CN112156089A - 苯溴马隆在抗结核分枝杆菌感染中的应用 - Google Patents
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Abstract
本发明提供了一种针对结核分枝杆菌(Mycobacterium tuberculosis，Mtb)中的核黄素生物合成酶(ribA2)的化合物，该化合物为苯溴马隆，对结核分枝杆菌中的核黄素生物合成酶具有显着的抑制活性，因此本发明提供的化合物能够用来制备针对结核分枝杆菌中核黄素生物合成酶的小分子抑制剂，有望成为抗Mtb感染的潜在药物。
Description
技术领域
本发明涉及药学的技术领域，具体说是苯溴马隆在抗结核分枝杆菌感染中的应用。
背景技术
结核病(Tuberculosis，TB)是一种慢性传染病，通过肺部途径作为气溶胶传播，仅需要很少的杆菌来建立感染。近年来，在结核病的控制方面，由于抗生素的滥用及其联合用药，导致多种耐药菌株的出现，且感染人数逐年递增，所以，我们迫切的需要寻找结核分枝杆菌中的新型靶点，进而针对这些靶点开发新型的抗结核分枝的药物。结核分枝杆菌编码的蛋白酶具有100多种，这些蛋白酶的结核分枝杆菌的生长周期中发挥着重要的作用，然而，对于蛋白酶的研究却很少。
在结核分枝杆菌中，ribA2基因分别在N-和C-末端编码具有3,4-二羟基-2-丁酮4-磷酸合酶(DHBPS)和GTP环化水解酶-II(GTPCH-II)结构域的双功能酶,DHBPS和GTPCH-II是参与核黄素生物合成途径的两种初始酶，已显示其对于病原体是必需的，但不存在于人类中。因其具有传递氢的作用，多数生物生长和生存都不离开该酶。因此，核黄素生物合成酶成为一个关键的抗结核分枝杆菌的药物靶标，所以针对核黄素生物合成酶进行抑制剂筛选对结核分枝杆菌感染的相关的药物研发具有很大的意义。
苯溴马隆为苯骈呋喃衍生物，英文名Benzbromarone，具有降低尿酸的作用，口服易吸收，苯溴马隆由于毒性低，对肾功能不全者更适合，有广泛痛风石的患者可以首选该药。不良反应较为少见，不过较为轻微。据报道，肺结核患者使用吡嗪酰胺抗结核治疗后血尿酸水平增高明显，对于持续性增高患者使用苯溴马隆干预可有效控制血尿酸水平。
发明内容
针对相关技术中的问题，本发明提供苯溴马隆在抗结核分枝杆菌感染中的应用。
本发明还提供了针对结核分枝杆菌中核黄素生物合成酶的抑制剂。
本发明所涉及苯溴马隆CAS号为3562-84-3，购买于aladdin公司。在分子水平上，通过设立阴性对照，发现苯溴马隆对结核分枝杆菌中的核黄素生物合成酶有很好的抑制活性，因此该化合物有望作为抑制结核分枝杆菌感染的潜在药物。
本发明提供一种用于预防或治疗结核分枝杆菌中的核黄素生物合成酶感染的药物，其活性成分为苯溴马隆，该药物包含上述含有苯溴马隆以及一种或多种药学上可接受的载体。所述载体包括药学领域常规的稀释剂、表面活性剂、吸附载体、润滑剂、增效剂。该药物可制成片剂、丸剂、胶囊、悬浮剂或乳剂的形式使用。其给药途径为口服。
本发明具有的优点和积极效果是：
本发明的针对结核分枝杆菌中的核黄素生物合成酶的抑制剂，这种抑制剂为苯溴马隆。苯溴马隆对结核分枝杆菌中的核黄素生物合成酶活性具有显着的抑制效果。
附图说明
图1是苯溴马隆对结核分枝杆菌中的核黄素生物合成酶的抑制作用示意图。
图2是苯溴马隆对结核分枝杆菌中的核黄素生物合成酶的IC50的测定示意图。
图3是苯溴马隆对结核分枝杆菌中的核黄素生物合成酶的抑制剂类型。
具体实施方式：
为了更好地说明本发明，在下面将详述本发明的具体实施方式。
1.结核分枝杆菌中核黄素生物合成酶的表达与纯化
(1)将含有编码Mtb-ribA2基因的pET28a载体转化Escherichia coli BL21(DE3)的菌株，并筛选阳性克隆。
(2)在平板上挑取阳性克隆，37℃培养过夜后转入0.8L的LB培养基，培养6小时后，加入0.1mM IPTG(异丙基硫代半乳糖苷)在20℃培养16小时。
(3)用5000rpm离心10min收集细胞后高压破菌；破菌液用10000rpm离心30min后收集上清液。
(4)将上清液加入破菌buffer(50mM Tris-HCl,150mM NaCl,Ph8.0)预平衡的Ni-NTA亲和层析柱中，使目的蛋白与Ni充分结合，使目的蛋白充分富集。
(5)用含有40mM咪唑的破菌buffer洗掉未结合的杂蛋白，考马斯亮蓝G250检测流出液不变蓝时，说明大部分杂蛋白被冲洗干净。用200mM咪唑的破菌buffer洗脱，然后用30kD的浓缩管浓缩换液，用阴离子交换层析进行纯化来获得具有电荷均一性的目的蛋白。
2.Mtb-ribA2的活性测定
采用GTP作为底物，仪器波长为310nm。
蛋白缓冲液组分为50mM Tris-HCl,100mM NaCl，10mMMgCl2，5％甘油，pH＝8.0，用缓冲液配置Mtb-ribA2(终浓度5μM)，加入溶解于DMSO(二甲基亚砜)的化合物(终浓度为20μM),室温放置5min,迅速加入底物GTP，底物浓度为150μM。每1min记录一次读数，共测定50min。654rpm震荡10s，检测吸亮度。阴性对照不加备选样品，其它实验条件均相同。
所有测定都做三次平行，在整个实验中保持合适的阳性和阴性对照。用酶标仪测定酶动力学曲线，分析初速率。计算出每个化合物的剩余活性和抑制率。
对于剩余活性<15％的化合物进行复筛，排除操作失误造成假阳性的可能。
3.化合物苯溴马隆IC50的测定
在测定IC50时，我们首先配置实验所需的蛋白Mtb-ribA2,终浓度为5μM，再用95％的DMSO配置底物GTP,使其终浓度为150μM。我们首先根据初筛结果粗略的设定8个抑制剂浓度(一般是通过梯度稀释得到)，扎鲁司特的浓度分别是100uM、50μM、25μM、12,5μM、6.25μM、3.125μM、1.5625μM、0μM。之后与之前的操作基本一样，先将蛋白加入酶标板中与抑制剂在37℃孵育5min后，迅速加入10μL底物，记录时间与吸亮度变化曲线。我们通过Graphpadprism 6.0软件得到蛋白酶吸光反应初速率，并拟合化合物浓度与剩余活性的量效关系曲线，得出IC50值。
4.化合物苯溴马隆抑制剂类型的测定
在测定抑制剂类型时，我们首先配置实验所需的蛋白Mtb-ribA2,其浓度为0μM、0.625μM、1,25μM、2.5μM、5μM、10μM、15μM、20μM，再用95％的DMSO配置底物GTP,使其终浓度为150μM。我们首先根据初筛结果粗略的设定3个抑制剂浓度(一般是通过梯度稀释得到)，苯溴马隆的浓度分别是0uM、10μM、20μM、。之后与之前的操作基本一样，记录时间与吸亮度变化曲线。我们通过Graphpad prism 6.0软件得到蛋白酶吸光反应初速率，平行测定3组数据，得到抑制剂类型。
本发明涉及药学的技术领域，具体说是苯溴马隆在抗结核分枝杆菌感染中的应用，苯溴马隆在抑制结核分枝杆菌中核黄素生物合成酶时候Ir>75％以上,在制备抗结核分枝杆菌中核黄素生物合成酶的小分子抑制剂方面有很大应用潜力，有望成为抗结核分枝杆菌感染的潜在药物。
以上所使用的方法，如无特殊说明，均为本领域常用的方法。
以上仅为本发明的具体实施方式，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
【参考文献】
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Claims (7)
1.苯溴马隆在治疗结核分枝杆菌感染中的应用。
2.苯溴马隆是结核分枝杆菌中核黄素生物合成酶的小分子抑制剂。
3.根据权利要求1或2所述的应用，其中，苯溴马隆的结构式为：
4.根据权利要求书1或2所述的治疗结核分枝杆菌感染的药物，其特征是它的片状制备方法为混合，制粒，干燥，整粒，总混，压片。
5.一种治疗结核分枝杆菌感染的药物，其特征在于它包含权利要求书1或2所述的苯溴马隆以及一种或多种药学上可接受的载体；所述载体包括药学领域常规的稀释剂、吸收促进剂、表面活性剂、吸附载体、润滑剂、增效剂。
6.根据权利要求1或2所述的药物组合物，其特征在于：所述药物组合物还包含药物学上可接受的辅料。
7.根据权利要求书1或2所述的治疗结核分枝杆菌感染的药物，其特征是它所述药物组合物为口服剂或注射剂；所述口服剂包括：片剂，颗粒剂，滴丸，软胶囊，悬浮剂，溶液剂，以及糖浆中的至少一种；所述注射剂包括：冻干粉剂，溶液型注射剂，混悬型注射剂，以及乳剂型注射剂中的至少一种。
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Citations (3)
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|---|---|---|---|---|
| CN102429881A (zh) * | 2011-12-01 | 2012-05-02 | 常州康普药业有限公司 | 一种苯溴马隆片的制备方法 |
| CA2826506A1 (en) * | 2011-02-04 | 2012-08-09 | Biocopea Limited | Compositions and methods for treating chronic inflammation and inflammatory diseases |
| WO2014052836A2 (en) * | 2012-09-27 | 2014-04-03 | Dunman Paul M | Methods and compositions for treating infection |
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| CA2826506A1 (en) * | 2011-02-04 | 2012-08-09 | Biocopea Limited | Compositions and methods for treating chronic inflammation and inflammatory diseases |
| CN102429881A (zh) * | 2011-12-01 | 2012-05-02 | 常州康普药业有限公司 | 一种苯溴马隆片的制备方法 |
| WO2014052836A2 (en) * | 2012-09-27 | 2014-04-03 | Dunman Paul M | Methods and compositions for treating infection |
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