New Approaches for the Identification of Drug Targets in Protozoan Parasites - International Review of Cell and Molecular Biology - page 377

except genistein, which is well characterized as a tyrosine kinase inhibitor
(EGF receptor kinase inhibitor) in mammalian cells. This effect depends on
the presence of hydroxyl groups in position 5, 7 and 4′ of the isoflavone
ring, the closely related daidzein with hydroxyl groups in positions 7 and
4′ only being ineffective as tyrosine kinase inhibitor ( Akiyama et al., 1987 ).
In G. lamblia , isoflavones without hydroxyl groups in these positions inhibit
growth ( Sterk et al., 2007 ). Antigiardial effects of isoflavones are thus not
due to similar effects as in mammalian cells.
Concerning anti-apicomplexan activities, a panel of 52 genistein deriva-
tives with a receptor kinase as alleged target has been described with good
in vitro activities against Sarcocystis neurona , N. caninum and C. parvum two
of them being effective also against C. parvum in immunosuppressed gerbils
( Gargala et al., 2010 ). The authors, however, do not address the question
whether these compounds really target receptor kinases since the panel of
compounds did not contain derivatives differing only in the presence of
an unsubstituted hydroxyl group in position 5. Moreover, simple controls
with the mother compounds genistein and daidzein are lacking ( Gargala
et al., 2010 ). Besides receptor kinases, genistein and related isoflavones with
hydroxyl groups in positions 7 and 4′ bind to estrogen receptors what may
lead to potential side effects ( Morito et al., 2002 ). For the treatment of
chronic parasitoses, isoflavones with a modified estrogen receptor binding
site would therefore be preferred, as exemplified by an in vitro study on
E. multilocularis and Echinococcus granulosus , two helminths causing chronic
diseases ( Naguleswaran et al., 2006 ).
3.3.3. Calcium-Dependent Protein Kinases in Apicomplexan Parasites
A shining example for a target-based development of antiparasitic drugs
interfering with intracellular signaling is given in the case of calcium-depen-
dent protein kinases containing calmodulin-like domains (calmodulin-like
domain protein kinase; CDPK) in apicomplexan parasites. Apicomplexans
contain CDPKs of a type commonly found in plants ( Billker et al., 2009 ).
Toxoplasma has more than 20 CDPK, Plasmodium and Cryptosporidium have
fewer than half this number. Several of these CDPKs have been shown to
play vital roles in protein secretion, invasion, and differentiation ( Nagamune
et al., 2008 ). These kinases have two features required for a successful target-
based drug development, namely i) they are essential for the development
of the parasite in the host and ii) the differences between them and their
mammalian homologs are big enough to create inhibitors with a suitable
therapeutic window ( Jirage et al., 2010 ).