New Approaches for the Identification of Drug Targets in Protozoan Parasites - International Review of Cell and Molecular Biology - page 373

host cells, whereas noninfected host cells remain nonapoptotic; ii) histone
hyperacetylation itself is lethal for the parasite due to a generalized deregu-
lation of gene expression; iii) histone deacetylase is not the only target,
another—parasite-specific—enzyme system is inhibited by the same class
of compounds. More recent investigations using a member of another class
of cyclic tetrapeptides derived from Acremonium species provide novel and
important insights. One of these tetrapeptides induces hyperacetylation and
inhibits proliferation of T. gondii , N. caninum and P. falciparum with an IC 50 of
approximately 10 nM, and inhibits human foreskin fibroblasts and a resis-
tant T. gondii strain at concentrations one magnitude higher. The histone
deacetylase HDAC3 appears as a probable target since the recombinant
enzyme is inhibited by the tetrapeptide (but with a Ki orders of magnitude
higher than the in vivo IC 50 ), and since resistant mutants show distinct
point mutations at a single locus in a conserved region of this gene ( Boug-
dour et al., 2009 ).
Histone acetylation can be influenced also by inhibition of histone
acetylation via histone acetyltransferase. A quinoline derivative inhibit-
ing the histone acetyltransferase GCN5 from yeast does not inhibit the
homologous enzyme from T. gondii nor does it interfere with histone
acetylation of this parasite but inhibits proliferation with a moderate IC 50
of around 100 µM. Clearly, another target must be present in this case
( Smith et al., 2007 ).
3.1.4. Translation
Aminoglycosides such as tetracycline bind to the small subunit of prokary-
ote-type ribosomes, more exactly to distinct features of the 16S-rRNA
secondary structure, and thereby inhibit translation. A detailed structural
analysis is given by Brodersen et al. (2000) . This explains why specific muta-
tions in this region confer resistance to various aminoglycosides in various
prokaryotes. Giardia lamblia has a 16S-rRNA structure similar to prokaryotes
with a primary sequence suggesting that only paromomycin and hygromy-
cin are effective, and other well-known aminoglycosides such as kanamycin
are not. This pattern correlates well with observed susceptibilities or resis-
tance to a panel of aminoglycosides ( Edlind, 1989 ).
Due to its prokaryote origin, the apicomplexan plastid is a suitable tar-
get for antibiotics interfering with protein biosynthesis ( Fichera and Roos,
1997 ; Fleige and Soldati-Favre, 2008 ). The aminoglycoside paromomycin is
a well-established drug that is effective against intestinal infections and also
moderately acts against Cryptosporidium parvum . However, Cryptosporidium