Harris, Michael T.;
Walker, Dawn M.;
Drew, Mark E.;
Mitchell, William G.;
Dao, Kevin;
Schroeder, Chad E.;
Flaherty, Daniel P.;
Weiner, Warren S.;
Golden, Jennifer E.;
Morris, James C.
Interrogating a Hexokinase-Selected Small-Molecule Library for Inhibitors of Plasmodium falciparum Hexokinase
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Media type:
E-Article
Title:
Interrogating a Hexokinase-Selected Small-Molecule Library for Inhibitors of Plasmodium falciparum Hexokinase
Contributor:
Harris, Michael T.;
Walker, Dawn M.;
Drew, Mark E.;
Mitchell, William G.;
Dao, Kevin;
Schroeder, Chad E.;
Flaherty, Daniel P.;
Weiner, Warren S.;
Golden, Jennifer E.;
Morris, James C.
imprint:
American Society for Microbiology, 2013
Published in:Antimicrobial Agents and Chemotherapy
Language:
English
DOI:
10.1128/aac.00662-13
ISSN:
0066-4804;
1098-6596
Origination:
Footnote:
Description:
<jats:title>ABSTRACT</jats:title>
<jats:p>
Parasites in the genus
<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium</jats:named-content>
cause disease throughout the tropic and subtropical regions of the world.
<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>
, 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
<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>
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 (IC
<jats:sub>50</jats:sub>
s) 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
<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>
growth
<jats:italic>in vitro</jats:italic>
(50% effective concentration [EC
<jats:sub>50</jats:sub>
] of ≥0.6 and <6.8 μM). These findings suggest that the chemotypes identified here could represent leads for future development of therapeutics against
<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>
.
</jats:p>