The design and synthesis of drug-like trypanosome alternative oxidase inhibitors for the treatment of African trypanosomiasis

West, Ryan (2019) The design and synthesis of drug-like trypanosome alternative oxidase inhibitors for the treatment of African trypanosomiasis. Doctoral thesis (PhD), University of Sussex.

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Abstract

Trypanosome alternative oxidase (TAO) is the sole terminal oxidase responsible for the
aerobic respiration of the parasite T. b. brucei. Specific strains of this parasite cause the
neglected tropical disease Human African trypanosomiasis (HAT), and thus TAO is an
interesting target for the potential treatment of this disease.

Inhibition of TAO with the natural product inhibitors colletochlorin B or ascofuranone has
been shown to clear infections of T. b. brucei in mice at high concentrations. However, these
natural product inhibitors contain undesirable chemical functionality and have poor
physicochemical properties, preventing adequate drug exposure to effectively treat HAT.

Robust protocols for the expression and purification of recombinant TAO were developed,
which enabled the development of biochemical assays to identify inhibitors of TAO function.
Single point inhibition screening of the Medicines Malaria Venture ‘kinetoplastid collection’
of 400 compounds identified a range of micro-molar inhibitors of TAO.

A program of chemical optimisation was carried out around the natural product inhibitor
colletochlorin B, with the aim to improve the physicochemical properties and retain
inhibitory potency against TAO. The structure activity relationships generated over the
course of this exploration identified a dependency on high lipophilicity to retain potent TAO
inhibition. The TAO inhibitors synthesised were also assessed for parasite growth inhibition
and mammalian cell cytotoxicity to correlate inhibition data with cellular efficacy, in
collaboration with Novartis. The physicochemical properties of these novel compounds
showed improvement over the natural product colletochlorin B and prompted further
assessment of leading compounds in advanced parasite kill kinetic and parasite clearance
assays at Novartis. The data generated in these assays for compounds synthesised in this
thesis determined that TAO inhibition results in a trypanostatic response, and not a preferred
trypanocidal response in T. b. brucei.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Chemistry
Subjects: R Medicine > RC Internal medicine > RC0109 Infectious and parasitic diseases > RC0186.T82 Trypanosomiasis, African. Sleeping sickness
Depositing User: Library Cataloguing
Date Deposited: 11 Jan 2019 07:36
Last Modified: 11 Jan 2019 07:36
URI: http://sro.sussex.ac.uk/id/eprint/81228

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