New Approaches for the Identification of Drug Targets in Protozoan Parasites - International Review of Cell and Molecular Biology - page 387

powerful in the case of diseases caused by mutations in single genes but has
only limited impact in cases of diseases where multiple genes (i.e. poten-
tial targets) are involved as it is the case, e.g. for obesity, and mental disor-
ders ( Sams-Dodd, 2005 ). Target-based drug development against parasites
may thus be successful where products of single genes are involved in the
mechanism of action, e.g. enzymes activating prodrugs. In this case, however,
rapid resistance formation may occur.
In most of the other cases of antiparasitic drug targets, we do not fully
understand the physiological responsiveness of the parasite in the presence
of the drug. In the case of intracellular parasites, reactions of the host cell
render the situation even more complex. As a consequence, the general
concept of antiparasitic drug development should be refined. Whole organ-
ism screenings are too tedious, and for target-based screenings, the base of
knowledge is still too narrow, except in some very promising cases where
target molecules that are essential for the parasite, but absent in the host,
have been identified. Therefore, a third strategy that combines the positive
aspects of both approaches should be chosen as follows.
In the first step, libraries of anti-infective or anticancer compounds are
screened using in vitro systems with the parasite of interest. For instance,
since some apicomplexan parasites circumvent host cell death by secret-
ing proteins that interfere with apoptotic pathways ( Dobbelaere et al.,
2000 ; Lang et al., 2007 ), compounds inducing apoptosis (e.g. derived
from anticancer research) may be suitable candidates for drugs against
these parasites. Successfully tested compounds will then be tested in ani-
mal models. This step is similar to the starting point of whole organ-
ism screenings, except the fact that compounds with known effects are
screened. If the drug target is known from other systems, the homologous
protein is identified in the parasite of interest, expressed in a suitable sys-
tem, purified and subjected to binding assays with effective and ineffec-
tive compounds. If there is a correlation between growth inhibition and
target binding, the target can be validated by overexpression and silencing
experiments.
If the target is unknown, identification will be performed by the meth-
ods discussed above. In the case of intracellular parasites, the target search
should be extended to the host cells. In a second round, trained chemists
may synthesize even more effective derivatives of the compounds having
successfully past the first round, and a second round of test series may follow.
Then, the most effective compounds are subject to in vivo trials in a suitable
animal model followed by preclinical and clinical studies.