In vitro and computational studies of Syk inhibitors as new antimalarial drugs

Resistance to antimalarial drugs has spread rapidly over the past few decades. WHO recommends Artemisinin based combination therapies (ACTs) for the treatment of uncomplicated Malaria, but unfortunately they are loosing their efficacy in large areas of Southeast Asia. In 2016, artemisinin resistance has been confirmed in 5 countries of the Greater Mekong sub region. We focused our study on Syk inhibitors as antimalarial drugs. Syk protein is present in human erythrocytes and membrane protein band 3 is its major target following activation by oxidant stress. Tyr phosphorylation of band 3 occurs during P. falciparum growth development leading to the release of microparticles containing hemicromes and structural weakening of the host cell membrane, simplifying merozoites reinfection. Syk inhibitors block these events interacting with Syk protein catalytic site. We have performed and also compared the results of in vitro/proteomics and in silico studies. In vitro studies were based on treatment of parasite's cellular coltures with different concentration of Syk inhibitors and proteomics studies was focused about the Tyr phosphorylation of band 3 by Syk protein with the same concentrations of drugs. In silico studies were based to different approaches of molecular modelling, to analyze and to optimize the interaction ligand-protein and obtain the highest efficacy in vitro. In presence of Syk inhibitors we observed a marked decrease of band 3 phosphorylation and an increase of band 3 protein amount according to the increase of drug's concentration. Our studies could be useful in the structural optimization of these compounds and they are interesting to design the novel Syk inhibitors in the future.