TRYPOBASE · Nucleobase derivatives as drugs against trypanosomal diseases

The protozoan diseases, leishmaniasis, African trypanosomiasis and Chagas’ disease are responsible for substantial global morbidity, mortality, and economic adversity, and in most countries, existing strategies for control and treatment are either failing or under serious threat. New tools for combating pathogenic protozoa and the development and exploitation of new drug targets are required. This proposal builds on several achievements and observations of the consortium in the area of nucleotide metabolism. •Pyrimidine and purine metabolism exhibits unique features in trypanosomes. •The identification of a unique enzyme involved in pyrimidine metabolism restricted to trypanosomes and essential for viability: the dimeric all-alpha dUTPase. •An exceptional collection of purine and pyrimidine analogues is available through the consortium for antiprotozoal screening and lead identification. •The consortium brings together an outstanding combination of expertise for drug discovery. The main objective is the identification of new purine and pyrimidine derivatives for the treatment of the leishmaniases and trypanosomiases. A two-pronged approach is proposed to discover new leads for the treatment of leishmaniasis and trypanosomiasis targeting nucleoside/ nucleotide metabolism. 1)The phenotypic approach exploring the potential of large collections of novel nucleobase derivatives against trypanosomal diseases. 2)The target-based approach specifically centred on the development of inhibitors of the enzyme deoxyuridine triphosphate nucleotidohydrolase. The trypanosomal enzyme shows structural and functional characteristics which differ profoundly from the mammalian counterpart. The aim is to identify potent inhibitors that are active against parasitic protozoa, active in rodent models of infection and have drug-like properties.