Thesis
The use of contemporary chemoproteomic techniques in antimalarial target identification
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2020
- Thesis identifier
- T16428
- Person Identifier (Local)
- 201685549
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Malaria remains a significant public health burden, with antimalarial resistance threatening the efficacy of current antimalarial medicines and resulting in an immense need to develop novel disease treatments. In our laboratories, an antimalarial quinazolinamine hit with a novel mechanism of action was identified in a phenotypic screen against the blood stage Plasmodium falciparum parasite. This thesis discloses the identification of the target proteins of this potential drug series, through use and analysis of contemporary chemoproteomic techniques for target identification. The introductory chapter of this thesis provides: an overview of malaria biology; current antimalarial treatments and their limitations; and a discussion of contemporary chemoproteomic techniques for target identification. The nascent antimalarial quinazolinamine series is introduced, and the aim to identify the protein targets of this series is described. Chapter 2 describes the synthesis of three chemical probes based on the quinazolinamine series. These probes incorporate an alkyne functional handle for immobilisation onto solid beads, which were used in affinity-based chemoproteomic experiments to affinity-capture protein targets in Plasmodium falciparum lysates. However, using this typical workflow, the appropriate target proteins were not successfully identified. As a result, attention was turned to the use of a photoaffinity labelling technique for target identification. Chapter 3 describes the synthesis of photoreactive probes of the quinazolinamine series. These were used in an innovative photoaffinity labelling assay which was established for the first time in our laboratories, enabling the covalent capture of target proteins in live P. falciparum parasites. Two transporter proteins, P. falciparum apicomplexan amino acid transporter 2 (PfApiAT2) and P. falciparum equilibrative nucleoside transporter 1 (PfENT1) were captured as target proteins of the antimalarial quinazolinamine series. These proteins have both been reported as essential for parasite survival and have no known human homologues. Chapter 3 concludes with a discussion of their key features, and Chapter 4 provides an analysis and comparison of the techniques used in their identification.
- Advisor / supervisor
- Jamieson, Craig
- Patel, Vipul
- Resource Type
- Note
- Previously held under moratorium in Chemistry Department (GSK) from 17/06/2020 to 23/11/2022.
- The confidentiality statement on each page of this thesis DOES NOT apply
- DOI
- Funder
- Embargo Note
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