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Deoxyuridine Triphosphate Nucleotidohydrolase as a drug target against Malaria

Final Report Summary - PLASMODIUMDUTPASE (Deoxyuridine Triphosphate Nucleotidohydrolase as a Drug Target against Malaria)

The overall objective of the PLASMODIUMDUTPASE project was to develop inhibitors of Plasmodium dUTPase to generate advanced leads or preclinical drug candidates for the treatment of malaria. 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 because of drug resistance issues. New drugs should have novel mechanisms of action to prevent cross-resistance with existing drugs. As part of the Fifth Framework Programme (FP5), the project team discovered novel, drug-like and selective inhibitors of the enzyme, deoxyuridine triphosphate nucleotidohydrolase (dUTPase) from Plasmodium falciparum, the causative agent of malaria. This enzyme has not previously been examined as a drug target for malaria. This enzyme is a house-keeping enzyme, responsible for hydrolysing the nucleotide dUTP to dUMP. If the enzyme is blocked, it will affect the ability of the parasite to replicate itself. The aim of this project is to optimise these early lead molecules to generate late-stage leads or preclinical drug candidates.

Within the project, compounds were designed using information on the structure of the protein and from the results of assays. Compounds were prepared and then evaluated against the enzyme from both Plasmodium falciparum and the human enzyme. Compounds were also screened against the intact parasite and counter-screened against mammalian cells as an initial indication of toxicity. Appropriate compounds were crystallised with the enzyme to assist in the design process. The drug-like properties of compounds which were active and selective were investigated. The mode of action of the most active compounds was investigated using a variety of cellular and enzymatic studies.

The project prepared and investigated a wide variety of chemical types for inhibition of both the parasite enzyme, dUTPase, and the intact parasite. We have developed potent and selective inhibitors of the enzyme. We have also developed potent and selective inhibitors of parasite growth. The compounds are still in the process of optimisation. Further work is required to optimise these compounds to the level of preclinical candidates.