New Approaches for the Identification of Drug Targets in Protozoan Parasites - International Review of Cell and Molecular Biology - page 380

development of novel drugs ( Patel et al., 2008 ; Slavic et al., 2011 ). Uptake
of hexoses by the hexose transporter from P. falciparum (PfHT) expressed
in Xenopus oocytes is inhibited by 3-O-alkyl-D-glucose analogs, whereas
hexose transport by the major mammalian glucose and fructose transporters
remains unaffected. Inhibition of PfHT in vitro is correlated with inhibi-
tion of P. falciparum in culture medium containing either glucose or fructose
as a carbon source, as well as with multiplication of P. berghei in a mouse
model ( Joet et al., 2003 ). After molecular characterization of the hexose
transporter from Plasmodium vivax , a novel glucose analog inhibiting isolates
from patients was identified ( Joët et al., 2004 ). Moreover, 2-O-alkyl-glucose
analogs inhibit PfHT ( Ionita et al., 2007 ) and 4-O and 6-O analogs, the
hexose transporter from Babesia bovis ( Derbyshire et al., 2008 ). These stud-
ies are based on the expression of recombinant HTs in Xenopus oocytes.
Another, perhaps more appropriate system, especially for drug screening
purposes, is the expression of recombinant HTs in a glucose transporter null
mutant of Leishmania mexicana ( Feistel et al., 2008 ).
Another suitable target in glucose metabolism is glucose-phosphate-
isomerase (GPI). In T. gondii , genes encoding GPI and another glycolytic
enzyme, enolase, are highly homologous to higher plant genes and differ
from those of animals. Moreover, they are expressed in bradyzoites, a stage
refractory to drug treatment. They thus might offer novel chemotherapeutic
targets ( Dzierszinski et al., 1999 ). As for the glucose transporter, monosac-
charide derivatives would be suitable inhibitors. Recombinant GPI from
T. brucei is inhibited by a series of arabinose derivatives, a pentose with a
spatial structure similar to fructose, one of them, D-arabinonhydroxamic
acid-5-phosphate, having an IC 50 as low as 50 nM ( Hardré et al., 2000 ).
More recent results obtained with GPI from Eimeria sp. suggest that these
results could be extended to other apicomplexan parasites ( Loo et al., 2010 ).
3.5.2. Prokaryote-like Pathways in Apicomplexa
Intermediary metabolism of pathogens provides suitable target options in
all cases where a pathway is essential for the pathogen and is absent, or
of minor importance, for the host cell. Besides traditional knowledge of
intermediary metabolism of parasites, genome mining is a new, powerful
tool for drug target search in this field. Prokaryote-like metabolic pathways
of apicoplasts provide some good examples for this approach ( Dahl and
Rosenthal, 2008 ; Fichera and Roos, 1997 ).
The apicoplast organelle exhibits a type of fatty acid biosynthesis
resembling biosynthetic pathways of prokaryotes and plastids from higher