The development of thiosulfonates as cysteine protease inhibitors

Ward, David John (2019) The development of thiosulfonates as cysteine protease inhibitors. PhD thesis, University of Glasgow.

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Cysteine proteases are ubiquitous throughout nature as proteolytic machinery that are responsible for key physiological processes. Unregulated, uncontrolled or undesired proteolysis is often a key process in many disease states. As such, specific inhibitors of cysteine proteases offer a unique therapeutic target for chemotherapeutic intervention. This is particularly true in many diseases caused by parasitic infections, such as Malaria, Schistosomiasis and Chagas disease, as the parasitic lifecycle is often highly dependent upon cysteine proteases.

The majority of attempts at conferring specificity of covalent inhibitors have been derived from classical structure activity relationship (SAR) studies. Such studies place emphasis on the primary non-covalent interaction with little optimisation of the electrophillic trap, which forms the covalent bond, being attempted. In this work a new class of electrophillic traps, the thiosulfonates, will be developed as cysteine protease inhibitors. This aims to take advantage of the differing chemistry observed for cysteine proteases, with a sulfur centred nucleophile, rather than the oxygen centred nucleophile which is present in all other protease classes. When combined with classical SAR this two pronged attack should greatly increase inhibitor specificity and reduce off target effects, adding to the chemical toolkit available to medicinal chemists.

Throughout this work the synthesis, reactivity profiles and biological evaluation of thiosulfonates as cysteine protease inhibitors will be explored. Computational modelling studies will be incorporated, highlighting the synergy between classical SAR and electrophilic trap optimisation. This will culminate in the application of thiosulfonates towards schistosomiasis, the second biggest neglected tropical disease after malaria.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Cysteine, protease, inhibitor, neglected tropical disease, schistosomiasis, docking study, DrawToDock, warhead, electrophilic trap, sulfur.
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Supervisor's Name: Liskamp, Professor Robert M.J.
Date of Award: 2019
Depositing User: Dr David John Ward
Unique ID: glathesis:2019-78987
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 30 Jan 2020 10:50
Last Modified: 10 Aug 2022 09:52
Thesis DOI: 10.5525/gla.thesis.78987
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