title: Computational and experimental analysis identified 6-diazo-5-oxonorleucine as a potential agent for treating infection by Plasmodium falciparum.
abstract: Plasmodium falciparum (PF) is the most severe malaria parasite. It is developing resistance quickly to existing drugs making it indispensable to discover new drugs. Effective drugs have been discovered targeting metabolic enzymes of the parasite. In order to predict new drug targets, computational methods can be used employing database information of metabolism. Using this data, we performed recently a computational network analysis of metabolism of PF. We analyzed the topology of the network to find reactions which are sensitive against perturbations, i.e., when a single enzyme is blocked by drugs. We now used a refined network comprising also the host enzymes which led to a refined set of the five targets glutamyl-tRNA (gln) amidotransferase, hydroxyethylthiazole kinase, deoxyribose-phophate aldolase, pseudouridylate synthase, and deoxyhypusine synthase. It was shown elsewhere that glutamyl-tRNA (gln) amidotransferase of other microorganisms can be inhibited by 6-diazo-5-oxonorleucine. Performing a half maximal inhibitory concentration (IC50) assay, we showed, that 6-diazo-5-oxonorleucine is also severely affecting viability of PF in blood plasma of the human host. We confirmed this by an in vivo study observing Plasmodium berghei infected mice.
authors.affiliation: Advanced Virtual and Intelligent Computing Research Center (AVIC), Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Phayathai, Bangkok 10330, Thailand.
authors.forename: Kitiporn
authors.initials: K
authors.lastname: Plaimas
authors.forename: Yulin
authors.initials: Y
authors.lastname: Wang
authors.forename: Solomon O
authors.initials: SO
authors.lastname: Rotimi
authors.forename: Grace
authors.initials: G
authors.lastname: Olasehinde
authors.forename: Segun
authors.initials: S
authors.lastname: Fatumo
authors.forename: Michael
authors.initials: M
authors.lastname: Lanzer
authors.forename: Ezekiel
authors.initials: E
authors.lastname: Adebiyi
authors.forename: Rainer
authors.initials: R
authors.lastname: König
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use; D001391:Azo Compounds / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D051379:Mice; D019884:Nitrogenous Group Transferases / Q000037:antagonists & inhibitors*; D009646:Norleucine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors
chemical_list: D000962:Antimalarials; D001391:Azo Compounds; D015800:Protozoan Proteins; D009646:Norleucine; D019884:Nitrogenous Group Transferases; C047694:glutamyl-tRNA(Gln) amidotransferase; C000590535:6-diazo-5-oxonorleucine
keywords: 6-Diazo-5-oxonorleucine; Chokepoint; Malaria; Metabolic network; Plasmodium