Novel drugs against trypanosomal diseases
Protozoa of the genera Leishmania and Trypanosoma are responsible for Leishmaniasis, and African trypanosomiasis and Chagas disease, respectively. Leishmaniasis alone gives rise to over 2 million clinical cases annually, while nearly 18 million people are infected with Trypanosoma cruzi (Chagas disease). Overall, these infected diseases have been relatively neglected in research but are the cause of substantial morbidity and mortality in endemic regions, found mainly in tropical and sub-tropical areas. As a result, new tools and drug targets are required for combating pathogenic protozoa. Antimetabolites against purine and pyrimidine (components of DNA helix nucleobases) have been used with great success in the treatment of a wide range of diseases, including cancer and AIDS. The EU-funded 'Nucleobase derivatives as drugs against trypanosomal diseases' (TRYPOBASE) project explored the anti-parasite potential of novel nucleobase derivatives. Details on the TRYPOBASE project are available at http://www.ipb.csic.es/trypobase/index.html online. Among the project's objectives were to screen drug-like compounds in vitro and in vivo, as well as to synthesise novel ones. To this end, a library of nearly 7 000 nucleoside and nucleobase derivatives was screened and several compounds exhibited anti-parasite activity especially against T. cruzi. An alternative strategy was explored by the TRYPOBASE consortium; this entailed the targeting of the deoxyuridine triphosphate nucleotidohydrolase (dUTPase) enzyme implicated in nucleotide metabolism. Using RNA interference, the consortium unveiled the importance of dUTPase for parasite growth and proliferation. Parasites with reduced enzyme levels exhibited either absence of or an enlarged nucleus, and presented with defects in cell cycle progression. To prepare inhibitors for the dUTPase enzyme, scientists screened a chemical library of over 62 000 compounds. Three-dimensional (3D) analysis of the enzyme for the identification of potential targets revealed a polar active site requiring significant further structural optimisation of the selected compounds. Although the nucleotide antimetabolite work of the TRYPOBASE project exhibited higher anti-parasite potential, information generated on the dUTPase enzyme in particular is expected to drive future research on this target. Following optimisation, the identified compounds have the potential to progress down the development pathway rapidly toward clinical candidates.
