涤3次,加入20μL/孔的标准溶液。再加入100μL/孔工作浓度的HRP-阿立哌唑偶联物;室温下孵育30min后磷酸钾缓冲液洗板5次;然后每孔加入100μL的TMB 底物,室温孵育30min。再每孔加入100μL的终止液(2.0mol/L的硫酸)。使用酶标仪测定450nm的吸光值。根据各标准溶液所对应的450nm的吸光值定标,制作标准曲线,结果如图1所示。
待测样品中阿立哌唑含量的检测:
(1)制作待测样品:
制备方法:将阿立哌唑纯品粉末(购于Sigma公司) 溶解于甲醇溶液制成1.0mg/mL的储存液,并将此储存液稀释于空白血浆中,至终浓度分别为0.00ng/mL、150.00ng/mL、300.00ng/mL、1200.00ng/mL,分别形成空白、低、中、高浓度的血浆样本。所述空白血浆为不含阿立哌唑的健康人血浆。
(2)测试方法:
利用上述阿立哌唑的ELISA检验方法,将上述空白、低、中、高浓度的血浆样本代替标准溶液,测试上述空白、低、中、高浓度的血浆样本在450nm的吸光值。
(3)测试结果:
对照图1中所示的阿立哌唑的ELISA检验的标准曲线,计算每个样本中阿立哌唑含量,并对每个样本进行3个复孔测定,根据上述样本中阿立哌唑的实际含量计算回收率,结果如表1所示。
表1 阿立哌唑的ELISA检测结果
血浆样本 | 空白 | 低值 | 中值 | 高值 |
样本浓度(ng/mL) | 0.00 | 150.00 | 300.00 | 1200.00 |
测定1 | 0.00 | 151.43 | 303.91 | 1212.25 |
测定2 | 0.00 | 151.52 | 296.04 | 1197.83 |
测定3 | 0.00 | 151.98 | 305.00 | 1203.29 |
平均值(ng/mL) | 0.00 | 151.64 | 301.65 | 1204.46 |
回收率(%) | - | 101.09 | 100.55 | 100.37 |
由表1中结果可知:使用本发明阿立哌唑特异性抗体的ELISA检测方法测定不同浓度样本中的阿立哌唑回收率都较高,均在97%-103%之间,说明本发明所述的抗阿立哌唑特异性抗体可以用于样本中阿立哌唑的检测,并且灵敏度高,检测结果准确度高。
实施例5:100种常见药物干扰试验
选取100种常见药物作为干扰物进行干扰试验,将100种常见药物纯品粉末配制成浓度为100.0ng/mL的溶液作为待测干扰物样本,采用实施例4的ELISA检验方法对相应干扰物的浓度进行检测,100种常见药物名称以及检测结果详见表2。
表2 常见药物干扰试验检测结果
序号 | 化合物名称 | 实际检测值(ng/mL) | 序号 | 化合物名称 | 实际检测值 (ng/mL) |
1 | 阿司匹林 | 0.00 | 2 | 苯丙醇胺 | 0.00 |
3 | β-苯基乙胺 | 0.00 | 4 | 普鲁卡因酰胺 | 0.00 |
5 | 安非他命 | 0.00 | 6 | 普鲁卡因 | 0.00 |
7 | 氨苄青霉素 | 0.00 | 8 | 奎尼丁 | 0.00 |
9 | 甲氨二氮卓 | 0.00 | 10 | 佐美酸 | 0.00 |
11 | 氯丙嗪 | 0.00 | 12 | 苯肾上腺素 | 0.00 |
13 | 氯拉卓酸 | 0.00 | 14 | 桂皮酰艾克宁 | 0.00 |
15 | 二甲苯氧庚酸 | 0.00 | 16 | 芽子碱 | 0.00 |
17 | 非诺洛芬 | 0.00 | 18 | 地西洋 | 0.00 |
19 | 甲基苯丙胺 | 0.00 | 20 | 可替宁 | 0.00 |
21 | 龙胆酸 | 0.00 | 22 | 阿替洛尔 | 0.00 |
23 | 吉非贝齐 | 0.00 | 24 | 心得安 | 0.00 |
25 | 氢可酮 | 0.00 | 26 | 苯乙哌啶酮 | 0.00 |
27 | 布洛芬 | 0.00 | 28 | 苯基丁氮酮 | 0.00 |
29 | 丙咪嗪 | 0.00 | 30 | 麦角酸二乙基酰胺 | 0.00 |
31 | 二氨基二苯砜 | 0.00 | 32 | 大麻酚 | 0.00 |
33 | 萘普生 | 0.00 | 34 | 洛哌丁胺 | 0.00 |
35 | 氢氯噻嗪 | 0.00 | 36 | 异克舒令 | 0.00 |
37 | 哌替啶 | 0.00 | 38 | 苯基丙氨酸 | 0.00 |
39 | 烯丙羟吗啡酮 | 0.00 | 40 | 盐酸氟西汀 | 0.00 |
41 | 麻黄素 | 0.00 | 42 | 柳丁氨醇 | 0.00 |
43 | 烟酰胺 | 0.00 | 44 | 青霉素 | 0.00 |
45 | 甲胺呋硫 | 0.00 | 46 | 甲基二乙醇胺 | 0.00 |
47 | 异戊巴比妥 | 0.00 | 48 | 二亚甲基双氧苯丙胺 | 0.00 |
49 | 甲撑二氧苯丙胺 | 0.00 | 50 | 琥珀酸多西拉敏 | 0.00 |
51 | 四氢大麻酚 | 0.00 | 52 | 纳布啡 | 0.00 |
53 | 制霉菌素 | 0.00 | 54 | 去甲吗啡 | 0.00 |
55 | 乙酰吗啡 | 0.00 | 56 | 羟考酮 | 0.00 |
57 | 苄非他明 | 0.00 | 58 | 克他命 | 0.00 |
59 | 异丙嗪 | 0.00 | 60 | 苯海拉明 | 0.00 |
61 | 阿司帕坦 | 0.00 | 62 | 苯丁胺 | 0.00 |
63 | 奥卡西平 | 0.00 | 64 | 氟康唑 | 0.00 |
65 | 氯氮平 | 0.00 | 66 | 呋塞米 | 0.00 |
67 | 艾司西酞普兰 | 0.00 | 68 | 加巴喷丁 | 0.00 |
69 | 伊马替尼 | 0.00 | 70 | 华法林 | 0.00 |
71 | 拉莫三嗪 | 0.00 | 72 | 瑞舒伐他汀 | 0.00 |
73 | 利奈唑胺 | 0.00 | 74 | 对乙酰氨基酚 | 0.00 |
75 | 利培酮 | 0.00 | 76 | 舒必利 | 0.00 |
77 | 舍曲林 | 0.00 | 78 | 氟伏沙明 | 0.00 |
79 | 托吡酯 | 0.00 | 80 | 氟西汀 | 0.00 |
81 | 文拉法辛 | 0.00 | 82 | 齐拉西酮 | 0.00 |
83 | 伏立康唑 | 0.00 | 84 | 氟哌啶醇 | 0.00 |
85 | 左乙拉西坦 | 0.00 | 86 | 亚胺培南 | 0.00 |
87 | 奥氮平 | 0.00 | 88 | 阿昔替尼 | 0.00 |
89 | 唑尼沙胺 | 0.00 | 90 | 培唑帕尼 | 0.00 |
91 | 阿米替林 | 0.00 | 92 | 瑞戈非尼 | 0.00 |
93 | 氯丙嗪 | 0.00 | 94 | 异烟肼 | 0.00 |
95 | 多虑平 | 0.00 | 96 | 利福平 | 0.00 |
97 | 帕罗西汀 | 0.00 | 98 | 左氧氟沙星 | 0.00 |
99 | 氯霉素 | 0.00 | 100 | 莫西沙星 | 0.00 |
测定结果显示:采用实施例4的ELISA检验方法对相应干扰物的浓度进行检测,上述100种常见药物实际检测值均为0.00ng/mL。由此可见,本发明的抗阿立哌唑特异性抗体具有较强的抗原识别特异性,与100种常见药物无任何交叉反应。
实施例6:阿立哌唑均相酶免疫检测试剂的制备
阿立哌唑均相酶免疫检测试剂的制备方法,具体步骤如下:
(1)将250.0mg牛血清白蛋白、250.0mg葡萄糖-6-磷酸及50.0mg氧化型烟酰胺腺嘌呤二核苷酸依次加入250mL Tris缓冲液(50mmol/L,pH=8.5)中搅拌溶解制成R1缓冲液,再将抗阿立哌唑特异性抗体以1∶1000的体积比加入到上述R1缓冲液中混匀,再用1.0 mol/L的盐酸调节pH至7.6,制成R1试剂;
(2)将250.0mg牛血清白蛋白加入250mL Tris缓冲液(100mmol/L,pH=8.7)中搅拌溶解制成R2缓冲液,再将阿立哌唑葡萄糖-6-磷酸脱氢酶标记偶联物以1∶1000的体积比加入到上述R2缓冲液中混匀,再用1.0 mol/L的盐酸调节pH至8.0,制成R2试剂。
所述的阿立哌唑葡萄糖-6-磷酸脱氢酶标记偶联物的制备方法,包含以下步骤:
(1)称取20.0 mg活力单位为200KU的葡萄糖-6-磷酸脱氢酶,在室温条件下溶解于50.0mL磷酸钠(100mmol/L,pH=8.0)缓冲液中,然后加入150.0 mg还原态的烟酰胺腺嘌呤二核苷酸、75.0 mg葡萄糖-6-磷酸以及0.75 mL卡必醇,再逐滴加入2.5 mL二甲基亚砜,搅拌溶解,得到葡萄糖-6-磷酸脱氢酶溶液;
(2)在无水状态下称取15.0 mg实施例1合成的阿立哌唑关键基团衍生物,溶解于500.0 µL二甲基甲酰胺中,将上述溶液温度降到0℃后加入4.5 µL三丁胺、2.5 µL氯甲酸异丁酯、3.5 µL N,N′-二环己基碳二亚胺,0℃下搅拌45分钟,得到阿立哌唑关键基团衍生物激活液;
(3)将阿立哌唑关键基团衍生物激活液逐滴加入到葡萄糖-6-磷酸脱氢酶溶液中,-4℃搅拌反应12小时,反应结束后经G-25凝胶层析柱纯化得到阿立哌唑葡萄糖-6-磷酸脱氢酶标记偶联物。
实施例7:阿立哌唑校准品、质控品的制备
(1)校准品的制备:将阿立哌唑纯品粉末分别加入6份浓度为50.0mmol/L pH=7.2的Tris-HCl缓冲液中,搅拌溶解,至终浓度分别为0.00ng/mL、100.00ng/mL、200.00ng/mL、400.00ng/mL、800.00ng/mL、1600.00ng/mL,然后在每份溶液中分别加入质量分数为0.5%的氯化钠、1.0%的牛血清白蛋白、0.75%的乙二胺四乙酸、0.05%的叠氮钠,搅拌均匀,即为阿立哌唑校准品(6个浓度)。
(2)质控品的制备:将阿立哌唑纯品粉末分别加入4份浓度为50.0mmol/L pH=7.2的Tris-HCl缓冲液中,搅拌溶解,至终浓度分别为0.00ng/mL、150.00ng/mL、300.00ng/mL、1200.00ng/mL,然后在每份溶液中分别加入质量分数为0.5%的氯化钠、1.0%的牛血清白蛋白、0.75%的乙二胺四乙酸、0.05%的叠氮钠,搅拌均匀,即为阿立哌唑质控品(4个浓度)。
实施例8:阿立哌唑均相酶免疫检测试剂校准曲线制作及质控实验
1. 制作阿立哌唑均相酶免疫检测校准曲线:
在迈瑞 BS480全自动生化分析仪中放入R1试剂、R2试剂及校准品,然后对生化分析仪进行反应参数设置,具体参数详见表3;实际操作过程中需不断调整R1试剂和R2试剂的体积比例,同时调整测光点,最后由生化分析仪自动得出均相酶免疫检测校准曲线,如图2所示。
表3 迈瑞 BS480全自动生化分析仪反应参数设置
项目名称 | 阿立哌唑 |
R1试剂 | 160.0µL |
R2试剂 | 40.0µL |
样本量 | 10.0µL |
定标方法 | 两点终点法 |
主波长 | 340nm |
次波长 | 405nm |
反应时间 | 10分钟 |
温育时间 | 8分钟 |
反应方向 | 上升 |
结果 | ng/mL |
结果精度 | 0.01 |
拟合方法 | Line graph |
校准品浓度 | 0.00ng/mL、100.00ng/mL、200.00ng/mL、400.00ng/mL、800.00ng/mL、1600.00ng/mL |
2. 质控品检测实验:
利用上述的阿立哌唑均相酶免疫检测方法,对质控品进行测定,并根据步骤1中制作的均相酶免疫检测校准曲线,计算每个质控品中阿立哌唑的含量,每个质控品重复测定10次,检测结果及数据分析详见表4。
表4 阿立哌唑均相酶免疫检验试剂检测结果及数据分析
质控品 | 空白 | 低值 | 中值 | 高值 |
浓度 (ng/mL) | 0.00 | 150.00 | 300.00 | 1200.00 |
测试1 | 0.00 | 152.00 | 302.24 | 1220.29 |
测试2 | 0.00 | 149.41 | 307.68 | 1208.70 |
测试3 | 0.00 | 148.12 | 303.27 | 1205.43 |
测试4 | 0.00 | 149.26 | 298.52 | 1193.00 |
测试5 | 0.00 | 147.34 | 295.04 | 1203.39 |
测试6 | 0.00 | 151.01 | 306.11 | 1200.76 |
测试7 | 0.00 | 153.93 | 300.02 | 1214.20 |
测试8 | 0.00 | 148.77 | 299.97 | 1195.12 |
测试9 | 0.00 | 149.32 | 304.20 | 1207.25 |
测试10 | 0.00 | 150.85 | 296.00 | 1198.49 |
平均值(ng/mL) | 0.00 | 150.00 | 301.31 | 1204.66 |
标准差(SD) | / | 1.96 | 4.16 | 8.44 |
精密度(CV%) | / | 1.31 | 1.38 | 0.70 |
回收率(%) | / | 100.00 | 100.44 | 100.39 |
实验结果表明:测定不同浓度质控品中阿立哌唑含量的CV值均低于5%,回收率均在95%-105%之间,说明本发明的阿立哌唑均相酶免疫检测试剂测定生物样本中阿立哌唑含量的精密度较高,结果准确。
实施例9:阿立哌唑胶乳增强免疫比浊检测试剂的制备
阿立哌唑胶乳增强免疫比浊检测试剂的制备方法,包含以下步骤:
(F1)将5.0mL的抗阿立哌唑特异性抗体溶解于250.0mL磷酸钾缓冲液(50.0 mmol/L pH=8.0)中,然后添加100.0mg牛血清白蛋白、25.0mg氯化钠、250.0μL吐温-20、250.0μL丙三醇、100.0μL的乙二胺四乙酸、150.0μL的PEG-4000以及5.0mg叠氮钠,搅拌均匀,调节pH=7.3,制成L1试剂;
(F2)将1.5mg表面带有羧基的直径为125nm的聚苯乙烯胶乳颗粒加入15.0mL的MES缓冲液(50.0mmol/L,pH=7.0)中,然后加入5.0mg碳二亚胺,在25℃下反应3小时,制成胶乳颗粒溶液,再将1.2mg阿立哌唑-牛血清白蛋白复合体用7.5mL的硼酸盐缓冲液(50.0mmol/L,pH=9.2)稀释后,立即加入到上述胶乳颗粒溶液中,在41℃下反应18小时,然后加入3.0mL的甘氨酸缓冲液(100.0mmol/L,pH=8.0)搅拌3小时,反应终止后离心去除上清液,再将沉淀物用20.0mL的Tris-HCl缓冲液(50.0mmol/L,pH=8.0)洗涤3次,再用50.0mL的甘氨酸缓冲液(50.0mmol/L,pH=8.6)稀释成胶乳悬浊液,最后加入质量分数为100.0mg牛血清白蛋白、25.0mg氯化钠、250.0μL吐温-20、250.0μL丙三醇、100.0μL的乙二胺四乙酸以及5.0mg叠氮钠,搅拌均匀,制成L2试剂。
所述的阿立哌唑-牛血清白蛋白复合体的制备方法,包含以下步骤:
将10.0mg牛血清白蛋白用7.5mL的磷酸钠缓冲液(100.0mmol/L,pH=7.5)稀释,然后加入100.0mg实施例1合成的阿立哌唑关键基团衍生物,再加入50.0mg的1-乙基-3-(3-二甲基氨基丙基)碳二亚胺,在0℃下反应10 小时,再用100.0mL磷酸盐缓冲液(100.0mmol/L,pH=7.5)在-4℃下透析12小时,得到阿立哌唑-牛血清白蛋白复合体。
实施例10:阿立哌唑胶乳增强免疫比浊检测试剂校准曲线制作及质控实验
1. 制作阿立哌唑胶乳增强免疫比浊检测试剂校准曲线:
在奥林巴斯AU480全自动生化分析仪中放入L1试剂、L2试剂及校准品,然后对生化分析仪进行反应参数设置,具体参数详见表5;实际操作过程中需不断调整L1试剂和L2试剂的体积比例,同时调整测光点,最后由生化分析仪自动得出胶乳增强免疫比浊检测校准曲线,如图3所示。
表5 奥林巴斯AU480全自动生化分析仪反应参数
项目名称 | 阿立哌唑 |
L1试剂 | 160.0µL |
L2试剂 | 40.0µL |
样本量 | 10.0µL |
定标方法 | 两点终点法 |
主波长 | 570nm |
次波长 | 412nm |
反应时间 | 10分钟 |
温育时间 | 5分钟 |
反应方向 | 下降 |
结果 | ng/mL |
结果精度 | 0.01 |
拟合方法 | Logit-log 4P |
校准品浓度 | 0.00ng/mL、100.00ng/mL、200.00ng/mL、400.00ng/mL、800.00ng/mL、1600.00ng/mL |
2. 质控品检测实验:
利用上述的胶乳增强免疫比浊检测方法,对质控品进行测定,并根据步骤1中制作的胶乳增强免疫比浊检测校准曲线,计算每个质控品中阿立哌唑的含量,每个质控品重复测定10次,检测结果及数据分析详见表6。
表6 阿立哌唑胶乳增强免疫比浊试剂检测结果及数据分析
质控品 | 空白 | 低值 | 中值 | 高值 |
浓度 (ng/mL) | 0.00 | 150.00 | 300.00 | 1200.00 |
测试1 | 0.00 | 150.37 | 302.24 | 1196.05 |
测试2 | 0.00 | 152.34 | 305.74 | 1198.32 |
测试3 | 0.00 | 149.68 | 300.87 | 1202.24 |
测试4 | 0.00 | 145.25 | 303.88 | 1209.40 |
测试5 | 0.00 | 150.00 | 297.68 | 1220.13 |
测试6 | 0.00 | 158.52 | 299.01 | 1203.95 |
测试7 | 0.00 | 151.61 | 300.90 | 1201.58 |
测试8 | 0.00 | 152.09 | 306.04 | 1207.89 |
测试9 | 0.00 | 147.40 | 303.12 | 1218.00 |
测试10 | 0.00 | 150.46 | 302.50 | 1201.07 |
平均值(ng/mL) | 0.00 | 150.77 | 302.20 | 1205.86 |
标准差(SD) | / | 3.48 | 2.69 | 8.02 |
精密度(CV%) | / | 2.31 | 0.89 | 0.67 |
回收率(%) | / | 100.51 | 100.73 | 100.49 |
实验结果表明:测定不同浓度质控品中阿立哌唑含量的CV值均低于5%,回收率均在95%-105%之间,说明本发明的阿立哌唑胶乳增强免疫比浊检测试剂测定生物样本中阿立哌唑含量的精密度较高,结果准确。
对于本领域的技术人员来说,可根据以上描述的技术方案以及构思做出其它各种相应的变更以及修改,而所有的这些变更以及修改都应该属于本发明权利要求的保护范围之内。
序列表
<110> 苏州博源医疗科技有限公司
<120> 一种阿立哌唑关键基团衍生物、免疫原、抗阿立哌唑特异性抗体及其制备方法与应用
<130> 2020.12.13
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 609
<212> PRT
<213> 人工合成(Artificial Sequence)
<400> 1
Met Lys Trp Val Thr Phe Ile Ser Leu Lys Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys Ser Glu Val Ala
20 25 30
His Arg Phe Lys Asp Leu Gly Glu Lys Asn Phe Lys Ala Leu Val Leu
35 40 45
Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val
50 55 60
Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Lys Ala Asp
65 70 75 80
Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
85 90 95
Lys Leu Cys Thr Val Ala Thr Lys Arg Glu Thr Tyr Gly Glu Met Ala
100 105 110
Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln
115 120 125
His Lys Asp Asp Asn Pro Asn Leu Pro Arg Lys Val Arg Pro Glu Val
130 135 140
Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys
145 150 155 160
Lys Tyr Leu Tyr Glu Ile Ala Arg Arg Lys Pro Tyr Phe Tyr Ala Pro
165 170 175
Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys
180 185 190
Cys Gln Ala Ala Asp Lys Ala Lys Cys Leu Leu Pro Lys Leu Asp Glu
195 200 205
Leu Arg Asp Glu Gly Lys Ala Ser Lys Ala Lys Gln Arg Leu Lys Cys
210 215 220
Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val
225 230 235 240
Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser
245 250 255
Lys Leu Val Thr Lys Leu Thr Lys Val His Thr Glu Cys Cys His Gly
260 265 270
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Lys Leu Ala Lys Tyr Ile
275 280 285
Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu
290 295 300
Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Lys
305 310 315 320
Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser
325 330 335
Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Lys Gly
340 345 350
Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val
355 360 365
Leu Leu Lys Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys
370 375 380
Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu
385 390 395 400
Phe Lys Pro Leu Val Glu Lys Pro Gln Asn Leu Ile Lys Gln Asn Cys
405 410 415
Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Lys
420 425 430
Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val
435 440 445
Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His
450 455 460
Pro Glu Ala Lys Arg Lys Pro Cys Ala Glu Asp Tyr Leu Ser Val Val
465 470 475 480
Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg
485 490 495
Val Thr Lys Lys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe
500 505 510
Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala
515 520 525
Lys Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu
530 535 540
Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys
545 550 555 560
Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Lys
565 570 575
Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe
580 585 590
Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Lys Ala Leu Gly
595 600 605
Leu
Claims (4)
1.一种应用抗阿立哌唑特异性抗体制备的阿立哌唑检测试剂,其特征在于:所述阿立哌唑检测试剂为阿立哌唑均相酶免疫检测试剂或阿立哌唑胶乳增强免疫比浊检测试剂;
所述阿立哌唑均相酶免疫检测试剂,由R1试剂与R2试剂组成,所述R1试剂包含所述的抗阿立哌唑特异性抗体与R1缓冲液,所述R2试剂包含阿立哌唑葡萄糖-6-磷酸脱氢酶标记偶联物与R2缓冲液;
所述的R1缓冲液含有酶底物、辅酶、牛血清白蛋白及Tris缓冲液,所述的酶底物为葡萄糖-6-磷酸,所述的辅酶为氧化型烟酰胺腺嘌呤二核苷酸;
所述的阿立哌唑葡萄糖-6-磷酸脱氢酶标记偶联物由阿立哌唑关键基团衍生物与葡萄糖-6-磷酸脱氢酶偶联而成;其结构式如式Ⅲ所示:
所述的R2缓冲液为含有牛血清白蛋白的Tris缓冲液;
所述阿立哌唑胶乳增强免疫比浊检测试剂,由L1试剂与L2试剂组成;
所述L1试剂由所述的抗阿立哌唑特异性抗体、pH=8.0的缓冲液、牛血清白蛋白、氯化钠、吐温-20、丙三醇、乙二胺四乙酸、促凝剂以及防腐剂组成;
所述L2试剂由阿立哌唑-牛血清白蛋白复合体包被的聚苯乙烯胶乳颗粒、pH=8.0的缓冲液、牛血清白蛋白、氯化钠、吐温-20、丙三醇、乙二胺四乙酸以及防腐剂组成;
所述的阿立哌唑-牛血清白蛋白复合体由阿立哌唑关键基团衍生物与牛血清白蛋白偶联而成,其结构式如式Ⅳ所示:
所述的聚苯乙烯胶乳颗粒直径范围为50-250nm;
所述的缓冲液为磷酸盐缓冲液、甘氨酸缓冲液、MES缓冲液、硼酸盐缓冲液、Tris-HCl缓冲液或巴比妥缓冲液中的一种;
所述促凝剂为PEG-4000、PEG-6000、PEG-8000或硫酸葡聚糖钠中的一种;
所述防腐剂为叠氮钠、硫柳汞、苯酚或乙基汞硫代硫酸钠中的一种;
所述抗阿立哌唑特异性抗体为使用阿立哌唑免疫原对实验动物进行注射后所得到的特异性抗体,所述的实验动物为兔子、山羊、绵羊、小鼠、大鼠、豚鼠或马中的一种;
所述阿立哌唑免疫原由阿立哌唑关键基团衍生物与载体蛋白连接而成,其结构式如式Ⅱ所示:
其中,载体蛋白为重组人血清白蛋白;所述重组人血清白蛋白的氨基酸序列如序列表SEQ ID NO:1所示;
所述的阿立哌唑关键基团衍生物,其结构式如式Ⅰ所示:
2.根据权利要求1所述的应用抗阿立哌唑特异性抗体制备的阿立哌唑检测试剂,其特征在于:所述阿立哌唑关键基团衍生物的合成方法,如下式所示:
3.根据权利要求1所述的应用抗阿立哌唑特异性抗体制备的阿立哌唑检测试剂,其特征在于:所述阿立哌唑免疫原的制备方法,包括以下步骤:
(B1)载体蛋白溶液的制备:将权利要求1中所述的重组人血清白蛋白溶解于磷酸盐缓冲液中,得到载体蛋白溶液;
(B2)阿立哌唑关键基团衍生物溶液的制备:将权利要求1中所述的阿立哌唑关键基团衍生物与二甲基甲酰胺、乙醇、磷酸钾缓冲液、1-乙基-3-(-3-二甲氨丙基)碳二亚胺和N-羟基硫代琥珀酰亚胺混合,搅拌溶解,得到阿立哌唑关键基团衍生物溶液;
(B3)阿立哌唑免疫原的合成:将步骤(B2)得到的阿立哌唑关键基团衍生物溶液加入到步骤(B1)得到的载体蛋白溶液中,搅拌反应,经透析纯化,得到阿立哌唑免疫原。
4.根据权利要求1所述的应用抗阿立哌唑特异性抗体制备的阿立哌唑检测试剂,其特征在于:所述抗阿立哌唑特异性抗体的制备方法,包含以下步骤:
(C1)将权利要求1中所述的阿立哌唑免疫原用磷酸盐缓冲液稀释,得到阿立哌唑人工抗原溶液,然后将阿立哌唑人工抗原溶液与等量弗氏完全佐剂混合,对权利要求1中所述的实验动物进行多点注射;
(C2)3-6周后,再用相同的阿立哌唑人工抗原溶液与等量弗氏不完全佐剂混合,对上述实验动物进行多点注射,之后每隔3-6周注射一次,共计注射3-10次;
(C3)对步骤(C2)中完成注射的实验动物取血,分离纯化,得到抗阿立哌唑特异性抗体。
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