New Approaches for the Identification of Drug Targets in Protozoan Parasites - International Review of Cell and Molecular Biology - page 375

Another class of compounds interacting with the cytoskeleton is taxanes
including taxol, the first natural product shown to stabilize microtubules.
This unique mechanism of action is in contrast to benzimidazoles and other
microtubule poisons, such as colchicine, which inhibit tubulin polymeriza-
tion, and thus destabilize microtubules. In cancer cells, taxanes block cell
cycle progression and sometimes trigger apoptosis ( Abal et al., 2003 ). Taxol
is also active against Leishmania promastigotes ( Moulay et al., 1996 ) affecting
the assembly of purified tubulin and interfering with mitosis ( Havens et al.,
2000 ). Issuing from these findings, novel antileishmanial compounds inter-
acting with tubulin have been identified ( Morgan and Werbovetz, 2008 ).
Similar to the benzimidazoles, the major problem is to find taxanes with a
high potential against Leishmania and a low teratogenic potential for patients.
3.3. Drug Targets in Intracellular Signaling
3.3.1. cAMP-Dependent Pathways
Intracellular signaling pathways are a source for drug target search not only
in antiparasitic drug development but also in other fields including inflam-
mation, neurodegeneration and cancer ( Cunningham et al., 2008 ; Lugnier,
2006 ; Savai et al., 2010 ). In some lymphomas, inhibition of cAMP-depen-
dent protein kinases or phosphodiesterases (PDEs) interferes in cAMP-
related signaling pathways ( Lerner et al., 2000 ). The classical approach is
that the putative target enzymes are cloned from drug-susceptible parasites
(genome mining), and inhibition constants are determined in the presence
of the drug and derivatives ( Liotta and Siekierka, 2010 ). The underlying idea
is that like in cancer cells, these drugs interfere with the cAMP-dependent
regulation of the cell cycle of the parasites, thereby inhibiting proliferation
and/or differentiation ( Hammarton et al., 2003 ).
Plasmodium contains a panel of cAMP-dependent and other protein
kinases ( Leroy and Doerig, 2008 ) which may constitute suitable targets for
antimalarial drug development ( Jirage et al., 2010 ). Obviously, similar stud-
ies have to be performed with enzymes from the (hopefully) resistant host
in order to forecast potential side effects. In a recent study, the cAMP-
dependent protein kinase PKA from P. falciparum has gained importance
as a target since it has important differences to PKAs from mammalian
hosts ( Haste et al., 2012 ). In a study concerning the potential effects of
various antimalarials on host cells, inhibition of cAMP-dependent protein
kinase from rat liver and bovine heart and of calmodulin-dependent myo-
sin light chain kinase has been studied in the presence of halofantrine and
related phenantrenes. In this study, also mefloquine, allegedly acting on a