毛细管电泳在药物筛选中的应用和技术开发
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摘要
毛细管电泳是一种高效、快速、微量的分离分析技术,在生物分析领域应用广泛。本文利用毛细管电泳的技术特点将其应用于药物筛选中,针对药物活性筛选中的关键技术问题,如高效快速的筛选方法和新药物靶点寻找,进行了一系列的新探索。
首先,药物活性筛选新方法的开发。对化合物进行活性筛选,主要是研究化合物与药物靶点的相互作用。亲和毛细管电泳是研究分子间相互作用的常用方法,以待测样品的有效电泳淌度为参数计算分子间的结合常数。淌度的准确测定是该方法的重要前提,但是由于受到温度变化、电渗流波动等因素的影响,重现性较差,限制了其发展。本文在上述技术的基础上,开发了一种压力驱动的亲和毛细管电泳方法,通过将气压推动过程和电泳过程相结合,有效的避免了因素的干扰,分析时间也大大缩短。采用该方法研究了8种具有不同pKa值、不同结合能力的药物与牛血清白蛋白之间的结合情况,并计算了结合常数值。通过与传统的荧光分光光度法的测定结果比较,验证了该方法的可行性和准确性。同时,明确了该方法适用于研究结合较弱的反应体系。
其次,药物结构筛选模型的建立。活性筛选是目前常用的筛选方法,但是因筛选指标单一,筛选结果具有误导性,单纯的增加筛选数量难以找到有活性又未知的化合物,因此筛选成本高,效率低。为此,本文探索了一种全新的结构筛选方法,以抗原特殊结构为核心,利用抗原和抗体特异性识别能力,筛选具有抗原类似结构的化合物。以抗真菌药物棘球白素B的母核和其多克隆抗体为样品,采用毛细管电泳配体分离法和激光诱导荧光检测技术,通过研究二者的结合行为,初步建立了以抗原有效电泳淌度变化为判断依据的结构筛选模型。该模型旨在用于筛选具有潜在抗真菌活性的化合物。
最后,药物靶点发现方面的应用。差异蛋白质组学是发现药物作用靶点的重要方法,二维凝胶电泳和质谱是分离和鉴定蛋白质的核心技术。经二维凝胶电泳分离的蛋白质,在进入质谱之前需要长时间、繁琐的样品处理过程,难以满足自动化的需要。针对该问题,本文在前人工作的基础上,开发出一种集凝胶中蛋白质转移和在线酶解的毛细管电泳方法。以SDS-聚丙烯酰胺凝胶中的牛血清白蛋白条带为研究对象,采用三电极的转移模式,将蛋白质高效、快速的从凝胶中转移到毛细管中。采用溶胶-凝胶技术制备固定胰蛋白酶的毛细管整体柱,通过与转移毛细管相连,实现了转移出来蛋白质的在线酶解和检测。该技术的开发大大提高了转移效率,为二维凝胶电泳和质谱提供了一个有效的连接手段。
Capillary elcotrophoresis (CE) is an analytical technique of high efficiency, fast speed and microscale, which is widely used in bioanalysis. In this article, according to its characteristics, CE was applied to drug screening, and new explorations were carried out in view of the key problems in drug activity screening, for example, developing fast and high efficiency screening methods and searching for new drug targets.
Firstly, development of new method of drug activity screening. The study of interaction between compounds and a drug target is critical in drug screening. Affinity capillary electrophoresis is a common method used to determine their binding, but bad reproducibility, caused by temperature change, electroosmotic flow fluctuation and so on, limits its development. Based on the techniques discussed above, a pressure-mediated affinity capillary electrophoresis method was developed in this article. By using a special sequence of pressure and electrophoresis, the influence of factors was effectively avoided and the analysis time was greatly reduced. Using this method, the binding of eight drugs with different pKa and binding abilities and bovine serum albumin (BSA) was evaluated and binding constants were calculated. By comparison with results determined by traditional fluorescence spectrophotometry, the feasibility and accuracy of this method were verified. The results were shown that this method was well suitable for studying weak interacting systems.
Secondly, establishment of drug structure screening model. Up to now, activity screening is one of the most popular screening methods. However, using single screening standard is prone to result in misleading effect. Merely increasing the number of compounds to be screened makes it difficult to find active but unknown compounds. As a result, all of those lead to high screening cost as well as low efficiency. In this article, a newly structure screening method was explored, which depended on the specific recognition ability between antigen and antibody to screen compounds with similar structure to antigen. Using CE ligands separation method and laser induced fluorescence detection technology, the binding of anti-fungal Echinocandin B nucleus and its polyclonal antibody was studied, and a structure screening model based on electrophoretic mobility changes of fluorescence labeled antigen was preliminary established. This screening model can be used to screen compounds with special structure and potential anti-fungal activities.
Lastly, application in discovery of drug targets. Differential proteomic is an important method to discover drug targets. Two-dimensional gel electrophoresis and mass spectrometry are its key technologies to separate and identify proteins. Prior to mass spectrometry analysis, proteins separated by two-dimensional gel electrophoresis need a long and complex process, which makes it difficult to meet the requirements of automation. In order to resolve this problem, based on the work of the formers, a capillary electrophoresis method involving gel protein transfer and on-line proteolytic digestion was developed. Bovine serum albumin present in SDS-polyacrylamide gel as the model protein can be transferred fast and effectively from the gel to capillary by three-electrode transfer method. A capillary monolithic column which immobilized trypsin by the sol-gel method was used to digest the transferred protein. After connecting the capillary monolithic column to transference capillary, on-line digestion and detection of transferred proteins was carried out. This technique significantly improved transference efficiency, and provided an efficient way for the connection of two-dimensional gel electrophoresis and mass spectrometry.
首先,药物活性筛选新方法的开发。对化合物进行活性筛选,主要是研究化合物与药物靶点的相互作用。亲和毛细管电泳是研究分子间相互作用的常用方法,以待测样品的有效电泳淌度为参数计算分子间的结合常数。淌度的准确测定是该方法的重要前提,但是由于受到温度变化、电渗流波动等因素的影响,重现性较差,限制了其发展。本文在上述技术的基础上,开发了一种压力驱动的亲和毛细管电泳方法,通过将气压推动过程和电泳过程相结合,有效的避免了因素的干扰,分析时间也大大缩短。采用该方法研究了8种具有不同pKa值、不同结合能力的药物与牛血清白蛋白之间的结合情况,并计算了结合常数值。通过与传统的荧光分光光度法的测定结果比较,验证了该方法的可行性和准确性。同时,明确了该方法适用于研究结合较弱的反应体系。
其次,药物结构筛选模型的建立。活性筛选是目前常用的筛选方法,但是因筛选指标单一,筛选结果具有误导性,单纯的增加筛选数量难以找到有活性又未知的化合物,因此筛选成本高,效率低。为此,本文探索了一种全新的结构筛选方法,以抗原特殊结构为核心,利用抗原和抗体特异性识别能力,筛选具有抗原类似结构的化合物。以抗真菌药物棘球白素B的母核和其多克隆抗体为样品,采用毛细管电泳配体分离法和激光诱导荧光检测技术,通过研究二者的结合行为,初步建立了以抗原有效电泳淌度变化为判断依据的结构筛选模型。该模型旨在用于筛选具有潜在抗真菌活性的化合物。
最后,药物靶点发现方面的应用。差异蛋白质组学是发现药物作用靶点的重要方法,二维凝胶电泳和质谱是分离和鉴定蛋白质的核心技术。经二维凝胶电泳分离的蛋白质,在进入质谱之前需要长时间、繁琐的样品处理过程,难以满足自动化的需要。针对该问题,本文在前人工作的基础上,开发出一种集凝胶中蛋白质转移和在线酶解的毛细管电泳方法。以SDS-聚丙烯酰胺凝胶中的牛血清白蛋白条带为研究对象,采用三电极的转移模式,将蛋白质高效、快速的从凝胶中转移到毛细管中。采用溶胶-凝胶技术制备固定胰蛋白酶的毛细管整体柱,通过与转移毛细管相连,实现了转移出来蛋白质的在线酶解和检测。该技术的开发大大提高了转移效率,为二维凝胶电泳和质谱提供了一个有效的连接手段。
Capillary elcotrophoresis (CE) is an analytical technique of high efficiency, fast speed and microscale, which is widely used in bioanalysis. In this article, according to its characteristics, CE was applied to drug screening, and new explorations were carried out in view of the key problems in drug activity screening, for example, developing fast and high efficiency screening methods and searching for new drug targets.
Firstly, development of new method of drug activity screening. The study of interaction between compounds and a drug target is critical in drug screening. Affinity capillary electrophoresis is a common method used to determine their binding, but bad reproducibility, caused by temperature change, electroosmotic flow fluctuation and so on, limits its development. Based on the techniques discussed above, a pressure-mediated affinity capillary electrophoresis method was developed in this article. By using a special sequence of pressure and electrophoresis, the influence of factors was effectively avoided and the analysis time was greatly reduced. Using this method, the binding of eight drugs with different pKa and binding abilities and bovine serum albumin (BSA) was evaluated and binding constants were calculated. By comparison with results determined by traditional fluorescence spectrophotometry, the feasibility and accuracy of this method were verified. The results were shown that this method was well suitable for studying weak interacting systems.
Secondly, establishment of drug structure screening model. Up to now, activity screening is one of the most popular screening methods. However, using single screening standard is prone to result in misleading effect. Merely increasing the number of compounds to be screened makes it difficult to find active but unknown compounds. As a result, all of those lead to high screening cost as well as low efficiency. In this article, a newly structure screening method was explored, which depended on the specific recognition ability between antigen and antibody to screen compounds with similar structure to antigen. Using CE ligands separation method and laser induced fluorescence detection technology, the binding of anti-fungal Echinocandin B nucleus and its polyclonal antibody was studied, and a structure screening model based on electrophoretic mobility changes of fluorescence labeled antigen was preliminary established. This screening model can be used to screen compounds with special structure and potential anti-fungal activities.
Lastly, application in discovery of drug targets. Differential proteomic is an important method to discover drug targets. Two-dimensional gel electrophoresis and mass spectrometry are its key technologies to separate and identify proteins. Prior to mass spectrometry analysis, proteins separated by two-dimensional gel electrophoresis need a long and complex process, which makes it difficult to meet the requirements of automation. In order to resolve this problem, based on the work of the formers, a capillary electrophoresis method involving gel protein transfer and on-line proteolytic digestion was developed. Bovine serum albumin present in SDS-polyacrylamide gel as the model protein can be transferred fast and effectively from the gel to capillary by three-electrode transfer method. A capillary monolithic column which immobilized trypsin by the sol-gel method was used to digest the transferred protein. After connecting the capillary monolithic column to transference capillary, on-line digestion and detection of transferred proteins was carried out. This technique significantly improved transference efficiency, and provided an efficient way for the connection of two-dimensional gel electrophoresis and mass spectrometry.
引文
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