CN111487206A - 6-磷酸葡萄糖脱氢酶突变体及其在制备万古霉素检测试剂中的用途 - Google Patents
6-磷酸葡萄糖脱氢酶突变体及其在制备万古霉素检测试剂中的用途 Download PDFInfo
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- CN111487206A CN111487206A CN202010000321.7A CN202010000321A CN111487206A CN 111487206 A CN111487206 A CN 111487206A CN 202010000321 A CN202010000321 A CN 202010000321A CN 111487206 A CN111487206 A CN 111487206A
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Abstract
本申请涉及6‑磷酸葡萄糖脱氢酶突变体及其在制备万古霉素检测试剂中的用途。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
本申请要求2019年1月9日提交的201910017764.4和2019年5 月21日提交的201910423122.4《6-磷酸葡萄糖脱氢酶突变体及其在制备检测试剂中的用途》的优先权,其通过引用并入此处。
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)及其在万古霉素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。
万古霉素(Vancomycin)结构式如下所示:
万古霉素分子量为1485.71,为窄谱抗生素,仅对革兰阳性菌有效 (如溶血性链球菌、肺炎球菌及肠球菌等),对耐药金葡菌本品尤为敏感。
万古霉素的作用机制是抑制细菌细胞壁的合成,它主要和细菌细胞壁结合,而使某些氨基酸不能进入细胞壁的糖肽中。临床主要用于耐青霉素金葡菌所引起的严重感染,如肺炎、心内膜炎及败血症等,对溶血性链球菌引起的感染及败血症等也有较好的疗效。万古霉素还可以用于治疗结肠炎和肠道炎症;万古霉素还经常用于安装心脏导管、静脉导管等装置时的预防感染。
万古霉素可以单独用药,也可以联合用药。万古霉素与其他抗生素无交叉耐药性,极少耐药菌株。主要用于心内膜炎、败血症、伪膜性肠炎等。
万古霉素口服不吸收,单剂静脉滴注400mg,滴注完毕即达到血药峰浓度25.18mg/L,8小时血浓度平均为1.90mg/L,有效血浓度可维持6至8小时。单次静脉滴注800mg,高峰血浓度平均为50.07mg/L。静脉滴注后,主要经肾脏***,单次静滴400mg,24小时尿中平均总***率为81.1%;单次静滴800mg,24小时尿中平均总***率为85.9%。
目前已知的万古霉素检测方法主要有:高效液相色谱法(HPLC)、发光免疫、酶联免疫吸附剂测定(ELISA)等方法。HPLC法需要复杂的样品前处理,操作复杂周期长且成本昂贵;发光免疫法试剂成本昂贵,不适合常规治疗药物检测,更不利于大范围推广。
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CN108717117A描述了一种万古霉素检测试剂盒。然而,现有技术的方法依赖于对小分子药物(万古霉素)自身所带反应基团进行的激活,之后再与酶进行反应。这样的偶联方法会出现同一葡萄糖六磷酸脱氢酶上链接有多个万古霉素的情况,且偶联位点难以确保一致性,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、及其在制备万古霉素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(例如万古霉素),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:万古霉素、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,半抗原是万古霉素或其衍生物。
在具体的实施方案中,半抗原是万古霉素衍生物,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,半抗原是万古霉素衍生物,如式I所示:
在一些实施方案中,m为1至10的整数,优选1至5的整数,例如1、2、3、4、5。
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万古霉素检测试剂中的用途。
根据一些实施方案,提供了本申请的偶联物在制备万古霉素检测试剂中的用途。
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万古霉素检测装置中的用途。
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,提供了一种万古霉素检测试剂盒,其包含:
-第一试剂,所述第一试剂包含底物、缓冲液和万古霉素抗体;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、 0μg/ml至100μg/ml万古霉素;以及
-任选地,质控品,所述质控品包含10mM至500mM缓冲液、 4μg/ml至45μg/ml万古霉素。
根据一个实施方案,提供了一种万古霉素检测试剂盒,其包含:
第一试剂,其包含:
10mM至500mM缓冲液、
5mM至50mM底物、
0.5至5(优选1至3)mg/L万古霉素抗体、
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、
10至500(优选50至200)ng/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:TAPS、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50至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,所述万古霉素抗体源自: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,所述万古霉素抗体选自: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)提供根据本申请的万古霉素衍生物,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万古霉素衍生物;
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℃,将所述万古霉素衍生物和所述6-磷酸葡萄糖脱氢酶突变体按照摩尔比1:n接触1小时至4小时(优选2小时至3 小时)使得所述万古霉素衍生物和所述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500,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、100、200、300、400、500及其任意上述数值之间的范围。
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,从而允许和万古霉素实现定向反应。
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1.万古霉素结构图。
图2.万古霉素衍生物结构图。
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)。
具体实施方式
实施例
实施例1.万古霉素衍生物的合成
1.化合物2的合成
向圆底烧瓶中加入DCM,向其中加入化合物1(100mg,0.47 mmol),并加入DMF(2滴),冰浴、隔绝空气条件下向其中缓慢加入草酰氯(90mg,0.74mmol),将反应体系加热回流2-4h,减压除去溶剂,使用DCM反复(2-3次)带出多余的草酰氯,不经纯化,直接用于下一步。
2.万古霉素衍生物的合成
将万古霉素(100mg)溶于DMF中,然后将如上步骤合成得到的化合物2加入反应体系中,室温搅(18-28℃)拌约2小时,HPLC纯化,得到万古霉素衍生物(50mg,47%):
按常规方法确认产物结构。
本实施例使得万古霉素带有一个可以和酶结合的基团。
实施例2.万古霉素衍生物与G6PDH分子的偶联
一、本申请的偶联方法
根据本申请的G6PDH-万古霉素偶联物,按照以下方式进行偶联:万古霉素衍生物分子上的巯基反应性基团(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.将实施例1制备的万古霉素衍生物溶于N,N-二甲基甲酰胺中 (10mg/ml);
2.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;
3.将200μl G6PDH溶液加入至750μl缓冲溶液(0.05M Na2HPO4、 150mM NaCl、10mMEDTA、0.1%NaN3、pH=7.2)中;然后向其中加入万古霉素衍生物的N,N-二甲基甲酰胺溶液50μl;
4.上述混合溶液,在室温(18-28℃)下充分震荡2-3小时,脱盐处理,收集蛋白峰,所得产物即G6PDH-万古霉素偶联物。
二、对照偶联方法(参照CN108717117A的方法)
将5-30mg万古霉素溶于100-500μL二甲基甲酰胺中,轻微振荡溶解;同时取10-40mg的100-300KU的G6PDH溶解于PBS缓冲液中震荡、均匀溶解。
将万古霉素溶液在搅拌下缓慢加入G6PDH溶液中,同时缓慢滴入 10-50μL戊二醛溶液,滴加完毕后将溶液置于4℃搅拌反应过夜。
通过G-25凝胶层析柱纯化,得到G6PDH-万古霉素偶联物,于2- 8℃下储存。
实施例3.试剂盒的制备
制备以下检测万古霉素的试剂盒,其包含:
试剂R1,包含:
50mM TAPS,pH 8.0
15mM 6-磷酸葡萄糖
15mMβ-烟酰胺腺嘌呤二核苷酸
2.0mg/L万古霉素抗体(市售抗体)
100mM NaCl
1g/L牛血清白蛋白
1g/L Tween20
1g/L叠氮钠;
试剂R2,包括:
50mM Tris缓冲液,pH 8.0
100ng/mL G6PDH-万古霉素偶联物
100mM NaCl
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0μg/ml、5μg/ml、10μg/ml、 25μg/ml、50μg/ml、100μg/ml万古霉素(或按需加入);
质控品:20mM HEPES缓冲液,以及4-8μg/ml、15-20μg/ml、35-45 μg/ml万古霉素(或按需加入)。
将上述试剂(任选包含质控品、校准品),组装成万古霉素均相酶免疫检测试剂盒。
检测例
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-万古霉素)与非标记抗原(万古霉素),竞争与定量的抗体(万古霉素抗体)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,即可推算出液体中万古霉素的含量。
表1.全自动生化仪参数
检测方法 | 速率法 |
样本量 | 2.0μl |
试剂R1 | 150μl |
试剂R2 | 50μl |
读点 | 31-34点 |
检测波长(主) | 340 |
检测波长(副) | 405 |
曲线拟合方式 | Spline |
检测例1.本申请试剂盒的精密度、线性实验
1.定标实验
万古霉素校准品溶于缓冲溶液中(0.9%NaCl、0.1%NaN3),配制成共6种浓度的校准品,定标液的工作体积为2-10μl,然后加入100-200 μl的试剂R1和50-100μl的试剂R2。采用速率法检测主波长340nm,副波长405nm,读吸光度变化率,绘制成定标曲线。本申请中定标曲线的建立在日立7180上完成,但其他主流机型(AU680、雅培C16000 等)经检测可用。
2.精密度实验
利用如上建立起的定标曲线,测定高、中、低质控品、临床样本,分别检测20次。如表2所示,样本测试重复20次,偏差小于3%。
表2.精密度(针对D306C突变体)
3.线性实验
选择低值样本与高值样本按照等差稀释的方法进行稀释,每个样本重复检测3次,所测得线性数据如表3,线性公式为:
γ=8.8026x+2.9902
R2=0.9985
表3.万古霉素试剂盒(针对D306C突变体)线性数据
样本 | 测值1 | 测值2 | 测值3 | 均值 | 理论值 | 相对偏差 | 绝对偏差 |
0 | 1.99 | 1.99 | 2.23 | 2.11 | 1.84 | 0.27 | |
1 | 11.80 | 10.50 | 12.50 | 11.50 | 11.64 | -1.2% | |
2 | 21.93 | 21.93 | 21.04 | 21.49 | 21.44 | 0.2% | |
3 | 32.00 | 31.50 | 31.80 | 31.65 | 31.24 | 1.3% | |
4 | 41.50 | 40.21 | 41.30 | 40.76 | 41.03 | -0.7% | |
5 | 50.10 | 51.60 | 50.90 | 51.25 | 50.83 | 0.8% | |
6 | 58.90 | 59.75 | 57.86 | 58.81 | 60.63 | -3.0% | |
7 | 69.88 | 71.21 | 70.85 | 71.03 | 70.42 | 0.9% | |
8 | 80.11 | 80.34 | 79.88 | 80.11 | 80.22 | -0.1% | |
9 | 89.00 | 90.11 | 91.12 | 90.62 | 90.02 | 0.7% | |
10 | 98.31 | 96.55 | 101.00 | 98.78 | 99.81 | -1.0% |
检测例2.对常见药物的抗干扰作用
选取30种化合物或药物作为干扰物,在万古霉素浓度为25μg/ml 左右,干扰物浓度为500μg/ml时,如下干扰物无明显干扰(针对D306C 突变体):
对乙酰氨基酚、非那西丁、头孢唑啉、呋噻米、苯氟甲嗪、卡那霉素B、土霉素、氢***、西索米星、阿米卡星、***龙、头孢氨苄、夫西地酸、咖啡因、林可霉素、盘尼西林、布洛芬、大观霉素、二性霉素B、***、卡马西平、庆大霉素、头孢烷胺、苯妥英、氨必西林、卡那霉素A、肝素、水杨酸、氯拉卓酸。
检测例3.机载稳定性
选择高、中、低三个浓度的质控品,每天或者隔天检测三次,数据显示本申请的万古霉素检测试剂盒(针对375突变体)定标周期可以稳定两周以上。试剂开封之后,放置于机器上,检测显示在机稳定性超过40天(表6)。
检测例4.万古霉素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4.批间差
检测例5.抗体抑制率
1.抗体抑制率的检测原理
当抗体与G6PDH-万古霉素偶联物结合时,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5.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-万古霉素偶联物吸光度测值,即可得到抗体对G6PDH的抑制情况。
抗体抑制率=含抗体时G6PDH-万古霉素的吸光度变化值/不含抗体时G6PDH-万古霉素的吸光度变化值)×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35%以上(G426C:35%;D375C:50%),最高达56%(D306C)。而之前已发表的突变位点(例如A45C、K55C) 的抑制率为32%和41%。
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酶的活性影响最小,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。将酶的突变体与万古霉素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。
序列表
<110> 北京九强生物技术股份有限公司
<120> 6-磷酸葡萄糖脱氢酶突变体及其在制备万古霉素检测试剂中的用途
<130> 390272CG
<150> 201910017764.4
<151> 2019-01-09
<150> 201910423122.4
<151> 2019-05-21
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Claims (9)
2.根据权利要求1所述的偶联物,其中:
所述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:D306C、D375C、G426C;
优选地,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、SEQID No.3、SEQ ID No.4。
3.一种试剂,其包含权利要求1或2所述的偶联物。
4.权利要求1或2所述的偶联物在制备检测试剂中的用途,其中:
所述检测试剂是万古霉素的检测试剂;
优选地,所述检测试剂选自: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。
5.权利要求1或2所述的偶联物在制备检测装置中的用途:
所述检测装置是针对万古霉素的检测装置;
所述检测装置选自以下任一的形式:孔板、颗粒、芯片、试纸;
优选地,所述检测装置用于万古霉素的均相免疫检测。
6.一种万古霉素检测试剂盒,其包含:
第一试剂,所述第一试剂包含底物、万古霉素抗体、缓冲液;
第二试剂,所述第二试剂包含权利要求1或2所述的偶联物、缓冲液;
任选地,校准品,所述校准品包含10mM至500mM缓冲液、0μg/ml至100μg/ml万古霉素;以及
任选地,质控品,所述质控品包含10mM至500mM缓冲液、2μg/ml至60μg/ml万古霉素。
7.根据权利要求6所述的万古霉素检测试剂盒,其包含:
第一试剂,其包含:
10mM至500mM,优选50mM至300mM缓冲液、
5mM至50mM,优选10mM至20mM葡萄糖-6-磷酸、
5mM至50mM,优选10mM至20mM氧化型β-烟酰胺腺嘌呤二核苷酸、
0.5mg/L至5.0mg/L,优选1.0mg/L至3.0mg/L抗***抗体、
0.1g/L至5g/L,优选1g/L至5g/L稳定剂、
0.1g/L至5g/L,优选1g/L至5g/L表面活性剂、
0.1g/L至5g/L,优选1g/L至5g/L防腐剂;
第二试剂,其包含:
10mM至500mM,优选50mM至300mM缓冲液、
10ng/mL至500ng/mL,优选50ng/mL至200ng/mL权利要求1或2所述的偶联物、
0.1g/L至5g/L,优选1g/L至5g/L稳定剂、
0.1g/L至5g/L,优选1g/L至5g/L表面活性剂、
0.1g/L至5g/L,优选1g/L至5g/L防腐剂;
所述缓冲液选自以下的一种或组合:TAPS缓冲液、磷酸缓冲液、甘氨酸缓冲液、Tris缓冲液、硼酸缓冲液、MOPS缓冲液、HEPES缓冲液;
优选,第一试剂的缓冲液是TAPS缓冲液;
优选,第二试剂的缓冲液是Tris缓冲液;
所述缓冲液的pH为7至8;
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;
所述表面活性剂选自以下的一种或组合:Brij23、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;
所述防腐剂选自以下的一种或组合:叠氮化物、MIT、生物防腐剂PC、硫柳汞;
优选,所述防腐剂选自选自:叠氮钠、叠氮锂、PC-300。
8.根据权利要求6所述的万古霉素检测试剂盒,其包含:
第一试剂,其包含:
50mM TAPS缓冲液,pH 8.0、
15mM葡萄糖-6-磷酸、
15mM氧化型β-烟酰胺腺嘌呤二核苷酸、
2.0mg/L万古霉素抗体、
1g/L牛血清白蛋白、
1g/L Tween20、
1g/L叠氮钠;
第二试剂,其包含:
50mM Tris缓冲液,pH 8.0、
100ng/mL权利要求1或2所述的偶联物、
1g/L牛血清白蛋白、
1g/L Tween20、
1g/L叠氮钠。
9.一种偶联物的制备方法,其包括步骤:
1)提供万古霉素或其衍生物;
2)提供权利要求2所限定的6-磷酸葡萄糖脱氢酶突变体;
3)所述的6-磷酸葡萄糖脱氢酶突变体与所述万古霉素或其衍生物发生偶联;
所述万古霉素衍生物是式I所示:
其中,
m为1至10的整数,优选1至5的整数;
优选地,所述偶联物的制备方法,其包括步骤:
1)提供万古霉素衍生物,优选在非质子性溶剂中提供万古霉素衍生物;
2)提供权利要求2所限定的6-磷酸葡萄糖脱氢酶突变体,优选在缓冲液中提供所述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万古霉素衍生物接触1小时至4小时,优选2小时至3小时,使得所述万古霉素衍生物和所述6-磷酸葡萄糖脱氢酶突变体发生偶联,得到所述偶联物;
4)任选,对所述偶联物进行纯化,优选脱盐;
步骤1)和步骤2)可互换或并行;
所述缓冲液选自:PBS、Tris、TAPS、TAPSO,
所述缓冲液pH为6.0至8.0;
所述非质子性溶剂选自以下一种或组合:乙腈、二甲基甲酰胺、二甲基亚砜;
优选,在步骤3)之前,所述6-磷酸葡萄糖脱氢酶突变体包含一个游离巯基;更优选,所述6-磷酸葡萄糖脱氢酶突变体在第306、375或426位有游离巯基。
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