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. In 2016, artemisinin resistance has been confirmed in 5 countries of the Greater Mekong subregion. We focused our study on different Syk inhibitors as new 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 leading to the release of microparticles containing hemichromes and structural weakening of the host cell membrane. Syk inhibitors block these events interacting with Syk protein catalytic site. We have performed and compared the results of in vitro/proteomics and in silico studies. In vitro studies were based on the treatment of parasite's cellular cultures with different concentrations of Syk inhibitors and proteomics studies were focalized to study the modification of the Tyr phosphorylation residue of band 3 by Syk protein. Silico studies were based on different approaches of molecular modelling, 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 according to the increase of drugs concentration. The proteomic data trend regarding the inhibition values IC50 correspond to the computational studies results. Our studies and the obtained results could be useful to the structural optimization of these compounds and to design new promising antimalarial drugs.
IN VITRO AND COMPUTATIONAL STUDIES OF SYK INHIBITORS WITH ANTIMALARIAL ACTIVITY IN RCBs, NEW PERSPECTIVES
R Dallocchio;
2019
Abstract
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. In 2016, artemisinin resistance has been confirmed in 5 countries of the Greater Mekong subregion. We focused our study on different Syk inhibitors as new 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 leading to the release of microparticles containing hemichromes and structural weakening of the host cell membrane. Syk inhibitors block these events interacting with Syk protein catalytic site. We have performed and compared the results of in vitro/proteomics and in silico studies. In vitro studies were based on the treatment of parasite's cellular cultures with different concentrations of Syk inhibitors and proteomics studies were focalized to study the modification of the Tyr phosphorylation residue of band 3 by Syk protein. Silico studies were based on different approaches of molecular modelling, 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 according to the increase of drugs concentration. The proteomic data trend regarding the inhibition values IC50 correspond to the computational studies results. Our studies and the obtained results could be useful to the structural optimization of these compounds and to design new promising antimalarial drugs.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
