PMID- 23716053
OWN - NLM
STAT- MEDLINE
DCOM- 20140108
LR  - 20211203
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 57
IP  - 8
DP  - 2013 Aug
TI  - Interrogating a hexokinase-selected small-molecule library for inhibitors of 
      Plasmodium falciparum hexokinase.
PG  - 3731-7
LID - 10.1128/AAC.00662-13 [doi]
AB  - 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 muM. 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 muM). These 
      findings suggest that the chemotypes identified here could represent leads for 
      future development of therapeutics against P. falciparum.
FAU - Harris, Michael T
AU  - Harris MT
AD  - Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, 
      Clemson University, Clemson, South Carolina, USA.
FAU - Walker, Dawn M
AU  - Walker DM
FAU - Drew, Mark E
AU  - Drew ME
FAU - Mitchell, William G
AU  - Mitchell WG
FAU - Dao, Kevin
AU  - Dao K
FAU - Schroeder, Chad E
AU  - Schroeder CE
FAU - Flaherty, Daniel P
AU  - Flaherty DP
FAU - Weiner, Warren S
AU  - Weiner WS
FAU - Golden, Jennifer E
AU  - Golden JE
FAU - Morris, James C
AU  - Morris JC
LA  - eng
SI  - SWISSPROT/Q02155
GR  - R15 AI075326/AI/NIAID NIH HHS/United States
GR  - U54 HG005031/HG/NHGRI NIH HHS/United States
GR  - U54HG005031/HG/NHGRI NIH HHS/United States
GR  - 2R15AI075326/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130528
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Antimalarials)
RN  - 0 (Azoles)
RN  - 0 (Benzothiazoles)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Isoindoles)
RN  - 0 (Organoselenium Compounds)
RN  - 0 (Protozoan Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Small Molecule Libraries)
RN  - 40X2P7DPGH (ebselen)
RN  - EC 2.7.1.1 (Hexokinase)
SB  - IM
MH  - Amino Acid Sequence
MH  - Antimalarials/*pharmacology
MH  - Azoles/pharmacology
MH  - Benzothiazoles/*pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Inhibitors/pharmacology
MH  - Glycolysis
MH  - Hexokinase/*antagonists & inhibitors
MH  - Inhibitory Concentration 50
MH  - Isoindoles
MH  - Molecular Sequence Data
MH  - Organoselenium Compounds/pharmacology
MH  - Parasitic Sensitivity Tests
MH  - Plasmodium falciparum/*drug effects/enzymology/growth & development
MH  - Protozoan Proteins/*antagonists & inhibitors
MH  - Recombinant Proteins/metabolism
MH  - Small Molecule Libraries/*pharmacology
MH  - Structure-Activity Relationship
PMC - PMC3719756
EDAT- 2013/05/30 06:00
MHDA- 2014/01/09 06:00
PMCR- 2014/02/01
CRDT- 2013/05/30 06:00
PHST- 2013/05/30 06:00 [entrez]
PHST- 2013/05/30 06:00 [pubmed]
PHST- 2014/01/09 06:00 [medline]
PHST- 2014/02/01 00:00 [pmc-release]
AID - AAC.00662-13 [pii]
AID - 00662-13 [pii]
AID - 10.1128/AAC.00662-13 [doi]
PST - ppublish
SO  - Antimicrob Agents Chemother. 2013 Aug;57(8):3731-7. doi: 10.1128/AAC.00662-13. 
      Epub 2013 May 28.