Plasmodium falciparum (P. falciparum) causes the most widespread and virulent form of human malaria, anddrug resistance is a major factor in reduced effectiveness of our current treatment options. Our goal is todetermine how new iron (Fe) chelators: 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), 2-hydroxy-1 -naphthylaldehyde-4-phenyl-3-thiosemicarbazone (N4pT), and (2-hydroxy-1 -naphthylaldehyde-4-methyl-3-thiosemicarbazone (N4mT) interact with hemoglobin S (HbS) in sickle erythrocytes to inhibitplasmodial growth. Our overall hypothesis is that the presence of HbS in sickle red blood cells (RBCs) willfurther enhance the antimalarial effects of 311, N4pT and N4mT in AS- and SS-infected RBCs than in HbAA-infectedRBCs. Sickle erythrocytes are associated with accumulation of Hb degradative products (Fedeposits) on the inner cytoplasmic surface of the membrane which favor oxidative reaction, and P.falciparum is sensitive to oxidative stress. Fe chelators are used to treat many clinical and infectiousconditions including malaria, and desferrioxamine (DFO) has clinically detectable antimalarial activity inhuman malaria. Poor membrane permeability and other problems have precluded DFO from being used asanti-malarial. Hence new Fe chelators are being developed. The mechanism (s) of antiplasmodial actions ofFe chelators is not clear. Initial data showed a significantly greater anti-malarial activity of 311, N4pT andN4mT over DFO in chloroquine-resistant (CQ-R) and -sensitive (CQ-S) clones of P. falciparum in HbAARBCs and also in HbS-infected RBCs. Evidence that the Fe-complexes of these chelators have oxidativeproperties makes them good antimalarial candidates.
Aim 1 : will compare the anti-parasite effects of 311,N4pT and N4mT on CQ-S and CQ-R clones of P. falciparum-infected HbAS, HbSS and HbAA RBCs in vitroby (a) measuring the time of onset of parasite growth inhibition and the 50% inhibitory concentration (IC50),(b) examining chelator effects on red cell membrane shape.
Aim 2 : Determine mechanism of parasite growthinhibition by 311, N4pT and N4mT. We will (a) examine the effects of iron complexation of chelators andanalysis of labile iron pools in HbAS, HbSS and HbAA RBCs compared to uninfected RBCs, (b) measureoxidant effects of the chelators on infected RBCs. Fe chelators may suppress parasite growth by interferingwith Hb breakdown, thus we will (c) evaluate the effect of chelators for their inhibition of the polymerization ofhematin to beta-hematin in cell-free systems.
Aim 3 : Determine the uptake, cellular distribution, and retention ofchelators in infected and non-infected RBCs. We will measure drug levels within cells and parasite usingradioactive chelators ([14C]-chelators). Studies will shed insight into role of abnormal hemoglobin in antimalariaresponses and also antimalaria mechanism of action of Fe chelators. Data will enable us apply forRO1 to do animal studies and opportunity to design treatment programs towards patient's genetic status.
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