New Approaches for the Identification of Drug Targets in Protozoan Parasites - International Review of Cell and Molecular Biology - page 372

prokaryote topoisomerases. Moreover, fluoroquinolones are effective against
some apicomplexans including T. gondii most probably due to interference
with the prokaryote type of translation that takes place in the apicoplast
( Fichera and Roos, 1997 ). Compounds interfering with DNA-modifying
enzymes can be screened using a single molecule sensor as demonstrated for
topoisomerase I ( Koster et al., 2007 ). This method is investigated in more
detail in a recent EU project developing a nanotechnology-based device
for the study of drug-target interactions at the limit of sensitivity ( Firman
et al., 2012 ).
3.1.3. Transcriptional Activation or Silencing of Gene Expression
as a Target
Regulation of gene expression via transcriptional activation and silencing
via covalent modifications of histones represents a key event in eukary-
otic development ( Berger, 2002 ). These modifications include acetylation
or deacetylation of lysine residues rendering the DNA in the vicinity of the
residues more or less accessible for transcription. Histone methylation and
demethylation exhibit the opposite effects and are part of the complex pro-
cesses leading to chromatin remodeling ( Ho and Crabtree, 2010 ). Enzymes
involved in these steps are of increasing interest as targets for antiparasitic
and other drugs ( Unoki et al., 2009 ). Apicidin, a cyclic tetrapeptide from
fungal origin, is one of the first antiprotozoal compounds characterized
as a histone deacetylase inhibitor ( Darkin-Rattray et al., 1996 ). Apicidin
is highly effective (with IC 50 is in the nanomolar range) against a panel of
apicomplexans including P. falciparum and T. gondii , similar to the structurally
similar HC-toxin. HC-toxin, as well as the related peptides trapoxin A and
trichostatin, inhibits the proliferation of neoplastic cells and are irreversible
inhibitors of mammalian histone deacetylase. Moreover, apicidin inhibits
recombinant Plasmodium histone deacetylase and affects histone acetylation
in P. falciparum -parasitized erythrocytes ( Darkin-Rattray et al., 1996 ). More
recently, derivatives of apicidin with even enhanced antiprotozoal proper-
ties have been synthesized and characterized with respect to binding and
inhibition properties on histone deacetylases from Eimeria and host cells
( Singh et al., 2002 ).
Since inhibition of host cell histone deacetylases occurs in the same
range as for parasite enzymes, it remains unclear how inhibition of histone
deacetylase interferes with parasite survival. One could imagine the follow-
ing hypotheses in order to explain the observed effects: i) histone hyper-
acetylation in the parasite and the host cell leads to apoptosis of infected