diamide and Malaria--Falciparum

The protozoan Plasmodium falciparum is the main aetiological agent of tropical malaria. Characteristic of the phylum is the presence of a plastid-like organelle which hosts several homologs of plant proteins, including a ferredoxin (PfFd) and its NADPH-dependent reductase (PfFNR). The PfFNR/PfFd redox system is essential for the parasite, while mammals share no homologous proteins, making the enzyme an attractive target for novel and much needed antimalarial drugs. Based on previous findings, three chemically reactive residues important for PfFNR activity were identified: namely, the active-site Cys99, responsible for hydride transfer; Cys284, whose oxidation leads to an inactive dimeric form of the protein; and His286, which is involved in NADPH binding. These amino acid residues were probed by several residue-specific reagents and the two cysteines were shown to be promising targets for covalent inhibition. The quantitative and qualitative description of the reactivity of few compounds, including a repurposed drug, set the bases for the development of more potent and specific antimalarial leads.

Topics: Antineoplastic Agents, Alkylating; Biocatalysis; Carmustine; Catalytic Domain; Cysteine; Diamide; Enzyme Inhibitors; Ferredoxin-NADP Reductase; Kinetics; Malaria, Falciparum; Molecular Structure; NADP; Organomercury Compounds; Plasmodium falciparum; Protein Binding; Protein Domains; Protozoan Proteins; Substrate Specificity

The redox metabolism of the malaria parasite Plasmodium falciparum and its human host has been suggested to play a central role for parasite survival and clearance. A common approach to test hypotheses in redox research is to challenge or rescue cells with pro- and antioxidants. However, quantitative data on the susceptibility of infected erythrocytes towards standard redox agents is surprisingly scarce. Here we determined the IC

Topics: Acetylcysteine; Antioxidants; Ascorbic Acid; Benzothiazoles; Diamide; Diamines; Dithiothreitol; Dose-Response Relationship, Drug; Erythrocytes; Fluorescent Dyes; Host-Parasite Interactions; Humans; Hydrogen Peroxide; Inhibitory Concentration 50; Malaria, Falciparum; Organic Chemicals; Oxidants; Oxidation-Reduction; Oxidative Stress; Parasitemia; Plasmodium falciparum; Quinolines; tert-Butylhydroperoxide; Time Factors