Iron Chelators: Role in Sickle Cell Malaria (pilot)

Howard University, Washington DC

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Abstract

Plasmodium falciparum (P. falciparum) causes the most widespread and virulent form of human malaria, and[unreadable] drug resistance is a major factor in reduced effectiveness of our current treatment options. Our goal is to[unreadable] determine how new iron (Fe) chelators: 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), 2-[unreadable] hydroxy-1 -naphthylaldehyde-4-phenyl-3-thiosemicarbazone (N4pT), and (2-hydroxy-1 -naphthylaldehyde-4-[unreadable] methyl-3-thiosemicarbazone (N4mT) interact with hemoglobin S (HbS) in sickle erythrocytes to inhibit[unreadable] plasmodial growth. Our overall hypothesis is that the presence of HbS in sickle red blood cells (RBCs) will[unreadable] further enhance the antimalarial effects of 311, N4pT and N4mT in AS- and SS-infected RBCs than in HbAA-infected[unreadable] RBCs. Sickle erythrocytes are associated with accumulation of Hb degradative products (Fe[unreadable] deposits) on the inner cytoplasmic surface of the membrane which favor oxidative reaction, and P.[unreadable] falciparum is sensitive to oxidative stress. Fe chelators are used to treat many clinical and infectious[unreadable] conditions including malaria, and desferrioxamine (DFO) has clinically detectable antimalarial activity in[unreadable] human malaria. Poor membrane permeability and other problems have precluded DFO from being used as[unreadable] anti-malarial. Hence new Fe chelators are being developed. The mechanism (s) of antiplasmodial actions of[unreadable] Fe chelators is not clear. Initial data showed a significantly greater anti-malarial activity of 311, N4pT and[unreadable] N4mT over DFO in chloroquine-resistant (CQ-R) and -sensitive (CQ-S) clones of P. falciparum in HbAA[unreadable] RBCs and also in HbS-infected RBCs. Evidence that the Fe-complexes of these chelators have oxidative[unreadable] properties makes them good antimalarial candidates. Aim 1: will compare the anti-parasite effects of 311,[unreadable] N4pT and N4mT on CQ-S and CQ-R clones of P. falciparum-infected HbAS, HbSS and HbAA RBCs in vitro[unreadable] by (a) measuring the time of onset of parasite growth inhibition and the 50% inhibitory concentration (IC50),[unreadable] (b) examining chelator effects on red cell membrane shape. Aim 2: Determine mechanism of parasite growth[unreadable] inhibition by 311, N4pT and N4mT. We will (a) examine the effects of iron complexation of chelators and[unreadable] analysis of labile iron pools in HbAS, HbSS and HbAA RBCs compared to uninfected RBCs, (b) measure[unreadable] oxidant effects of the chelators on infected RBCs. Fe chelators may suppress parasite growth by interfering[unreadable] with Hb breakdown, thus we will (c) evaluate the effect of chelators for their inhibition of the polymerization of[unreadable] hematin to beta-hematin in cell-free systems. Aim 3: Determine the uptake, cellular distribution, and retention of[unreadable] chelators in infected and non-infected RBCs. We will measure drug levels within cells and parasite using[unreadable] radioactive chelators ([14C]-chelators). Studies will shed insight into role of abnormal hemoglobin in antimalaria[unreadable] responses and also antimalaria mechanism of action of Fe chelators. Data will enable us apply for[unreadable] RO1 to do animal studies and opportunity to design treatment programs towards patient's genetic status.