SLAS

Poster: Multiple drug design strategies for the discovery of new treatments for human African trypanosomiasis

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Poster presentation at MipTec 2013
Winner of a SLAS Young Scientist Award.

Eyram Adjogatse1, Peter Erskine1, John Kelly2, Steve Wood1, Jon Wilden3, Jon Cooper1
(1) Laboratory for Protein Crystallography, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London
(2) Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine'
(3) Department of Chemistry, University College London

Abstract

Human African trypanosomiasis (HAT) is a debilitating and fatal neglected tropical disease (NTD) that is prevalent in regions of rural Africa. As with many NTDs, it has historically received a lack of investment into pharmaceutical R&D, meaning that only a few drugs are available to treat HAT. Some of these drugs are toxic and difficult to administer, so there is an urgent need for novel therapeutics.

The enzyme L-threonine 3-dehydrogenase (TDH) has been validated as a drug target for TDH. Exposure of the HAT causing parasite, Trypanosoma brucei, to a TDH inhibitor causes its rapid death. The absence of functional TDH in man, and the reliance of the parasite on this enzyme make it an attractive target for the development of a safe, but potent treatment.

Using a combination of X-ray crystallography, enzyme kinetics assays and other biochemical techniques, we have obtained information on the relationships between the structure and function of TDH. Several high-resolution structures of TDH from T. brucei have been solved for the first time, including the apoenzyme and ligand-bound forms of the enzyme. We have also observed multiple quaternary structures of TDH which may relate to the atypical kinetic characteristics observed. The structural data were used to perform in silico high-throughput screens (HTS) using Autodock 4.0. A combination of diversifying and focused ligand-based approaches were tested in parallel by combining a diversity set of compounds, a set of natural products, a set of TDH ligand-analogues and a set of known trypanocidal compounds. From a small selection of the top scoring compounds, two in vitro inhibitors were identified. These results have been employed in the design and execution of an in vitro HTS against TDH. In summary, we have demonstrated how the structural characterisation of a validated therapeutic target can yield valuable information that can be used to drive early-stage drug discovery in an academic setting.

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