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Metallodrug interactions with proteins in biological systems studied by Fourier Transform-Ion Cyclotron Resonance Mass Spectrometry
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Chiu, Cookson (2019) Metallodrug interactions with proteins in biological systems studied by Fourier Transform-Ion Cyclotron Resonance Mass Spectrometry. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3511927~S15
Abstract
The work presented herein focuses on the study of novel metallodrugs (transition metal-based drugs) and their interaction with different biomolecules in the form of peptides, proteins, and cellular components via the use of ultra-high resolution Fourier Transform-Ion Cyclotron Resonance Mass Spectrometry (FT-ICR MS).
A LC-MS/MS methodology with a specialised peak picking algorithm was developed for automatic detection of metallated species and information of metallodrug-binding was successfully elucidated. An alternative digestion method for bottom-up study was examined, however, standard tryptic digestion showed better and more predictable results. Further, the performance and efficiency of two distinct disulfide bond reduction methods: electrochemical reduction and radical-induced reduction were investigated. Results showed that both techniques can effectively reduce disulfide bonds of model proteins, opening the protein structure and enhancing fragmentation efficiency during MS/MS experiments to different controllable degrees; Better protein identification and characterisation was therefore afforded using these methods.
A range of octahedral iridium-(III)-based anticancer complexes were found to be capable of generating toxic singlet oxygen upon irradiation of visible blue light (463 nm), as evidenced by the production of a specific oxidised form of tryptophan, 3-hydroxykynurenine, on a model peptide. Proteomics studies of human lung cancer cells (A549) revealed the photoactivation of the iridium complex caused selective oxidative damage to specific histidine residues in key cellular proteins; Heat shock protein 70 kDa and aldose reductase.
The overall effects of an osmium-based anticancer drug against A2780 human ovarian cancer cells and an iridium-based antimicrobial complex against Staphylococcus aureus were studied using quantitative nLC-FT-ICR-MS/MS. The osmium-based anticancer complex affected the energy production pathway of the cancer cell, whereas the iridium-based antimicrobial complex was found to be capable of triggering a series of secondary responses from bacterial cells by inducing a vast amount of stress, including oxidative stress.
| Item Type: | Thesis or Dissertation (PhD) | ||||
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| Subjects: | Q Science > QC Physics Q Science > QD Chemistry Q Science > QP Physiology R Medicine > RM Therapeutics. Pharmacology R Medicine > RS Pharmacy and materia medica |
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| Library of Congress Subject Headings (LCSH): | Metalloenzymes, Fourier transform spectroscopy, Electrolytic reduction, Metals in medicine, Pharmaceutical chemistry, Mass spectrometry | ||||
| Official Date: | September 2019 | ||||
| Dates: |
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| Institution: | University of Warwick | ||||
| Theses Department: | Department of Chemistry | ||||
| Thesis Type: | PhD | ||||
| Publication Status: | Unpublished | ||||
| Supervisor(s)/Advisor: | O’Connor, Peter B. ; Sadler, Peter J. | ||||
| Format of File: | |||||
| Extent: | xxxvii, 250 leaves: illustrations, plates, charts. | ||||
| Language: | eng |
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