Marchetti, Giuseppe (2019) In vitro and in silico studies of Syk inhibitors as new antimalarial drugs. Doctoral Thesis.
Malaria remains one of the most devastating infectious diseases and despite the current therapies are efficient, the WHO recommends Artemisinin Combination Therapies (ACTs) as the treatments against P. falciparum malaria to limit the artemisinin resistance. Unfortunately, in the Greater Mekong subregion, their efficacy has recently questioned. A new mechanism of action based on the release of denatured haemoglobin products (haemichromes) bound to erythrocyte membrane through the Band 3 protein has recently characterized. This process, mediated by erythrocytic spleen tyrosine kinase (Syk), entails the Tyr phosphorylation of band 3. The consequent membrane destabilization could be essential for P. falciparum egress, since inhibitors of Syk block these events. The aim of this study was to examine the effects of the Syk inhibitors during parasite growth within the human erythrocyte through in vitro experiments and to explore current molecular docking strategies used in drug discovery and medicinal chemistry. In vitro studies have involved the treatment of parasitized erythrocytes with different concentrations of Syk inhibitors and the Tyr phosphorylation levels in Band 3 residues by proteomic approach was evaluated. In silico studies were based on different approaches of molecular modelling. In presence of Syk inhibitors we observed both in silico and in vitro experiments a marked decrease of band 3 phosphorylation which is proportional to the increase of drug dosage. These studies enabled us to better analyse the structure of different compounds and to possibly discover new Syk inhibitors through virtual screening analysis.
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