Abstract
This thesis describes approaches to develop selective, covalent inhibitors of enzymes in infectious diseases.Covalent inhibitors are drugs which are capable of forming a covalent bond to their target. This can give them many advantages over traditional, non-covalent drugs from a pharmacokinetics perspective. These include high potencies, long durations of action and excellent selectivity (Chapter 1).
Several approaches were used to investigate the development of covalent inhibitors. Firstly, an NMR based assay was developed and used to measure the reactivity of various covalent warheads with both the normally targeted amino acids, cysteine and serine, and other amino acids identified as being potential targets of covalent drugs (Chapter 2).
A known, non-covalent inhibitor of FabA, an enzyme involved in the fatty acid biosynthesis pathway in Pseudomonas aeruginosa, was modified to attempt to develop it into a covalent inhibitor (Chapter 3).
Using the knowledge of covalent warhead reactivity gained in Chapter 2 a covalent fragment library was designed and synthesised (Chapter 4). This library was screened against a variety of targets in both biochemical and cell based assays. Trypanosoma cruzi HisRS and Leishmania infantum HisRS, enzymes involved in protein synthesis in the causative parasites of Chagas disease and leishmaniasis, were selected as targets and it was shown that these enzymes could be covalently inhibited.
Finally, some of the hit compounds identified by screening the covalent fragment library against these targets were selected and further developed with the goal of increasing potency and selectivity (Chapter 5).
| Date of Award | 2021 |
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| Original language | English |
| Awarding Institution |
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| Sponsors | Medicines for Malaria Venture (MMV) |
| Supervisor | Ian Gilbert (Supervisor) |