New Approaches for the Identification of Drug Targets in Protozoan Parasites - International Review of Cell and Molecular Biology - page 379

blocked. Historically, these substances are called “uncouplers” since they
facilitate the passage of protons through the mitochondrial membrane
without ATP biosynthesis. Free fatty acids are well-understood examples of
chemical uncouplers with interesting functions in mammalian mitochon-
dria ( Di Paola and Lorusso, 2006 ). Depending on their chain length and
degree of saturation, fatty acids are also effective against a variety of bacteria
and against G. lamblia ( Rayan et al., 2005 ). Dodecanoic (“lauric”) acid accu-
mulates within minutes in G. lamblia trophozoites followed by the rupture
of the membrane within hours ( Rayan et al., 2005 ). Many other natural
compounds with similar properties may also act on the membrane integrity
by similar mechanisms ( Anthony et al., 2005 ). Moreover, the antihelmin-
thic salicylanilide closantel and related compounds are proton ionophores
( Martin, 1997 ).
The membrane system is a direct target for drugs that are incorporated
into the membrane bilayer because they share similarities with endogenous
membrane components. A well-studied example is the polyene macrolide
amphotericin B. Amphotericin B is an antifungal compound binding to
ergosterol in the cell membrane, and thus causes membrane depolarization
and cell damage by oxidative stress ( Blum et al., 2008 ). Another drug directly
affecting membrane integrity is miltefosine, a membrane active alkyl phos-
pholipid, originally described as an anticancer drug and used since the early
1990s against leishmaniasis alone or in combination with amphotericin B
( Moore and Lockwood, 2010 ).
A much more specific mode of action is observed with drugs acting on
plasma membrane ion channels. A well-studied example is the antihelmin-
thic praziquantel. Praziquantel causes a rapid uptake of calcium ions, prob-
ably by affecting voltage-gated channels ( Jeziorski and Greenberg, 2006 ). As
a consequence, the neuromuscular transmission of the helminth is affected
causing tegument disintegration (in the case of Schistosoma ) and rapid death.
Another example for drugs affecting membrane proteins are quinolones
like atoquanone, a ubiquinone analogon targeting the mitochondrial cyto-
chrome bc1 complex in Plasmodium thereby inhibiting the respiratory
chain. Resistance formation occurs, however, rapidly ( Winter et al., 2008 ).
3.5. Drug Targets in Intermediary Metabolism
3.5.1. Glucose Metabolism
Although ubiquitous, the metabolism of glucose via glycolysis has gained
some importance for the development of antiparasitic drugs. In Plasmo-
dium sp., the hexose transporter (HT) is a promising candidate for the