Deciphering the mechanisms of action of two antimalarial redox-active drugs with gametocytocidal and transmission-blocking properties - from yeast to malarial parasites – PlasmoPrim

With 429 000 deaths per year, malaria remains the most devastating parasitic disease for humans. It is caused by Plasmodium parasites and transmitted by Anopheles mosquitoes. The efficiency of artemisinin-based combination therapies (ACTs), the spearhead of malarial treatments, is now threatened by the appearance and spreading of artemisinin-resistant parasites. Moreover, the development of control strategies to block parasite transmission is a priority of WHO. In this project, we propose to study the mode of action of two antimalarial drugs, primaquine (PQ) and plasmodione (PD) that are active against gametocytes, the parasite stages responsible for human to mosquito transmission. PQ is the only available antimalarial medicine with established activity against mature gametocytes and is currently under intense clinical validation for widespread use in combination with ACTs. PD and derivatives are new early leads displaying fast-acting antimalarial activity and potent transmission-blocking properties. These drugs kill parasites most likely through pleiotropic redox-mediated mechanisms that remain poorly understood. While having distinct bioactivations, some of their modes of action seem to share common features. Indeed, while PQ is transformed by human cytochromes cytP450 into presumably highly active hydroxylated metabolites, the antimalarial activity of PD comes largely from its specific bioactivation within the infected erythrocytes and subsequent redox cycling properties. The existence of putative targets proteins for these compounds also remains an opened question.

To decipher their complex mode of action, we propose to set up a multidisciplinary approach combining different expertise in organic synthesis, chemical proteomics, biochemistry, cell biology, and genetics, and to use the yeast as a model in parallel to Plasmodium studies. Our project has three main objectives:
1) to monitor the oxidative damages caused by PQ/PD,
2) to identify target proteins and redox enzymes controlling drug sensitivity and resistance in yeast and parasites,
3) to confirm the contribution of these candidate genes to drug sensitivity and resistance in Plasmodium.

We expect that this proposal will allow us to shed light and understand the biochemical pathways and genes implicated in the modes of action of these antimalarials, and will allow their drug targeting as essential components in asexual and sexual parasites, responsible for malaria physiopathology and transmission, respectively.