NACOPAKI: identification of Natural COmpounds targeting the malaria PArasite pyruvate Klnases

Plasmodium is the parasite responsible for malaria, the leading cause of parasitic mortality in the world. According to the WHO, malaria caused 619 deaths in 000, mainly among children under five years old. It is therefore essential to enrich the therapeutic arsenal against this disease. Two pyruvate kinases of Plasmodium falciparum are essential for the survival of the parasite during its erythrocyte development, the symptomatic phase of the disease. These proteins appear to be prime therapeutic targets for antimalarial treatment. To date, no potent specific inhibitor of the enzymatic activities of these two proteins has been identified.
Thanks to an in silico screen, the UMR MERIT (parasitology and biochemistry) and the UMR CiTCoM / Natural Products Analysis and Synthesis team (PNAS; pharmacognosy and chemistry) of the Faculty of Pharmacy of Paris, have identified natural compounds from the chemical library of the PNAS team, likely to interact with the two proteins. We propose here to evaluate these compounds and analogues from the UMR CiTCoM chemical library in vitro for their interactions with parasitic proteins, then for their inhibition of enzymatic activities. This project also concerns the quantitative obtaining of compounds from the chemical library by optimized methodologies, in parallel with the implementation of semisynthesis reactions making it possible to improve the interactions observed in silico, with a view to the envisaged biological evaluations. Finally, the inhibition of parasite growth by the best compounds identified will also be evaluated in vitro.
The expected results will provide the first essential elements for the optimization of natural compounds and will make it possible to develop specific inhibitors of the two pyruvate kinases, and therefore of parasitic development in red blood cells.