title: Interrogating a hexokinase-selected small-molecule library for inhibitors of Plasmodium falciparum hexokinase.
abstract: Parasites in the genus Plasmodium cause disease throughout the tropic and subtropical regions of the world. P. falciparum, one of the deadliest species of the parasite, relies on glycolysis for the generation of ATP while it inhabits the mammalian red blood cell. The first step in glycolysis is catalyzed by hexokinase (HK). While the 55.3-kDa P. falciparum HK (PfHK) shares several biochemical characteristics with mammalian HKs, including being inhibited by its products, it has limited amino acid identity (~26%) to the human HKs, suggesting that enzyme-specific therapeutics could be generated. To that end, interrogation of a selected small-molecule library of HK inhibitors has identified a class of PfHK inhibitors, isobenzothiazolinones, some of which have 50% inhibitory concentrations (IC50s) of <1 μM. Inhibition was reversible by dilution but not by treatment with a reducing agent, suggesting that the basis for enzyme inactivation was not covalent association with the inhibitor. Lastly, six of these compounds and the related molecule ebselen inhibited P. falciparum growth in vitro (50% effective concentration [EC50] of ≥ 0.6 and <6.8 μM). These findings suggest that the chemotypes identified here could represent leads for future development of therapeutics against P. falciparum.
authors.affiliation: Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Harris
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Walker
authors.forename: Mark E
authors.initials: ME
authors.lastname: Drew
authors.forename: William G
authors.initials: WG
authors.lastname: Mitchell
authors.forename: Kevin
authors.initials: K
authors.lastname: Dao
authors.forename: Chad E
authors.initials: CE
authors.lastname: Schroeder
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Flaherty
authors.forename: Warren S
authors.initials: WS
authors.lastname: Weiner
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Golden
authors.forename: James C
authors.initials: JC
authors.lastname: Morris
mesh_terms: D000595:Amino Acid Sequence; D000962:Antimalarials / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006019:Glycolysis; D006593:Hexokinase / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D054833:Isoindoles; D008969:Molecular Sequence Data; D016566:Organoselenium Compounds / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D001393:Azoles; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D054833:Isoindoles; D016566:Organoselenium Compounds; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; C042986:ebselen; D006593:Hexokinase