Drug Target Identification in Intracellular and Extracellular Protozoan Parasites

Joachim      Muller; Andrew      Hemphill

Abstract

The increasing demand for novel anti-parasitic drugs due to resistance formation to well-established chemotherapeutically important compounds has increased the demands for a better understanding of the mechanism(s) of action of existing drugs and of drugs in development. While different approaches have been developed to identify the targets and thus mode of action of anti-parasitic compounds, it has become clear that many drugs act not only on one, but possibly several parasite molecules or even pathways. Ideally, these targets are not present in any cells of the host. In the case of apicomplexan parasites, the unique apicoplast, provides a suitable target for compounds binding to DNA or ribosomal RNA of prokaryotic origin. In the case of intracellular pathogens, a given drug might not only affect the pathogen by directly acting on parasite-associated targets, but also indirectly, by altering the host cell physiology. This in turn could affect the parasite development and lead to parasite death. In this review, we provide an overview of strategies for target identification, and present examples of selected drug targets, ranging from proteins to nucleic acids to intermediary metabolism.

Keywords: Apicoplast, chemotherapy, drug targets, Echinococcus, Giardia, mechanism of action, Neospora, Plasmodium, Toxoplasma, resistance formation, apicomplexan parasites, diarrhea, screening for inhibitors, chemical scaffolds