**11. Conclusion**

macrocyclic lactone ivermectin, an effective and safe microfilaricide (Basáňez et al., 2008).

tive against adult worms, it causes reproductive quiescence and disappearance of microfilaria from skin or blood. Interestingly, cultured microfilariae are unaffected by iver‐ mectin at concentrations found in treated patients (Bennett et al., 1993), making interference of the drug with protective mechanisms employed against the human immune response fea‐ sible (Geary et al., 2010). The development of ivermectin-resistant strains of *Caenorhabditis elegans* has shown that resistance to low levels of ivermectin is associated with an increased expression of drug efflux pumps and an increase in GSH-synthesis and -conjugation is ob‐ served. Since the overall levels of glutathione decrease, increased drug conjugation and re‐ moval from the cells is suggested (James and Davey, 2009). In a recent study, ivermectin has been identified as a cytotoxic agent to leukemia cells and a previously unknown indirect in‐ fluence of ivermectin on the intracellular redox balance was demonstrated. Mechanistically, ivermectin induced chloride influx, membrane hyperpolarization, and generated ROS, the latter being functionally important for ivermectin-induced cell death (Shrameen et al., 2010).

Diethylcarbamazine (DEC) is still the mainstay for the treatment of lymphatic filariasis and first choice of therapy of loiasis. Surprisingly, its molecular mechanism of action is still not completely understood. Since pharmacologically relevant concentrations of DEC do not have an effect on microfilariae in culture, its mode of action must involve both the worm and its host. A possible involvement of host arachidonate- and NO-dependent pathways was observed (McGarry et al., 2005). Currently no verification of an influence on the redox

It has been postulated that antioxidant enzymes, that defend against host-generated ROS, are of particular importance for long-lived tissue-dwelling parasites that are involved in chronic infections. Here, surface or secreted antioxidant enzymes are of great importance since they can directly neutralize ROS that pose real danger, thereby protecting surface membranes against peroxides. Secreted filarial antioxidant enzymes include SOD, GPx and Prx (Henkle-Dührsen and Kampkötter, 2001). Additionally to their antioxidant role, the Prx have recently been shown to contribute to the development of Th2-responses by altering the function of macrophages (Donnelly et al., 2008). Interestingly, GSH-dependent proteins have been observed that are capable of modifying the local environment via modulation of the immune response. Here the secretory GSTs from *O. volvulus* combine several features that make them excellent drug target: they are accessible since they are located directly at the parasite–host interface, they detoxify and/or transport various electrophilic compounds and secondary products of lipid peroxidation and they are involved in the synthesis of po‐ tential immunmodulators. Significant structural differences to the host homologues are ob‐ served in the xenobiotic binding site; this may support the structure-based design of specific

As outlined above, GSH-dependent detoxification pathways defend against current drugs and also play a role in mediating resistance to anthelmintics. The antioxidant pathways also provide the parasite with a means to protect against ROS-attack by its host and/or vector. In

inhibitors (Sommer et al., 2003; Perbandt et al., 2008; Liebau et al., 2008).

channels of invertebrates (Martin et al., 1997). While ivermectin is less effec‐

channels, with particular activity against gluta‐

Ivermectin is an agonist of ligand-gated Cl<sup>−</sup>

biology of helminths is available.

mate-gated Cl<sup>−</sup>

238 Drug Discovery

The current bottle-neck for the treatment of parasitic diseases with chemotherapeutics is the increasing drug resistance which forces the continuous discovery and development of new antiparasitic drugs. There is an urgent need for novel chemotherapeutic targets. New drugs should be generated to specifically target the parasite with minimal (or no) toxicity to the human host. Therefore, good drug targets should be distinctly different from processes in the host, or ideally be absent in the latter. Targeting the peculiarities - which are absent in the host - is proposed as such a strategy. In this sense, the parasite-specific biosyntheses rep‐ resent ideal drug targets; similar to the already exploited antifolate interference with the parasite's dihydrofolate (vitamin B9) biosynthesis. There are a variety of reports about reac‐ tive compounds that have antiparasitic activity; however, not all of these are therapeutically viable drug-like molecules due to various limitations such as toxicity, low bioavailability, rapid inactivation under *in vivo* conditions and development of resistance. Recently studies on drug synergism raised special attention, which can open new avenues to improve the ef‐ ficacy of antiparasitic drugs in combination with others. Since parasites such as *Plasmodium, Trypanosoma* or helminths are highly susceptible to oxidative stress - as outlined within this chapter - the identification of new lead compounds that target the parasite's redox systems by inducing oxidative stress, will be an efficient approach to discover novel drugs.

In this chapter we have tried to give an outline of the present situation of redox-active anti‐ parasitic molecules that target human infectious diseases. In future the mechanisms, evolu‐ tionarily developed by the parasite to circumvent the crucial presence of ROS, will open new avenues for the development of novel antiparasitic drugs that combat resistant human pathogens effectively.
