Computational and in vitro studies of Syk Inhibitors as new drugs in P. falciparum malaria

Malaria remains one of the most devastating infectious diseases. Although the current therapies are working well, the WHO recommends Artemisinin Combination Therapies (ACTs) as the frontline treatments against P. falciparum malaria to limit the artemisinin resistance. In 2017 it has been confirmed in 5 countries of the Greater Mekong subregion. An alternative way to fight the parasite resistance could be use Syk inhibitors as new antimalarial drugs. Syk protein is present in human erythrocytes; its activation by oxidant stress involves the band 3 (AE1) membrane protein. Tyr phosphorylation (AE1) occurs during P. falciparum growth leading to the release of microparticles containing hemichromes and RBCs structural weakening. Syk inhibitors block these events interacting with protein catalytic site. We have performed in vitro and in silico studies and compared the obtained results. In vitro we treated parasitized erythrocytes with different concentrations of Syk inhibitors and we evaluate the Tyr phosphorylation levels in Band 3 residues by proteomic analysis. In presence of Syk inhibitors we observed a marked decrease of band 3 phosphorylation according to drug concentration increase. The proteomic data trend relating to the inhibition values IC50 correspond to the computational studies. In silico studies were based on different approaches of molecular modeling aimed to deepen the knowledge about the ligand-protein interaction in order to obtain the highest efficacy in vitro. This study allow to optimize the structure of these compounds and to design and discover new promising antimalarial drugs.