ABSTRACT
Human-infecting parasite populations causing fatal diseases, such as sleeping sickness or malaria, undergo cycles of retreat and spreading. Newly gained drug resistance is one key initiator for peaks in disease incidents. Timely and costly eorts required for the development of anti-parasitic drugs are at odds with their expected time frame of usability. Looking at the sites of action of the current anti-parasitic drugs reveals a common theme: virtually all act on intracellular, mainly metabolic processes. As a consequence, this opens up multiple options for the parasite to defend itself against the treatment, that is by chemical modication of the compound, trapping it in intracellular compartments or expulsion from the cell. An outside attack to the parasites’ periphery would increase the
CONTENTS Abstract 233 12.1 Features of the Parasite AQP Protein Structures 234 12.2Conrmed and Putative Roles of AQPs in the Physiology of Parasites 237
12.2.1Malaria Parasites, Plasmodium spp. AQPs, PfAQP 237 12.2.2Toxoplasmosis parasites, Toxoplasma gondii AQP, TgAQP 238 12.2.3Sleeping Sickness Parasites, Trypanosoma brucei AQPs 238 12.2.4Chagas Disease Parasites, Trypanosoma cruzi AQPs, TcAQPs 239 12.2.5Leishmaniasis Parasites, Leishmania spp. AQPs, LmAQP1 239
12.3Using AQPs to Shuttle Cytotoxic Compounds into Parasites 239 12.4Challenges and Potential of AQP Inhibitors for Anti-Infectious erapy 241 References 243
chance of sustained usability of respective drugs. Transporters and channels that govern the uptake of vital nutrients and release of metabolic waste represent promising candidates as novel drug targets against parasitic diseases. In this regard, aquaporin (AQP) channels for water and small, uncharged solutes, such as glycerol, urea, or ammonia, are being studied. Biochemical and physiological data hint at several crucial functions of parasite AQPs: (1) alleviation of osmotic stress, for example during passage of the salt-laden kidneys or during transmission between the insect and the human host; (2) uptake of glycerol from the host blood serum as a precursor for glycerolipid synthesis enabling rapid parasite growth by extension of the lipid plasma membrane; (3) release of nitrogen waste, that is urea and ammonia, and of aldehyde metabolites, that is methylglyoxal, preventing self-intoxication of the parasite; (4) new data that suggest that cell motility of amoeba may depend on AQP water permeability and (5) drug resistance mechanisms which have been directly linked to AQP in Leishmania and Trypanosoma. is chapter gives an overview on the research eld and provides an outlook at potential therapeutic exploitation of parasite AQPs.
