CN116773827A - 偶联物在制备检测试剂中的用途 - Google Patents
偶联物在制备检测试剂中的用途 Download PDFInfo
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- CN116773827A CN116773827A CN202310724066.4A CN202310724066A CN116773827A CN 116773827 A CN116773827 A CN 116773827A CN 202310724066 A CN202310724066 A CN 202310724066A CN 116773827 A CN116773827 A CN 116773827A
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- cortisol
- glucose
- phosphate dehydrogenase
- detection
- mutant
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- G—PHYSICS
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Abstract
本申请涉及偶联物在制备检测试剂中的用途。具体而言,本申请的6‑磷酸葡萄糖脱氢酶突变体相较于野生型6‑磷酸葡萄糖脱氢酶包含选自以下的一个突变或其组合:D306C、D375C、G426C。使用本申请的6‑磷酸葡萄糖脱氢酶突变体所制备的检测试剂盒,其特异性强、灵敏度高、操作方便、检测时间短、定量准确,适合高通量检测。
Description
本申请是2019年12月31日提交的中国专利申请《6-磷酸葡萄糖脱氢酶突变体及其在制备皮质醇检测试剂中的用途》(申请号2019114041546)的分案申请。
技术领域
本申请涉及生物检测领域,特别是涉及一种突变的酶6-磷酸葡萄糖脱氢酶(简称G6PDH)及其在皮质醇检测试剂盒中的应用。
背景技术
半抗原,某些小分子物质(分子量小于4000Da),其单独不能诱导免疫应答,即不具备免疫原性,但当其与大分子蛋白质或非抗原性的多聚赖氨酸等载体交联或结合后可获得免疫原性,诱导免疫应答。这些小分子物质可与应答效应产物结合,具备抗原性,它只有免疫反应性,不具免疫原性,又称不完全抗原。
半抗原能与对应抗体结合出现抗原-抗体反应,又不能单独激发人或动物体产生抗体的抗原。它只有免疫反应性,不具免疫原性,又称不完全抗原。大多数多糖、类脂、激素、小分子药物都属于半抗原。如果用化学方法把半抗原与某种蛋白分子(载体)结合,会获得新的免疫原性,并能刺激动物产生相应的抗体。半抗原一旦与蛋白结合,就构成该蛋白质的一个抗原簇。一些比一般半抗原分子量小,但有特异结构的化学活性基团物质(如青霉素、磺胺剂等),称为简单半抗原。
小分子抗原或半抗原因缺乏可作夹心法的两个以上的位点,因此不能用双抗体夹心法进行测定,多采用竞争模式。原理是标本中的抗原和一定量的酶标抗原竞争与固相抗体结合。标本中抗原量含量愈多,结合在固相上的酶标抗原愈少,显色愈浅。小分子激素、药物等ELISA测定多用此法。
皮质醇(Cortisol)结构式如下所示:
皮质醇,亦称氢化可的松,又称氢皮质素或化合物F(compound F),是从肾上腺皮质中提取出的是对糖类代谢具有最强作用的肾上腺皮质激素(属于糖皮质激素的一种)。
皮质醇是通过肾上腺皮质线粒体中的11β-羟化酶的作用,由11-脱氧皮质醇生成。皮质醇也可通过11-β-羟类固醇脱氢酶(11-β-hydroxysteroid dehydrogenase)的作用变成皮质素。
皮质醇在许多重要生理过程的调节中发挥着重要作用,包括能量代谢、维持电解质和血压平衡、免疫调节、应激反应、细胞增殖和分化已经记忆调节和认知功能等等。血液中皮质醇主要与皮质类固醇结合球蛋白和白蛋白结合,游离的皮质醇只占3-5%,且皮质醇浓度水平每天呈现周期性变化,前半夜达到最低,并在凌晨达到峰值。
血液中测量皮质醇主要用于库欣综合征导致的皮质醇分泌过多和艾迪生病导致的皮质醇缺乏等人类疾病,以及治疗监测(***抑制疗法和激素替代疗法)。
目前已知的皮质醇检测方法主要有:酶联免疫吸附法、化学发光免疫分析法、高效液相色谱法、气液色谱法、气相色谱法和质谱联用等。但这些检测方法均存在较多的缺陷,如化学发光尽管灵敏度较好,但需要配套的专用设备,投入使用成本较高不利于推广。在临床检测诊断过程中,以均相酶免疫法(EMIT)和胶乳增强免疫比浊法检测为主。
均相酶免疫测定的原理:在液体均相反应体系中,酶标记抗原(如G6PDH-皮质醇)与非标记抗原(皮质醇),竞争与定量的抗体(皮质醇抗体)进行结合,当抗体与非标记抗原结合越多,酶标记抗原释放的活性就越多,酶催化底物NAD+生成NADH就越多,在340nm波长下检测NADH的吸光度变化,即可推算出液体中皮质醇的含量。
现有的均相酶免疫测定法、胶乳凝集比浊法常常因制备工艺复杂、批间差大,应用受到一定限制。
现有技术中描述了一种皮质醇衍生物-G6PDH偶联物及其制备方法:
1)将G6PDH室温溶解于含有Tris、MgCl2和NaCl的溶液中(pH=9.0);
2)加入NADH、葡萄糖6磷酸以及卡必醇;
3)再逐滴加入二甲基亚砜;
4)在无水状态下称取皮质醇衍生物,溶解于DMF中;使溶液温度降到-2至-8℃;加入三丁胺;
5)加入氯甲酸异丁酯,-2至-8℃搅拌30分钟;
6)将上述激活的皮质醇衍生物溶液逐滴加入到溶解的G6PDH溶液中,2至8℃搅拌过夜;
7)通过层析柱纯化步骤6)所得溶液,获得的最终产物为G6PDH-皮质醇衍生物的偶联物(例如,但不限于CN105131105A中所述方法)。
然而,现有技术的方法依赖于对小分子药物自身所带反应基团进行的激活,之后再与酶进行反应。这样的策略难以保证小分子药物和酶之间的定向1:1反应,而导致批间差异大。
发明内容
鉴于本领域的需求,本申请提供了一种新型的6-磷酸葡萄糖脱氢酶突变体、及其在制备皮质醇检测试剂盒中的用途。
根据一些实施方案,提供了一种6-磷酸葡萄糖脱氢酶突变体。区别于已有发表的专利US006090567A(Homogeneous immunoassays using mutant glucose-6-phosphatedehydrogenases)的6磷酸葡萄糖脱氢酶的突变体,本申请的6-磷酸葡萄糖脱氢酶突变体,其包含选自以下的突变:D306C、G426C、D375C。
根据一些实施方案,提供了一种6-磷酸葡萄糖脱氢酶突变体,所述6-磷酸葡萄糖脱氢酶突变体是选自以下的序列所示:SEQ ID No.2、SEQ ID No.3、SEQ ID No.4。
根据一些实施方案,提供了一种多核苷酸,其编码本申请的6-磷酸葡萄糖脱氢酶突变体。
根据一些实施方案,提供了一种表达载体,其包含本申请的多核苷酸。
根据一些实施方案,提供了一种宿主细胞,其包含本申请的表达载体。宿主细胞可以是原核(如细菌)或真核(如酵母)。
根据一些实施方案,提供了一种偶联物,其是本申请的6-磷酸葡萄糖脱氢酶突变体与半抗原按照摩尔比1:n偶联而成。
在一些实施方案中,n是1至50,例如,1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50。
在一些具体的实施方案中,本申请的6-磷酸葡萄糖脱氢酶突变体与半抗原按照摩尔比优选为1:1。
在一些具体的实施方案中,半抗原的分子量为100Da至4000Da,例如:100、150、200、250、300、350、400、410、420、430、440、450、460、470、480、490、500、520、550、570、600、620、650、700、750、800、850、900、950、1000、1100、1200、1300、1400、1500、1600、1700、1800、1900、2000、2100、2200、2300、2400、2500、2600、2700、2800、2900、3000、3100、3200、3300、3400、3500、3600、3700、3800、3900、4000。
根据本申请,技术人员将理解,“半抗原”还包含其衍生物的形式。为了便于和6-磷酸葡萄糖脱氢酶进行偶联,对于那些自身不带有偶联基团(例如,与巯基反应的基团)的半抗原(例如皮质醇),可以经改造而带有接头,以便和巯基共价结合。因此,在本申请中,半抗原衍生物是指,经改造而带有巯基反应基团的半抗原。
半抗原选自:小分子药物(如抗生素、精神药物)、激素、代谢物、糖、脂质、氨基酸。
半抗原例如但不限于:茶碱、苯妥英、维生素D、25羟维生素D、1,25双羟维生素D、叶酸、强心甙(包括洋地黄毒苷)、酶酚酸、雷帕明、环胞菌素A、乙胺碘复酮、甲胺喋呤、他克莫司、血清氨基酸、胆汁酸、甘胆酸、苯丙氨酸、乙醇、尿尼柯丁代谢产物柯替宁、尿***、尿单羟酚衍生物、神经肽酪氨酸、血浆甘丙素、多胺、组织胺、促甲状腺激素、泌乳素、胎盘泌乳素、生长激素、促***、促***、促肾上腺皮质激素、抗利尿激素、降钙素、降钙素原、甲状旁腺激素、甲状腺素、三碘甲状原氨酸、反三碘甲状原氨酸、游离甲状腺素、游离三碘甲状原氨酸、皮质醇、尿17-羟皮质类固醇、尿17-酮类固醇、脱氢表雄酮及硫酸酯、醛固酮、尿香草苦杏仁酸、血浆肾素、血管紧张素、***、睾酮、双氢睾酮、雄烯二酮、17α羟孕酮、雌酮、雌三醇、***、孕酮、人绒毛膜***、胰岛素、胰岛素原、C肽、胃泌素、血浆***素、血浆6-酮***素F1α、前列环素、肾上腺素、儿茶酚胺、去甲肾上腺素、胆囊收缩素、纳素、环磷酸腺苷、环磷酸鸟苷、血管活性肽、生长抑素、促胰液素、P-物质、神经降压素、血栓素A2、血栓素B2、5羟色胺、神经肽Y、骨钙素。
在具体的实施方案中,半抗原是皮质醇或其衍生物。
在具体的实施方案中,半抗原是皮质醇衍生物,其带有巯基反应基团,例如来酰亚胺、溴乙酰基、乙烯基砜或氮丙啶。
在具体的实施方案中,半抗原是皮质醇衍生物,如式I所示:
在一些实施方案中,m为0至20的整数,优选1至10的整数,优选1至6的整数,例如1、2、3、4、5、6。
在一些实施方案中,X是马来酰亚胺、溴乙酰基、乙烯基砜或氮丙啶。
技术人员能够理解,X功能在于和6-磷酸葡萄糖的巯基进行反应。马来酰亚胺、溴乙酰基、乙烯基砜、氮丙啶和巯基的共价结合是可以预期的。尽管实施例中,采用具体的特定基团,但不意图限制于此。
在一些具体的实施方案中,所述皮质醇衍生物,其具有选自下式的结构:
m为0至20的整数,优选1至10的整数,优选1至6的整数。
在一些具体的实施方案中,所述皮质醇衍生物,其具有选自下式的结构:
根据一些实施方案,提供了一种试剂,其包含本申请的偶联物。
根据一些实施方案,提供了本申请的6-磷酸葡萄糖脱氢酶突变体在制备皮质醇检测试剂中的用途。
根据一些实施方案,提供了本申请的偶联物在制备皮质醇检测试剂中的用途。
在具体的实施方案中,所述的检测试剂选自:酶联免疫法检测试剂、化学发光免疫法检测试剂、均相酶免疫法检测试剂、胶乳增强免疫比浊法检测试剂。
在具体的实施方案中,所述的检测试剂优选是基于竞争法检测的试剂。
根据一些实施方案,提供了本申请的偶联物在制备皮质醇检测装置中的用途。
在具体的实施方案中,所述的检测装置可以制备成孔板(例如96-孔板)的形式,比如板上包被根据本申请的试剂。
在具体的实施方案中,所述的检测装置可以制备成颗粒(例如胶乳、磁珠)的形式,比如颗粒上包被根据本申请的试剂。
根据一些实施方案,提供了一种皮质醇检测试剂盒,其包含:
-第一试剂,所述第一试剂包含底物、缓冲液和皮质醇抗体;所述底物是6-磷酸葡萄糖脱氢酶的底物;
-第二试剂,所述第二试剂包含本申请的偶联物和缓冲液;
-任选地,校准品,所述校准品包含10mM至500mM缓冲液、0ng/ml至800ng/ml皮质醇;以及
-任选地,质控品,所述质控品包含10mM至500mM缓冲液、100ng/ml至500ng/ml皮质醇。
根据一个实施方案,提供了一种皮质醇检测试剂盒,其包含:
第一试剂,其包含:
10mM至500mM缓冲液、
5mM至50mM底物、
10ng/ml至10μg/ml的皮质醇抗体、
0.1g/L至5g/L稳定剂、
0.1g/L至5g/L表面活性剂、
0.1g/L至5g/L防腐剂;
第二试剂,其包含:
10mM至500mM缓冲液、
0.01μg/ml至10μg/ml根据本申请的偶联物、
0.1g/L至5g/L稳定剂、
0.1g/L至5g/L表面活性剂、
0.1g/L至5g/L防腐剂。
在一些实施方案中,所述缓冲液选自以下的一种或组合:氨基丁三醇缓冲液、磷酸盐缓冲液、Tris-HCl缓冲液、柠檬酸-柠檬酸钠缓冲液、巴比妥缓冲液、甘氨酸缓冲液、硼酸盐缓冲液、三羟甲基甲烷缓冲液;优选,磷酸盐缓冲液;所述缓冲液的浓度为10mmol/L至500mmol/L,优选100mM;所述缓冲液的pH为7至8。
在一些实施方案中,所述稳定剂选自以下的一种或组合:牛血清白蛋白、海藻糖、甘油、蔗糖、甘露醇、甘氨酸、精氨酸、聚乙二醇6000、聚乙二醇8000;优选牛血清白蛋白。
在一些实施方案中,所述表面活性剂选自以下的一种或组合:Brij35、Triton X-100、Triton X-405、Tween20、Tween30、Tween80、椰子油脂肪酸二乙醇酰胺、AEO7,优选Tween20。
在一些实施方案中,所述的防腐剂选自以下的一种或组合:叠氮化物、MIT、生物防腐剂PC(如PC-300)、硫柳汞;所述叠氮化物选自:叠氮钠、叠氮锂。
在一些实施方案中,所述底物包含:6-磷酸葡糖糖、β-烟酰胺腺嘌呤二核苷酸。
在一些具体的实施方案中,所述皮质醇抗体源自:小鼠、大鼠、猫、犬、灵长类、牛、马、羊、骆驼科、禽、人。
在一些具体的实施方案中,所述皮质醇抗体选自:单抗、多抗、重组抗体、嵌合抗体、抗原结合片段。
根据一些实施方案,提供了一种偶联物的制备方法,包括步骤:
1)提供根据本申请的皮质醇衍生物,尤其是在非质子性溶剂(例如但不限于乙腈、二甲基甲酰胺、二甲基亚砜)中提供根据本申请的皮质醇衍生物;
2)提供6-磷酸葡萄糖脱氢酶突变体,优选在缓冲液(其提供反应环境,例如但不限于PBS、Tris、TAPS、TAPSO,所述缓冲液pH为6.0至8.0)中提供6-磷酸葡萄糖脱氢酶突变体;
3)在18℃至28℃,将所述6-磷酸葡萄糖脱氢酶突变体和所述皮质醇衍生物按照摩尔比1:n接触1小时至4小时(优选2小时至3小时)使得所述皮质醇衍生物和所述6-磷酸葡萄糖脱氢酶突变体发生偶联,得到所述种偶联物;
4)根据需要,任选对所述种偶联物进行纯化,例如脱盐处理等。
在一些实施方案中,反应体系中酶和半抗原的接触摩尔比1:n,其中n是1至50,例如,1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50。
在另一些实施方案中,反应体系中酶和半抗原的接触摩尔比1:n,其中n是0.01至1,例如0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9。
在一些具体的实施方案中,步骤1)和2)可互换或并行。
在一些具体的实施方案中,在偶联之前,所述6-磷酸葡萄糖脱氢酶包含一个或多个游离的巯基,从而允许和皮质醇实现定向反应。
野生型6-磷酸葡萄糖脱氢酶不含游离的巯基,因此在一些具体的实施方案中,6-磷酸葡萄糖脱氢酶是经过基因工程改造的,使其在特定位点(306、375或426位)上的氨基酸突变为半胱氨酸,从而带有一个游离巯基。
附图说明
图1.皮质醇结构图。
图2.皮质醇衍生物结构图。
图3A.G6PDH(野生型)氨基酸序列(SEQ ID No.1);源自明串珠菌属假肠膜明串珠菌Leuconostoc pseudomesenteroides。
图3B.G6PDH(D306C)氨基酸序列(SEQ ID No.2)。
图3C.G6PDH(D375C)氨基酸序列(SEQ ID No.3)。
图3D.G6PDH(G426C)氨基酸序列(SEQ ID No.4)。
图4.开盖稳定性。
具体实施方式
实施例
实施例1.皮质醇衍生物的合成
皮质醇(200mg,0.55mmol)、化合物2(78mg,2.20mmol),避光条件下溶于10ml甲醇中,避光条件下反应5分钟。
将反应体系加热至50℃,向反应体系中加入化合物2(78mg,2.20mmol)、化合物3(60mg,0.55mmol),保温反应5分钟。反应体系基本变无色或浅黄色,减压除去溶剂,柱层析纯化得产物180mg,产率75%。
将化合物5(100mg,0.23mmol)和化合物6(53mg,0.23mmol)溶于DCM(5mL)中,向其中滴加三乙胺(70mg,0.69mmol),加入HATU(105mg,0.28mmol),室温(18至28℃,优选20至25℃)搅拌5h。减压除去溶剂,得到皮质醇衍生物(80mg,57%)。
按常规方法确认产物结构。
本实施例使得皮质醇带有一个可以和酶结合的基团。
实施例2.皮质醇衍生物与G6PDH分子的偶联
一、本申请的测试方法
根据本申请的G6PDH-皮质醇偶联物,按照以下方式进行偶联:皮质醇衍生物分子上的巯基反应性基团(例如但不限于马来酰亚胺基团)与G6PDH分子上的巯基共价结合。
1.溶液配制:
皮质醇衍生物溶液:实施例1制备的皮质醇衍生物10mg/ml溶于DMF;
G6PDH溶液:G6PDH(本申请的突变体或现有技术突变体)溶于PB 100mmol、NaCl100mmol、pH=8.0;
偶联溶液:100mM PB/K、100mM EDTA、150mM NaCl,pH=7.2;
脱盐溶液:100mM PB/K、0.1%NaN3、1%NaCl,pH=8.0。
2.偶联操作:
将2ml G6PDH溶液、7.5ml偶联溶液和0.5ml皮质醇衍生物溶液,在室温反应4h。
3.将上述反应体系室温振荡反应4h后,用上述脱盐溶液使用脱盐柱进行洗脱,收集蛋白峰,所得产物即G6PDH-皮质醇偶联物。
二、对照偶联方法(参照CN105131105A的方法制定本实验规程)
1.称取15mg规格为100KU的G6PDH,室温溶解于12mL含有72.6mg(0.05M)Tris、8mgMgCl2(3.3mM)和100mg NaCl的溶液中(该溶液pH=9.0);
2.在上述烧杯中加入225mg还原态的烟酰胺腺嘌呤二核苷酸NADH,135mg葡萄糖-6-磷酸以及0.75mL卡必醇;
3.在上述烧杯中再逐滴加入2mL二甲基亚砜;
4.在无水状态下称取10mg皮质醇衍生物,溶解于600μL DMF中;使上述溶液温度降到-2至-8℃;加入3μL三丁胺;
5.加入1.5μL氯甲酸异丁酯,-2至-8℃搅拌30分钟;
6.将上述激活的皮质醇衍生物溶液逐滴加入到上述溶解的G6PDH溶液中,2至8℃搅拌过夜;
7.通过G-25凝胶层析柱纯化步骤6中的溶液,获得的最终产物为葡萄糖-6-磷酸脱氢酶-半抗原偶联物,于2至8℃储存。
实施例3.试剂盒的制备
制备以下检测皮质醇的试剂盒,其包含:
试剂R1,包含:
50mM HEPES,pH 7.0
10mM 6-磷酸葡萄糖
10mMβ-烟酰胺腺嘌呤二核苷酸
250ng/ml皮质醇抗体(市售抗体,无特殊限制)
1g/L牛血清白蛋白
1g/L Tween20
1g/L叠氮钠;
试剂R2,包括:
200mM Tris缓冲液,pH 8.0
0.1μg/ml G6PDH-皮质醇偶联物
1g/L牛血清白蛋白
1g/L Tween 20
1g/L叠氮钠;
校准品:20mM HEPES缓冲液,以及0.0、50.0、100.0、200.0、400.0、800.0ng/ml皮质醇(或按需加入);
质控品:20mM HEPES缓冲液,以及120ng/ml、260ng/ml、440ng/ml皮质醇(或按需加入)。
将上述试剂(任选包含质控品、校准品),组装成皮质醇均相酶免疫检测试剂盒。
检测例
表1.全自动生化仪参数
机型 | 日立7180 |
分析点 | [Rate-A][10][25][34] |
WAVE(SUB/MAIN) | [410][340] |
S.VIL. | [4.0] |
S.R1 | [100] |
S.R3 | [100] |
ABS.LIMIT: | [32000][递增] |
CALIB TYPE: | [Spline] |
POINT: | [6]SPAN PONIT[6] |
校准品 | 0.0、50.0、100.0、200.0、400.0、800.0ng/ml |
样本 | 待检样本为各种生理样本,如血清、血浆 |
检测例1.本申请试剂盒的准确度、精密度、线性实验
表2.准确度、精密度(针对D306C突变体)
表3.线性
测1 | 测2 | 测3 | 均值 | 理论值 | 相对偏差 | 绝对偏差 | |
1 | 5.9 | 7.6 | 4.0 | 5.8 | 1.53 | 4.30 | |
2 | 74.3 | 73.3 | 75.5 | 74.4 | 72.04 | 3.2% | 2.32 |
3 | 146.5 | 145.2 | 142.6 | 144.8 | 142.55 | 1.6% | 2.21 |
4 | 217.6 | 212.7 | 207.2 | 212.5 | 213.06 | -0.3% | -0.56 |
5 | 283.2 | 282.0 | 282.8 | 282.7 | 283.57 | -0.3% | -0.91 |
6 | 344.9 | 344.1 | 346.0 | 345.0 | 354.08 | -2.6% | -9.08 |
7 | 408.9 | 421.3 | 421.9 | 417.4 | 424.59 | -1.7% | -7.23 |
8 | 489.1 | 488.3 | 504.6 | 494.0 | 495.11 | -0.2% | -1.11 |
9 | 562.9 | 557.7 | 579.2 | 566.6 | 565.62 | 0.2% | 0.98 |
10 | 627.9 | 655.4 | 646.6 | 643.3 | 636.13 | 1.1% | 7.17 |
11 | 707.0 | 695.9 | 723.2 | 708.7 | 706.64 | 0.3% | 2.06 |
12 | 782.3 | 777.9 | 759.0 | 773.1 | 777.15 | -0.5% | -4.08 |
13 | 835.8 | 858.3 | 860.6 | 851.6 | 847.66 | 0.5% | 3.91 |
检测例2.常见药物抗干扰
表4.抗干扰的测定结果(针对D306C突变体)
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检测例3.相关性
1.试验方法
取新鲜血清样本100例,每例样本均分为两份,每份体积不少于500μl,使用本申请的试剂(针对375突变体)在日立7180仪器上测定其中一份样本两次,使用岛津HPLC测定另一份样本。两种方法测值使用散点图进行相关性分析。
2.试验结果:
所得函数为y=1.011x+1.9381,相关系数R2=0.9970。
结果表明本申请的试剂测定样本中皮质醇浓度值,与HPLC法(可视为金标准)测定样本中皮质醇浓度值具有良好相关性。
表5.相关性分析(单位:ng/ml)
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检测例4.皮质醇检测试剂盒的批间差
使用三批次本申请试剂(D306C突变体)和对照偶联方法制备的试剂,分别定标,计算不同批次吸光度变化差异。
表6.批次间的定标数据
表7.批次间的比较
检测例5.定标稳定性对比分析
将本申请试剂(G426C突变体)和对照偶联方法试剂分别放置在试剂仓内、开盖(图4)、定标后,隔一定时间测三水平血清样本各三次,持续测定14天,计算均值及偏差。
表8.定标稳定性(单位:ng/ml)
检测例6.抗体抑制率
1.抗体抑制率的检测原理
当抗体与G6PDH-皮质醇偶联物结合时,由于空间位阻导致G6PDH酶活性受到影响,从而使得其催化NAD转化为NADH的效率降低,通过检测NADH量的变化,从而比较加入抗体与未加入抗体的实验组的差异,这种差异即体现为抗体对G6PDH的抑制能力。
2.反应体系
表9.抗体抑制率的检测试剂制备
3.结果
比较加入抗体与未加入抗体时,分别检测G6PDH-皮质醇偶联物吸光度测值,即可得到抗体对G6PDH的抑制情况。
抗体抑制率=含抗体时G6PDH-皮质醇的吸光度变化值/不含抗体时G6PDH-皮质醇的吸光度变化值)×100%。
相对于已发表的突变位点(A45C),本申请的突变体在抗体抑制率上有明显提高,能达到33%以上(G426C:33%;D375C:48%),最高达54%(D306C)。而之前已发表的突变位点(例如A45C、K55C)的抑制率为31%和42%。
虽然不限于具体理论,但是可以部分地解释为:和现有技术中的G6PDH突变体(A45C、K55C)相比,本申请酶突变体中突变位点(即引入游离巯基的位点)是和半抗原(比如激素、小分子药物等)发生偶联的位置所在。半抗原在这个位置上与半抗原特异性抗体结合时,所构成的空间位阻对G6PDH酶的活性影响最大,同时在引入突变后,还不能实质上影响分子的空间折叠。因此,这个突变位点的位置非常重要,需要同时兼顾G6PDH酶的活性、偶联分子的空间折叠、以及半抗原表位的充分暴露。
由于酶的突变体在抗体抑制率上有明显的提高。将酶的突变体与皮质醇偶联后的偶联物配制成试剂盒后,试剂在批间变异系数、线性、特异性等性能方面有明显的性能提升。
检测例7.替代方案
参照实施例3的制备方法,分别配置不同的测试试剂盒和对照试剂盒,区别仅在于将实施例3制备的试剂盒进行如下替换:
方案1:第一试剂和第二试剂中的缓冲液在50至100mM PH 7.0-8.0范围内替换为磷酸缓冲液、甘氨酸缓冲液、硼酸缓冲液、或者MOPS缓冲液;
方案2:第一试剂和第二试剂中的稳定剂替换为0.5至2.5g/L海藻糖、蔗糖、甘露醇、或聚乙二醇6000;
方案3:第一试剂和第二试剂中的表面活性剂替换为0.5至2.5g/LTriton X-100、Tween 80、Brij 35、或Brij 23;
方案4:第一试剂和第二试剂中的防腐剂替换为叠氮锂或PC-300。
方案5:将化合物2分别替换为化合物3、化合物4、化合物5。
将上述各方案中三个不同批次的测试试剂盒和对照试剂盒参照检测例4的方法进行测试,比较结果和表6至表7接近,显示测试试剂盒的批间差变异小于对照试剂盒(数据未显示)。
Claims (1)
1.偶联物在制备检测试剂中的用途,其中:
所述检测试剂是皮质醇的均相酶免疫法检测试剂;
所述种偶联物是6-磷酸葡萄糖脱氢酶突变体与皮质醇衍生物按照摩尔比1:1偶联而成;
所述皮质醇衍生物是式I所示:
其中,
m为0至20的整数,优选1至10的整数,优选1至6的整数;
X选自以下的任一个:马来酰亚胺、溴乙酰基、乙烯基砜、氮丙啶;更优选地,X是马来酰亚胺;
相较于野生型6-磷酸葡萄糖脱氢酶,所述6-磷酸葡萄糖脱氢酶突变体包含D306C突变;所述6-磷酸葡萄糖脱氢酶突变体是SEQ ID No.2所示。
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