New Approaches for the Identification of Drug Targets in Protozoan Parasites - International Review of Cell and Molecular Biology - page 358

4. CaseStudies 386

4.1. Thiazolides,aNovelDrugFamily 386

4.2. Meloquine,AnotherCompoundwithDiferentTargets 387

5. ConclusionsandOutlook 388

Abstract
Antiparasiticchemotherapyisanimportantissuefordrugdevelopment.Traditionally,
novelcompoundswithantiprotozoanactivitieshavebeen identifiedbyscreeningof
compoundlibrariesinhigh-throughputsystems.Morerecentlydevelopedapproaches
employ target-baseddrugdesign supportedbygenomics andproteomicsofproto-
zoan parasites. In this chapter, the drug targets in protozoan parasites are reviewed.
The gene-expression machinery has been among the first targets for antiparasitic
drugs and is stillunder investigation as a target fornovel compounds.Other targets
includecytoskeletalproteins,proteins involved in intracellular signaling,membranes,
andenzymesparticipatinginintermediarymetabolism.Inapicomplexanparasites,the
apicoplastisasuitabletargetforestablishedandnoveldrugs.Somedrugsactonmul-
tiplesubcellulartargets.Drugswithnitrogroupsgeneratefreeradicalsunderanaerobic
growth conditions, anddrugswithperoxidegroupsgenerate radicalsunder aerobic
growth conditions, both affecting multiple cellular pathways. Mefloquine and thia-
zolidesarepresentedasexamples forantiprotozoancompoundswithmultiple (side)
effects.Theclassicapproachofdrugdiscoveryemployinghigh-throughputphysiologi-
cal screenings followedby identificationofdrug targetshas yielded themainstream
ofcurrentantiprotozoaldrugs.Target-baseddrugdesignsupportedbygenomicsand
proteomicsofprotozoanparasiteshasnotproducedanyantiparasiticdrugsofar.The
reasonforthisisdiscussedandasynthesisofbothmethodsisproposed.

1. INTRODUCTION

Protozoan parasites have constituted serious challenges to public health
since the beginning of mankind. Sustainable protection can only be achieved
by a combination of improved sanitary conditions, vaccination ( Chilengi and
Gitaka, 2010 ; Innes and Vermeulen, 2007 ), and chemotherapy. During the
past decades, novel anti-infective drugs have regained importance because of
the steady increase in resistance development against well-established anti-
biotics and due to the emergence of novel, previously unnoticed infectious
diseases ( Cassell and Mekalanos, 2001 ). This does account not only for bacte-
rial and viral diseases but also for infections caused by protozoans, especially
Toxoplasma , Giardia and Plasmodium ( Egan and Kaschula, 2007 ). Currently,
only a limited number of drugs are available on the market to confront a
plethora of parasites, and in case of resistance development, the arsenal of
alternative treatment options is limited ( Table 7.1 ). Giardia lamblia , responsible
for several million cases of persistent diarrhea worldwide, is currently treated
almost exclusively with metronidazole ( Gardner and Hill, 2001 ). The