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Investigation of protein-drug interaction using capillary isoelectric focusing with whole column imaging detection and spectroscopic techniques .

机译：使用毛细管等电聚焦结合全柱成像检测和光谱技术研究蛋白质-药物相互作用。

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摘要

In this work, the possibilities of understanding protein-drug interactions and the possible modes of action of the drug have been was explored using capillary isoelectric focusing (CIEF) and spectroscopic techniques.;This spectrometer is likely to be broadly applicable for simple to moderately complex samples. Furthermore, the future perspective of combining separation and spectroscopy technologies is a novel approach for capitalizing on the strengths of the two technologies.;Capillary isoelectric focusing (CIEF) with whole column imaging detection (WCID) was used to investigate the interaction of platinum-based anticancer drugs, cisplatin and oxaliplatin, with human hemoglobin A0 (Hb) and HSA. This technique facilitates the investigation and characterization of the formation of adducts between drugs and proteins. At higher drug to protein molar ratios (for both oxaliplatin and cisplatin), the results exhibit significant changes in the peak shapes and heights, which may indicate the destabilization of the protein. However, the conformational change was less evident at lower molar ratios. In addition, a major pI shift was observed for the oxaliplatin reaction mixtures (for 1:10, 1:50 and 1:100 ratios). In comparison with previously reported findings obtained by other analytical methods, conclusions were drawn about the validity of CIEF as a simple and convenient method for the investigation of protein-drug interactions. These results may provide useful information for further understanding the activity and toxicity of these chemotherapeutic drugs and improving their clinical performance.;Spectroscopic evidence also shows that oxaliplatin causes fluorescence quenching of HSA by formation of on HSA-oxaliplatin complex. The Stern-Volmer equation has been used to calculate the quenching constant in the linear range. The quenching rate constants Kq at three different temperatures indicate the presence of a static quenching mechanism in the interactions of oxaliplatin with HSA. The work describes the validity of the CIEF-WCID technique for the study of protein-drug interactions and provides useful information and insight into the interaction of anti-cancer drugs with HSA concerning their further toxicity of these chemotherapeutic drugs and ways of improving their clinical performance.;The first study involves the implementation and applications of the new high performance Raman spectrometer with volume phase (VPH) based grating system, which is integrated with a short liquid-core optical waveguide for characterization and analysis of a wide ranges of molecules. The high performance Raman spectrometer has allowed us to measure solid samples with minor differences in chemical compositions. In addition, spectral characteristics of the interactions between therapeutic drugs with human serum albumin have been examined in terms of the cleavage of disulfide (S-S) bonds. The relative intensity of the Raman signal decrease as a complex formation progressed, suggesting perturbation around the disulfide bonds of human serum albumin (HSA).
机译：在这项工作中，使用毛细管等电聚焦（CIEF）和光谱技术探索了理解蛋白质-药物相互作用的可能性以及药物可能的作用方式;该光谱仪可能广泛适用于简单到中度复杂的环境样品。此外，结合分离和光谱技术的未来前景是利用这两种技术的优势的一种新方法。毛细管等电聚焦（CIEF）和全柱成像检测（WCID）用于研究铂基化合物的相互作用抗癌药物顺铂和奥沙利铂，以及人类血红蛋白A0（Hb）和HSA。该技术有助于研究和表征药物和蛋白质之间加合物的形成。在较高的药物与蛋白质摩尔比下（对于奥沙利铂和顺铂而言），结果显示峰形和峰高发生显着变化，这可能表明蛋白质不稳定。然而，在较低的摩尔比下，构象变化不太明显。另外，对于奥沙利铂反应混合物观察到较大的pI变化（比例为1：10、1：50和1：100）。与以前通过其他分析方法获得的发现相比较，得出了关于CIEF作为研究蛋白质-药物相互作用的简便方法的有效性的结论。这些结果可能为进一步了解这些化疗药物的活性和毒性以及改善其临床性能提供有用的信息。光谱证据还表明，奥沙利铂通过在HSA-奥沙利铂复合物上形成而引起HSA的荧光猝灭。 Stern-Volmer方程已用于计算线性范围内的淬灭常数。在三个不同温度下的淬灭速率常数Kq表示奥沙利铂与HSA相互作用中存在静态淬灭机理。这项工作描述了CIEF-WCID技术在蛋白质-药物相互作用研究中的有效性，并为抗癌药物与HSA的相互作用提供了有用的信息和见解，涉及它们对这些化疗药物的进一步毒性以及改善其临床表现的方法。第一项研究涉及具有体积相位（VPH）的新型高性能拉曼光谱仪的实现和应用，该光栅系统与短液芯光波导集成在一起，用于表征和分析各种分子。高性能拉曼光谱仪使我们能够测量化学成分差异很小的固体样品。另外，已经根据二硫键（S-S）的裂解检查了治疗药物与人血清白蛋白之间相互作用的光谱特征。拉曼信号的相对强度随着复合物形成的进行而降低，这表明人血清白蛋白（HSA）的二硫键周围存在扰动。

著录项

  • 作者

    Mukria, Tibebe Lemma.;

  • 作者单位

    University of Waterloo (Canada).;

  • 授予单位 University of Waterloo (Canada).;
  • 学科 Chemistry Analytical.;Chemistry Pharmaceutical.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 206 p.
  • 总页数 206
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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