CN114436987A - 一种唑尼沙胺衍生物、均相酶免疫检测试剂及制备方法 - Google Patents
一种唑尼沙胺衍生物、均相酶免疫检测试剂及制备方法 Download PDFInfo
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- CN114436987A CN114436987A CN202210107239.3A CN202210107239A CN114436987A CN 114436987 A CN114436987 A CN 114436987A CN 202210107239 A CN202210107239 A CN 202210107239A CN 114436987 A CN114436987 A CN 114436987A
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- zonisamide
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Abstract
本发明公开了一种唑尼沙胺的衍生物、检测试剂及制备方法，涉及生物检测技术领域。利用该唑尼沙胺衍生物制备的唑尼沙胺免疫原，免疫原性高，得到的抗体特异性强、效价高；利用该衍生物制备得到的均相酶免疫检测试剂中唑尼沙胺酶标偶联物连接了经基因工程改造过的重组葡萄糖‑6‑磷酸脱氢酶，显著提高了检测灵敏度，可有效检测浓度低至2.00µg/mL及以下的样本，且特异性强，与常见的62种其它药物无交叉反应；可实现在全自动生化分析仪上对唑尼沙胺含量的高通量、快速化检测，检测结果稳定，准确度高，检测方法简单，易于实现和推广使用。
Description
技术领域
本发明涉及生物检测技术领域，具体涉及一种唑尼沙胺衍生物、均相酶免疫检测试剂及制备方法。
背景技术
唑尼沙胺（Zonisamide, ZNS）是一种新型抗癫痫药物(antiepileptic drugs，AEDs)，其化学名为1，2-苯并异噁唑-3-甲磺酰胺，分子量为212.23，分子式C8H8N2O3S，其化学结构式如式（Ⅳ）所示：
式（Ⅳ）。
唑尼沙胺主要通过三种作用机制发挥效果：(1)改变与动作电位传播或爆发性发放有关的电压相关性离子通道；(2) 增强GABA 介导的抑制性；(3)干扰氨基酸介导的兴奋性。临床主要应用于：治疗单纯和复杂部分性发作以及继发性全身强直-阵挛性发作、儿童部分性和全身性癫痫、婴儿痉挛症、Lennox-Gastaut综合征、青少年肌阵挛性癫痫等。唑尼沙胺药动学呈线性，长期用药无蓄积性，经肝脏与葡萄糖醛酸结合，被氧化、乙酰化和其他途径广泛代谢，最后由肾脏排泄。口服后吸收好，4～6h达峰浓度，单药治疗时半衰期约为50～70h。儿童抗癫痫药物（AEDs）的血浆清除率明显高于成人，个体间新陈代谢的差异较大，需进行血药浓度监测；同时接受其他抗癫痫药物治疗时，部分抗癫痫药物可以通过调节肝酶活性影响唑尼沙胺的药动学特征，需进行血药浓度监测；对于孕妇、老人、肝/肾功能不全、感染、烧伤、HIV感染或其他疾病除了由病理状态引起的改变外，用于治疗这些疾病的药物还可能引起药物与药物之间的药代动力学相互作用，进而导致唑尼沙胺药物浓度的变化。唑尼沙胺的不良反应有：嗜睡、神经衰弱、食欲不振、共济失调、反应迟钝、认知困难、肾结石等，偶尔可出现严重的皮疹和中毒性表皮坏死。为了合理控制抗癫痫用药，避免出现副反应以及调整剂量，需要对唑尼沙胺进行血药浓度监测，以提高唑尼沙胺应用的安全性和有效性。
检测唑尼沙胺的实验室方法有：高效液相色谱法、离子色谱-抑制电导检测法、胶乳增强免疫比浊法等。高效液相色谱法灵敏度高、检测范围广，但存在样品处理较复杂，高精密仪器价格昂贵，需经过专门培训的技术人员才能操作，维护成本较高等缺陷，难以在临床上大规模推广。离子色谱-抑制电导检测法的优点是便捷、灵敏度高、选择性好，且离子色谱-抑制电导检测法能与分析无机离子一样快速、方便地测定有机离子，不污染环境，但是该检测方法样品前处理步骤较为复杂，检测成本较高以及对操作人员专业要求较高，难以在临床上广泛应用。胶乳增强免疫比浊法的优点是精密度、准确性、灵敏度、稳定性均较好，操作简便，但胶乳微球制备复杂、成本较高。因此，针对现有技术中存在的缺陷，研发一种质量达到临床要求，且具有灵敏度高、特异性强、稳定性好、结果准确等优点，可应用于全自动生化分析仪的唑尼沙胺检测试剂已成为国内外治疗药物监测领域的热点。本发明采用的均相酶免疫法具有高灵敏度，高特异性、操作简便等优势，是一种快速、准确、稳定的检测方法，可在全自动生化分析仪上进行检测，降低了成本，适于临床推广使用。
发明内容
本发明的目的在于提供一种唑尼沙胺衍生物、均相酶免疫检测试剂及制备方法。该唑尼沙胺均相酶免疫检测试剂具有灵敏度高、稳定性好、特异性强、结果准确等优点，可实现大批量样品全自动快速检测，克服了现有技术存在的缺陷。
本发明一方面提供了一种唑尼沙胺衍生物，所述的唑尼沙胺衍生物的结构式如式（Ⅰ）所示：
式（Ⅰ），
式中X1为-CH2-(CH2)n-COOH，其中n为1至20之间的任意整数，优选地，所述X1为-CH2-(CH2)2-COOH。
本发明还提供了一种上述唑尼沙胺衍生物的制备方法，所述的制备方法具有以下的合成路径：
具体地，所述唑尼沙胺衍生物的制备方法包括以下步骤：
称取化合物1(7 g)溶解于甲苯(70 ml)中，然后加入琥珀酸酐(4 g)制成反应混合溶液，将上述反应混合溶液在回流条件下搅拌过夜。 反应结束后将上述反应混合溶液进行浓缩，然后再用快速色谱法进行纯化，得到唑尼沙胺衍生物。
通过1H NMR（Varian mercury plus 400 MHz）光谱扫描分析（TMS作为内标）与LC-MS（Agilent 1200A）对得到的唑尼沙胺衍生物进行化学结构鉴定。
本发明还提供了一种唑尼沙胺均相酶免疫检测试剂，所述的唑尼沙胺均相酶免疫检测试剂包括R1试剂和R2试剂；
所述的R1试剂包括抗唑尼沙胺特异性抗体和均相酶底物溶液；
所述的R2试剂包括唑尼沙胺酶标偶联物和R2缓冲液；
所述的抗唑尼沙胺特异性抗体是由唑尼沙胺免疫原免疫实验动物后产生的多克隆抗体；
所述的实验动物是哺乳动物；优选地，所述的哺乳动物是兔子、绵羊、山羊、小鼠、大鼠、豚鼠、驴、马或骆驼中的一种；更优选地，所述的哺乳动物是兔子。
所述的唑尼沙胺免疫原是由式（Ⅰ）所示的唑尼沙胺衍生物与载体连接得到的化合物，其结构式如式（Ⅱ）所示：
式（Ⅱ）；
式中X2为-CO-(CH2)n-CO-，其中n为1至20之间的任意整数，优选地，所述X2为-CO-(CH2)2-CO-；
所述的载体为具有免疫原性的蛋白质或多肽；
优选地，所述的具有免疫原性的蛋白质或多肽为血清蛋白、卵清蛋白、丙种球蛋白、甲状腺球蛋白、血蓝蛋白或多聚赖氨酸中的一种；更优选地，所述具有免疫原性的蛋白质或多肽为牛血清白蛋白。
所述的均相酶底物溶液是由葡萄糖-6-磷酸、氧化型烟酰胺腺嘌呤二核苷酸、三羟甲基氨基甲烷、氯化钠、氯化镁、牛血清白蛋白与防腐剂配制得到；
所述的唑尼沙胺酶标偶联物是由式（Ⅰ）所示的唑尼沙胺衍生物与重组葡萄糖-6-磷酸脱氢酶连接而成，其结构式如式（Ⅲ）所示：
式（Ⅲ）；
式中X2为-CO-(CH2)n-CO-，其中n为1至20之间的任意整数，优选地，所述X2为-CO-(CH2)2-CO-；
式中mG6PDH为重组葡萄糖-6-磷酸脱氢酶，所述重组葡萄糖-6-磷酸脱氢酶是由来源于肠膜明串珠菌的野生型葡萄糖-6-磷酸脱氢酶经过特异位点基因编辑之后得到，所述野生型葡萄糖-6-磷酸脱氢酶的氨基酸序列为SEQ ID NO：1所示，所述重组葡萄糖-6-磷酸脱氢酶的氨基酸序列为SEQ ID NO：2所示；
所述R2缓冲液是由三羟甲基氨基甲烷、氯化钠、氯化镁、牛血清白蛋白与防腐剂配制得到。
优选地，所述的唑尼沙胺免疫原的制备方法包括以下步骤：
（A1）载体溶液的制备：将载体溶解于磷酸盐缓冲液中，得到载体溶液；
（A2）唑尼沙胺衍生物溶液的制备：将上述的唑尼沙胺衍生物、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、N-羟基硫代琥珀酰亚胺混合，搅拌溶解，得到唑尼沙胺衍生物溶液；
（A3）唑尼沙胺免疫原的合成：将步骤（A2）得到的唑尼沙胺衍生物溶液加入到步骤（A1）得到的载体溶液中，搅拌反应，经透析纯化，得到唑尼沙胺免疫原。
具体地，所述的唑尼沙胺免疫原的制备方法包括以下步骤：
（A1）载体溶液的制备：将载体蛋白溶解于0.1-0.3mol/L的磷酸钾缓冲液（pH=8.5）中，载体蛋白的终浓度为5-8mg/mL，得到载体溶液；
（A2）唑尼沙胺衍生物溶液的制备：将100-300mg上述的唑尼沙胺衍生物、2-6mL二甲基甲酰胺、2-6mL乙醇、3-9mL的磷酸钾缓冲液（10mmol/L，pH=7.0）、100-300mg 1-乙基-3-(-3-二甲氨丙基)碳二亚胺、30-90mg N-羟基硫代琥珀酰亚胺混合，搅拌溶解反应60-180min，得到唑尼沙胺衍生物溶液；
（A3）唑尼沙胺免疫原的合成：将步骤（A2）得到的唑尼沙胺衍生物溶液加入到步骤（A1）得到的载体溶液中，并在0-8℃下搅拌过夜，经透析纯化，得到唑尼沙胺免疫原。
优选地，所述的抗唑尼沙胺特异性抗体的制备方法包括以下步骤：
（B1）将上述的唑尼沙胺免疫原用磷酸盐缓冲液稀释，得到人工抗原溶液，然后将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；
（B2）1-5周后，再用相同的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1-5周注射一次，共计注射3-6次；
（B3）对步骤（B2）完成注射的实验动物取血，分离纯化，得到抗唑尼沙胺特异性抗体。
具体地，所述的抗唑尼沙胺特异性抗体的制备方法包括以下步骤：
（B1）将上述的唑尼沙胺免疫原用0.01mol/L磷酸钠缓冲液（pH=6.5）稀释至终浓度为1.0-3.0mg/mL，得到人工抗原溶液，然后将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；
（B2）1-5周后，再用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1-5周注射一次，共计注射3-6次；
（B3）对步骤（B2）完成注射的实验动物兔子取血，分离纯化，得到抗唑尼沙胺特异性抗体。
优选地，所述的唑尼沙胺酶标偶联物的制备方法包括以下步骤：
（C1）重组葡萄糖-6-磷酸脱氢酶溶液的制备：将重组葡萄糖-6-磷酸脱氢酶、MgCl2和NaCl混合溶解于Tris缓冲液中，再加入还原型烟酰胺腺嘌呤二核苷酸、葡萄糖-6-磷酸、卡必醇和二甲基亚砜，搅拌溶解，得到重组葡萄糖-6-磷酸脱氢酶溶液；
（C2）唑尼沙胺衍生物溶液的制备：将上述的唑尼沙胺衍生物溶解于二甲基甲酰胺中，降温至-10℃以下，加入三丁胺和氯甲酸异丁酯，低温搅拌混匀，得到唑尼沙胺衍生物溶液；
（C3）唑尼沙胺酶标偶联物的合成：将步骤（C2）得到的唑尼沙胺衍生物溶液逐滴加入到步骤（C1）得到的重组葡萄糖-6-磷酸脱氢酶溶液中，搅拌反应，经凝胶层析柱纯化，得到唑尼沙胺酶标偶联物。
具体地，所述的唑尼沙胺酶标偶联物的制备方法包括以下步骤：
（C1）重组葡萄糖-6-磷酸脱氢酶溶液的制备：将5-25mg的重组葡萄糖-6-磷酸脱氢酶、3-15mg MgCl2和30-150mg NaCl混合溶解于5-25mL Tris缓冲液（1mol/L，pH=6.8）中；再加入100-500mg还原型烟酰胺腺嘌呤二核苷酸、50-250mg葡萄糖-6-磷酸、0.3-1.5mL卡必醇和1-5mL二甲基亚砜，搅拌溶解，得到重组葡萄糖-6-磷酸脱氢酶溶液；
（C2）唑尼沙胺衍生物溶液的制备：将3-15mg上述的唑尼沙胺衍生物溶解于300-1500µL二甲基甲酰胺中，降温至-18℃，加入1.5-7.5µL三丁胺和1-5µL氯甲酸异丁酯，低温搅拌混匀，得到唑尼沙胺衍生物溶液；
（C3）唑尼沙胺酶标偶联物的合成：将步骤（C2）得到的唑尼沙胺衍生物溶液逐滴加入到步骤（C1）得到的重组葡萄糖-6-磷酸脱氢酶溶液中，2-8℃搅拌反应过夜，经凝胶层析柱纯化，得到唑尼沙胺酶标偶联物。
本发明另一方面提供了一种上述的唑尼沙胺均相酶免疫检测试剂的制备方法，包括以下步骤：
（D1）均相酶底物溶液的制备：将葡萄糖-6-磷酸、氧化型烟酰胺腺嘌呤二核苷酸、三羟甲基氨基甲烷、氯化钠、氯化镁、牛血清白蛋白与防腐剂溶解于纯化水中，制得均相酶底物溶液；
（D2）R1试剂的制备：将上述的抗唑尼沙胺特异性抗体与步骤（D1）得到的均相酶底物溶液混合均匀，得到R1试剂，所述的R1试剂中抗唑尼沙胺特异性抗体与均相酶底物溶液的体积比为1∶100-8000；
（D3）R2缓冲液的制备：将三羟甲基氨基甲烷、氯化钠、氯化镁、牛血清白蛋白与防腐剂溶解于纯化水中，制得R2缓冲液；
（D4）R2试剂的制备：将上述的唑尼沙胺酶标偶联物溶解于R2缓冲液中，得到R2试剂，所述的R2试剂中唑尼沙胺酶标偶联物与R2缓冲液的体积比为1∶100-8000。
优选地，所述的R1试剂中抗唑尼沙胺特异性抗体与均相酶底物溶液的体积比为1∶500；所述的R2试剂中唑尼沙胺酶标偶联物与R2缓冲液的体积比为1∶1500。
具体地，所述的唑尼沙胺均相酶免疫检测试剂的制备方法，包括以下步骤：
（D1）均相酶底物溶液的制备：将2-10g葡萄糖-6-磷酸、3-15g氧化型烟酰胺腺嘌呤二核苷酸、16-80mg三羟甲基氨基甲烷、0.5-2.5g氯化钠、0.5-2.5g氯化镁、50-250mg牛血清白蛋白与10-50mg防腐剂溶解于1-5L纯化水中，调节pH至8.5，制得均相酶底物溶液；
（D2）R1试剂的制备：将上述的抗唑尼沙胺特异性抗体与步骤（D1）得到的均相酶底物溶液混合均匀，得到R1试剂，所述的R1试剂中抗唑尼沙胺特异性抗体与均相酶底物溶液的体积比为1∶600；
（D3）R2缓冲液的制备：将16-80mg三羟甲基氨基甲烷、0.5-2.5g氯化钠、0.5-2.5g氯化镁、50-250mg牛血清白蛋白与10-50mg防腐剂溶解于1-5L纯化水中，调节pH至8.0，制得R2缓冲液；
（D4）R2试剂的制备：将上述的唑尼沙胺酶标偶联物溶解于步骤（D3）得到的R2缓冲液中，得到R2试剂，所述的R2试剂中唑尼沙胺酶标偶联物与R2缓冲液的体积比为1∶1800。
本发明的有益效果为：提供了一种唑尼沙胺衍生物、均相酶免疫检测试剂及制备方法。由该衍生物制备得到的抗体特异性强、效价高，利用该衍生物制备得到的均相酶免疫检测试剂中的唑尼沙胺酶标偶联物连接了经基因编辑技术改造过的重组葡萄糖-6-磷酸脱氢酶（mG6PDH），显著提高了检测灵敏度，可有效检测浓度低至2.00 µg/mL及以下的样本；可实现在全自动生化分析仪上对唑尼沙胺含量的高通量、快速化检测，检测的稳定性好、准确度高、特异性强，与62种常见药物无交叉反应，检测效率显著提高，检测方法简单，易于实现和推广使用。
附图说明
图1是实施例6中唑尼沙胺均相酶免疫检测的标准曲线。
图2是式（Ⅴ）所示的唑尼沙胺衍生物的1H NMR光谱扫描分析谱图。
图3是式（Ⅴ）所示的唑尼沙胺衍生物的LC-MS分析谱图。
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，需要说明的是，在不相冲突的前提下，以下描述的各实施例之间或各技术特征之间可以任意组合形成新的实施例。
实施例1：唑尼沙胺衍生物的制备
唑尼沙胺衍生物的合成路径如下：
所述唑尼沙胺衍生物的制备方法包括以下步骤：
称取化合物1(7 g)溶解于甲苯(70 ml)中，然后加入琥珀酸酐(4 g)制成反应混合溶液，将上述反应混合溶液在回流条件下搅拌过夜。 反应结束后将上述反应混合溶液进行浓缩，然后再用快速色谱法进行纯化，得到4 g唑尼沙胺衍生物。
通过1H NMR（Varian mercury plus 400 MHz）光谱扫描分析（TMS作为内标）与LC-MS（Agilent 1200A）对得到的唑尼沙胺衍生物进行化学结构鉴定，结果表明：该唑尼沙胺衍生物即为结构式如式（Ⅴ）所示的唑尼沙胺衍生物。
式（Ⅴ）。
实施例2：唑尼沙胺免疫原的制备
唑尼沙胺免疫原的制备方法包括以下步骤：
（A1）载体溶液的制备：将载体蛋白溶解于0.2mol/L的磷酸钾缓冲液（pH=8.5）中，载体蛋白的终浓度为5.5mg/mL，得到载体溶液；
（A2）唑尼沙胺衍生物溶液的制备：将200mg上述的唑尼沙胺衍生物、4mL二甲基甲酰胺、4mL乙醇、6mL的磷酸钾缓冲液（10mmol/L，pH=7.0）、200mg 1-乙基-3-(-3-二甲氨丙基)碳二亚胺、60mg N-羟基硫代琥珀酰亚胺混合，搅拌溶解反应120min，得到唑尼沙胺衍生物溶液；
（A3）唑尼沙胺免疫原的合成：将步骤（A2）得到的唑尼沙胺衍生物溶液加入到步骤（A1）得到的载体溶液中，并在4℃下搅拌过夜，经透析纯化，得到唑尼沙胺免疫原。
实施例3：抗唑尼沙胺特异性抗体的制备
抗唑尼沙胺特异性抗体的制备方法包括以下步骤：
（B1）将上述的唑尼沙胺免疫原用0.01mol/L磷酸钠缓冲液（pH=6.5）稀释至终浓度为2.0mg/mL，得到人工抗原溶液，然后将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；
（B2）3周后，再用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3周注射一次，共计注射5次；
（B3）对步骤（B2）完成注射的实验动物兔子取血，分离纯化，得到抗唑尼沙胺特异性抗体。
实施例4：唑尼沙胺酶标偶联物的制备
唑尼沙胺酶标偶联物的制备方法包括以下步骤：
（C1）重组葡萄糖-6-磷酸脱氢酶溶液的制备：将15mg的重组葡萄糖-6-磷酸脱氢酶、9mg MgCl2和90mg NaCl混合溶解于15mL Tris缓冲液（1mol/L，pH=6.8）中；再加入300mg还原型烟酰胺腺嘌呤二核苷酸、150mg葡萄糖-6-磷酸、0.9mL卡必醇和3mL二甲基亚砜，搅拌溶解，得到重组葡萄糖-6-磷酸脱氢酶溶液；
（C2）唑尼沙胺衍生物溶液的制备：将9mg上述的唑尼沙胺衍生物溶解于900µL二甲基甲酰胺中，降温至-18℃，加入4.5µL三丁胺和3µL氯甲酸异丁酯，低温搅拌混匀，得到唑尼沙胺衍生物溶液；
（C3）唑尼沙胺酶标偶联物的合成：将步骤（C2）得到的唑尼沙胺衍生物溶液逐滴加入到步骤（C1）得到的重组葡萄糖-6-磷酸脱氢酶溶液中，2-8℃搅拌反应过夜，经凝胶层析柱纯化，得到唑尼沙胺酶标偶联物。
实施例5：唑尼沙胺均相酶免疫检测试剂的制备
唑尼沙胺均相酶免疫检测试剂的制备方法，包括以下步骤：
（D1）均相酶底物溶液的制备：将6g葡萄糖-6-磷酸、9g氧化型烟酰胺腺嘌呤二核苷酸、48mg三羟甲基氨基甲烷、1.5g氯化钠、1.5g氯化镁、150mg牛血清白蛋白与30mg防腐剂溶解于3L纯化水中，调节pH至8.5，制得均相酶底物溶液；
（D2）R1试剂的制备：将上述的抗唑尼沙胺特异性抗体与步骤（D1）得到的均相酶底物溶液混合均匀，得到R1试剂，所述的R1试剂中抗唑尼沙胺特异性抗体与均相酶底物溶液的体积比为1∶500；
（D3）R2缓冲液的制备：将48mg三羟甲基氨基甲烷、1.5g氯化钠、1.5g氯化镁、150mg牛血清白蛋白与30mg防腐剂溶解于3L纯化水中，调节pH至8.0，制得R2缓冲液；
（D4）R2试剂的制备：将上述的唑尼沙胺酶标偶联物溶解于步骤（D3）得到的R2缓冲液中，得到R2试剂，所述的R2试剂中唑尼沙胺酶标偶联物与R2缓冲液的体积比为1∶1500。
实施例6：唑尼沙胺均相酶免疫检验
（1）建立唑尼沙胺均相酶免疫检验标准曲线
按照表1设置迈瑞BS-480全自动生化分析仪反应参数。所用唑尼沙胺均相酶免疫检测试剂为实施例5制备得到的检测试剂。先加入R1试剂，再加入标准品，最后加入R2试剂。加入R2试剂后，测定不同时间点的OD340吸光值，计算出不同标准品浓度时的反应速率，绘制成反应标准曲线，如图1所示。
表1：迈瑞 BS-480全自动生化分析仪反应参数
| 项目名称 | 唑尼沙胺 |
| R1试剂 | 160µL |
| R2试剂 | 40µL |
| 样本量 | 10µL |
| 分析方法 | 两点终点法 |
| 主波长 | 340nm |
| 次波长 | 405nm |
| 反应时间 | 10分钟 |
| 孵育时间 | 5分钟 |
| 反应方向 | 上升 |
| 结果 | µg/mL |
| 结果精度 | 0.01 |
| 定标方法 | Line Graph |
| 标准品浓度 | 0.00、5.00、10.00、20.00、40.00、80.00 µg/mL |
表2：不同标准品浓度时的反应度数值
| 校准品浓度 （µg/mL） | △OD 340-1 | △OD 340-2 | △OD 340 Mean |
| 0.00 | 8081 | 8078 | 8080 |
| 5.00 | 9061 | 9080 | 9071 |
| 10.00 | 9979 | 9945 | 9962 |
| 20.00 | 11013 | 11012 | 11013 |
| 40.00 | 12341 | 12272 | 12307 |
| 80.00 | 13594 | 13647 | 13621 |
（2）待测样本检测：
待测样本是将唑尼沙胺标准品溶解于健康人尿液中，调整至浓度分别为7.50µg/mL、30.00µg/mL、60.00µg/mL。重复测定低、中、高浓度待测样本10次，根据图1所示的反应标准曲线，计算每个样本中唑尼沙胺的含量，并计算精密度和回收率，回收率=（检测浓度平均值/样本浓度）×100%，结果如表2所示。
表3：样本测定及精密度和回收率评估
| 尿液样本 | 低值 | 中值 | 高值 |
| 样本浓度 (µg/mL) | 7.50 | 30.00 | 60.00 |
| Rep.1 | 7.41 | 29.66 | 59.77 |
| Rep.2 | 7.32 | 29.35 | 59.47 |
| Rep.3 | 7.44 | 29.60 | 62.60 |
| Rep.4 | 7.35 | 29.09 | 62.28 |
| Rep.5 | 7.40 | 31.14 | 61.58 |
| Rep.6 | 7.52 | 30.50 | 59.32 |
| Rep.7 | 7.56 | 29.78 | 58.88 |
| Rep.8 | 7.63 | 31.43 | 61.14 |
| Rep.9 | 7.45 | 30.85 | 60.93 |
| Rep.10 | 7.39 | 31.00 | 58.96 |
| 平均值(µg/mL) | 7.45 | 30.24 | 60.49 |
| 标准差（SD） | 0.10 | 0.84 | 1.39 |
| 精密度（CV%） | 1.34 | 2.78 | 2.30 |
| 回收率 % | 99.33 | 100.80 | 100.82 |
检测结果：本发明的唑尼沙胺均相酶免疫检测试剂测定唑尼沙胺样本的精密度较高，CV均低于5%；准确度较高，回收率均达到95%-105%范围之内。
实施例7：常见其它药物交叉反应实验
选取62种常见其它药物进行交叉反应检测，将待测药物纯品溶解于空白血清样本中，调整待测药物浓度至100.00 µg/mL，采用实施例6中的唑尼沙胺均相酶免疫检测方法进行检测，根据图1所示的反应标准曲线得到相应药物的浓度。62种常见其它药物名称以及测定结果详见表3。
表4：常见药物交叉反应实验结果
| 序号 | 化合物名称 | 药物浓度检测值(µg/mL) | 序号 | 化合物名称 | 药物浓度检测值(µg/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 |
| 22 | 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 |
测定结果显示：上述62种常见其它药物浓度的检测值均为0.00 µg/mL。由此可见，本发明提供的唑尼沙胺均相酶免疫检验试剂的特异性强，与62种常见其它药物无任何交叉反应。
实施例8：日间精密度验证实验
实验方法：待测样本必须有很好的稳定性和均匀性，可选用商品化的质控品或校准品。进行精密度验证实验前应做好仪器的校准，使用质控品进行常规的质量控制，确保在控后方可进行日间精密度实验。如果出现室内质控失控或者出现其它操作问题，则必须将此批次数据弃去，另加一个批次测量。如在同一个分析系统上做多个项目检测，每个测试项目都要分别进行日间精密度验证实验。记录实验数据进行统计分析，以变异系数（CV）不超过10%为合格标准。
表5：日间精密度验证实验结果
实验结果表明：低值样本、中值样本、高值样本的日间精密度验证变异系数（CV）均低于10%，本发明提供的唑尼沙胺均相酶免疫检验试剂的日间精密度符合临床检验要求。
实施例9：线性范围的验证实验
取唑尼沙胺高值与低值血清样本，按照比例混合成10个浓度，每个浓度测定3次，对结果进行统计分析。依据实验结果逐渐减少数据点直至表现出线性关系，可得出最宽的线性范围，所有样本应在一次运行或几次间隔很短的运行中随机测定，所有检测在一天之内完成。
实验结果表明：本发明提供的唑尼沙胺均相酶免疫检验试剂在2.00～80.00 µg/mL区间内相关系数r=0.9998，r≥0.990，表明在此范围内线性相关性良好。在2.00～10.00µg/mL线性范围区间内，绝对偏差在±1.00 µg/mL以内，在10.00～80.00 µg/mL线性范围区间内，相对偏差在±10.0%以内。
以上所述实施例仅是为充分说明本发明而所举的较佳的实施例，本发明的保护范围不限于此。本技术领域的技术人员在本发明基础上所作的等同替代或变换，均在本发明的保护范围之内。本发明的保护范围以权利要求书为准。
序列表
<110> 安徽爱索特克医学检验实验室有限公司
<120> 一种唑尼沙胺衍生物、均相酶免疫检测试剂及制备方法
<130> 2022.1.26
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Claims (10)
1.一种唑尼沙胺衍生物，其特征在于，所述的唑尼沙胺衍生物的结构式如式（Ⅰ）所示：
式（Ⅰ），
式中X1为-CO-(CH2)n-COOH，其中n为1至20之间的任意整数，优选地，所述X1为-CO-(CH2)2-COOH。
2.根据权利要求1所述的唑尼沙胺衍生物，其特征在于，所述唑尼沙胺衍生物的制备方法具有以下的合成路径：
3.一种唑尼沙胺均相酶免疫检测试剂，其特征在于，所述的唑尼沙胺均相酶免疫检测试剂包括R1试剂和R2试剂；
所述的R1试剂包括抗唑尼沙胺特异性抗体和均相酶底物溶液；
所述的R2试剂包括唑尼沙胺酶标偶联物和R2缓冲液；
所述的抗唑尼沙胺特异性抗体是由唑尼沙胺免疫原免疫实验动物后产生的多克隆抗体；
所述的实验动物是哺乳动物；
所述的唑尼沙胺免疫原是由权利要求1所述的唑尼沙胺衍生物与载体连接得到的化合物，其结构式如式（Ⅱ）所示：
式（Ⅱ）；
式中X2为-CO-(CH2)n-CO-，其中n为1至20之间的任意整数，优选地，所述X2为-CO-(CH2)2-CO-；
所述的载体为具有免疫原性的蛋白质或多肽；
所述的均相酶底物溶液是由葡萄糖-6-磷酸、氧化型烟酰胺腺嘌呤二核苷酸、三羟甲基氨基甲烷、氯化钠、氯化镁、牛血清白蛋白与防腐剂配制得到；
所述的唑尼沙胺酶标偶联物是由权利要求1所述的唑尼沙胺衍生物与重组葡萄糖-6-磷酸脱氢酶连接而成，其结构式如式（Ⅲ）所示：
式（Ⅲ）；
式中X2为-CO-(CH2)n-CO-，其中n为1至20之间的任意整数，优选地，所述X2为-CO-(CH2)2-CO-；
式中mG6PDH为重组葡萄糖-6-磷酸脱氢酶，所述重组葡萄糖-6-磷酸脱氢酶是由来源于肠膜明串珠菌的野生型葡萄糖-6-磷酸脱氢酶经过特异位点基因编辑之后得到，所述野生型葡萄糖-6-磷酸脱氢酶的氨基酸序列为SEQ ID NO：1所示，所述重组葡萄糖-6-磷酸脱氢酶的氨基酸序列为SEQ ID NO：2所示；
所述R2缓冲液是由三羟甲基氨基甲烷、氯化钠、氯化镁、牛血清白蛋白与防腐剂配制得到。
4.根据权利要求3所述的唑尼沙胺均相酶免疫检测试剂，其特征在于，所述的哺乳动物是兔子、绵羊、山羊、小鼠、大鼠、豚鼠、驴、马或骆驼中的一种；所述的具有免疫原性的蛋白质或多肽为血清蛋白、卵清蛋白、丙种球蛋白、甲状腺球蛋白、血蓝蛋白或多聚赖氨酸中的一种。
5.根据权利要求3-4任一项所述的唑尼沙胺均相酶免疫检测试剂，其特征在于，所述的哺乳动物是兔子；所述具有免疫原性的蛋白质或多肽为牛血清白蛋白。
6.根据权利要求3所述的唑尼沙胺均相酶免疫检测试剂，其特征在于，所述的唑尼沙胺免疫原的制备方法包括以下步骤：
（A1）载体溶液的制备：将载体溶解于磷酸盐缓冲液中，得到载体溶液；
（A2）唑尼沙胺衍生物溶液的制备：将权利要求1所述的唑尼沙胺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，得到唑尼沙胺衍生物溶液；
（A3）唑尼沙胺免疫原的合成：将步骤（A2）得到的唑尼沙胺衍生物溶液加入到步骤（A1）得到的载体溶液中，搅拌反应，经透析纯化，得到唑尼沙胺免疫原。
7.根据权利要求3所述的唑尼沙胺均相酶免疫检测试剂，其特征在于，所述的抗唑尼沙胺特异性抗体的制备方法包括以下步骤：
（B1）将权利要求3中所述的唑尼沙胺免疫原用磷酸盐缓冲液稀释，得到人工抗原溶液，然后将人工抗原溶液与等量弗氏完全佐剂混合，对权利要求3中所述的实验动物进行多点注射；
（B2）1-5周后，再用相同的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1-5周注射一次，共计注射3-6次；
（B3）对步骤（B2）完成注射的实验动物取血，分离纯化，得到抗唑尼沙胺特异性抗体。
8.根据权利要求3所述的唑尼沙胺均相酶免疫检测试剂，其特征在于，所述的唑尼沙胺酶标偶联物的制备方法包括以下步骤：
（C1）重组葡萄糖-6-磷酸脱氢酶溶液的制备：将重组葡萄糖-6-磷酸脱氢酶、MgCl2和NaCl混合溶解于Tris缓冲液中，再加入还原型烟酰胺腺嘌呤二核苷酸、葡萄糖-6-磷酸、卡必醇和二甲基亚砜，搅拌溶解，得到重组葡萄糖-6-磷酸脱氢酶溶液；
（C2）唑尼沙胺衍生物溶液的制备：将权利要求1所述的唑尼沙胺衍生物溶解于二甲基甲酰胺中，降温至-10℃以下，加入三丁胺和氯甲酸异丁酯，低温搅拌混匀，得到唑尼沙胺衍生物溶液；
（C3）唑尼沙胺酶标偶联物的合成：将步骤（C2）得到的唑尼沙胺衍生物溶液逐滴加入到步骤（C1）得到的重组葡萄糖-6-磷酸脱氢酶溶液中，搅拌反应，经凝胶层析柱纯化，得到唑尼沙胺酶标偶联物。
9.一种权利要求3所述的唑尼沙胺均相酶免疫检测试剂的制备方法，其特征在于，所述制备方法包括以下步骤：
（D1）均相酶底物溶液的制备：将葡萄糖-6-磷酸、氧化型烟酰胺腺嘌呤二核苷酸、三羟甲基氨基甲烷、氯化钠、氯化镁、牛血清白蛋白与防腐剂溶解于纯化水中，制得均相酶底物溶液；
（D2）R1试剂的制备：将权利要求3中所述的抗唑尼沙胺特异性抗体与步骤（D1）得到的均相酶底物溶液混合均匀，得到R1试剂，所述的R1试剂中抗唑尼沙胺特异性抗体与均相酶底物溶液的体积比为1∶100-8000；
（D3）R2缓冲液的制备：将三羟甲基氨基甲烷、氯化钠、氯化镁、牛血清白蛋白与防腐剂溶解于纯化水中，制得R2缓冲液；
（D4）R2试剂的制备：将权利要求3中所述的唑尼沙胺酶标偶联物溶解于R2缓冲液中，得到R2试剂，所述的R2试剂中唑尼沙胺酶标偶联物与R2缓冲液的体积比为1∶100-8000。
10.根据权利要求9所述的唑尼沙胺均相酶免疫检测试剂的制备方法，其特征在于，所述的R1试剂中抗唑尼沙胺特异性抗体与均相酶底物溶液的体积比为1∶500；所述的R2试剂中唑尼沙胺酶标偶联物与R2缓冲液的体积比为1∶1500。
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