There are around 500 million clinical cases of malaria each year and about 1-2 million people die from this debilitating disease. There is an urgent need for the development of new drugs owing to problems with drug resistance. New drugs should have novel mechanisms of action to prevent cross-resistance with existing drugs. We have discovered some novel, drug-like and selective inhibitors of the Plasmodium enzyme, deoxyuridine triphosphate nucleotidohydrolase (dUTPase). The role of the enzyme is to hydrolyse dUTP to dUMP, maintaining a low dUTP:dTTP ratio. The aim of this project is to optimise these early lead molecules to generate preclinical drug candidates. The project will consist of: medicinal chemistry to prepare and optimise lead compounds; ADME-Tox assays to ensure that the compounds have correct 'drug-like' properties; assays to determine the efficacy of the compounds; mode of action studies; crystallography of inhibitors with the enzyme active site to assist in the drug design process.'
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