Discovery and design of Plasmodium falciparum enolase inhibitors as new antimalarial candidates.

Abstract

Malaria is a parasitic disease, widespread in tropical and subtropical regions of the world with high levels of mortality. The disease is a global problem that requires new safe treatment alternatives since the available chemotherapeutics have many issues related to toxicity, efficacy, and administration. Enolase (Pfen), a glycolytic enzyme from Plasmodium falciparum, is essential for parasite development. In this context, parasites are highly dependent on glycolysis as source of energy. Additionally, Pfen has been localized in several sub-cellular compartments (cytosol, nucleus, cell membrane, food vacuole, and cytoskeleton), and it has been related to additional functions (moonlight function). Therefore, Pfen is an attractive molecular target for antimalarial drug design. This project aims at identifing and developing new bioactive molecules as drug candidates for malaria. In this sense, an integrated strategy including structural and molecular biology, kinetic assays and medicinal chemistry methods was designed. The natural products were isolated from Brazilian plants extracts and selected on the basis of the chemotaxonomic and ethnobotanical knowledge. Synthetic compounds were provided by the non-governmental organization "Medicine for Malaria Venture" (MMV). The compounds have potent in vitro activity against the P. falciparum blood-stage, but their mechanism of action remains unknown. The combination of modern drug discovery strategies will be of paramount importance toward the evaluation of bioactive compounds mechanism of action as well as for the development of new molecules with enhanced properties as novel antimalarials candidates.