International Journal of Antimicrobial Agents 30 (2007) 410

Review
Novel molecular targets for antimalarial chemotherapy
Snehasis Jana, Jyoti Paliwal

Metabolism and Pharmacokinetics Division, Ranbaxy Research Laboratories, Plot-18, Sector-20,

Udyog Vihar, Industrial Area, Gurgaon, Haryana 122015, India
Received 11 December 2006; accepted 9 January 2007
Abstract
The emergence and spread of drug-resistant malaria parasites is a serious public health problem in the tropical world. Malaria control has
relied upon the traditional quinoline, antifolate and artemisinin compounds. Very few new antimalarials were developed in the last quarter
of the 20th century. An alarming increase in drug-resistant strains of the malaria parasite poses a signicant problem for effective control.
Recent advances in our knowledge of parasite biology as well as the availability of the genome sequence provide a wide range of novel targets
for drug design. Gene products involved in controlling vital aspects of parasite metabolism and organelle function could be attractive targets.
It is expected that the application of functional genomic tools in combination with modern approaches such as structure-based drug design
and combinatorial chemistry will lead to the development of effective new drugs against drug-resistant malaria strains. This review discusses
novel molecular targets of the malaria parasite available to the drug discovery scientist.
2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
Keywords: Drug targets; Parasite transporters; Parasite proteases; Apicoplast; Cyclin-dependent kinases
1. Introduction
Malaria is a devastating infectious disease and a major
cause of morbidity and mortality throughout the world. The
World Health Organization estimates that malaria kills an
African child every 30 s [1]. Approximately 40% of the
worlds population live in malaria-endemic areas and ca. 90%
of cases and most deaths occur in tropical Africa. There are
up to 500 million clinical cases and 3 million deaths annu-
ally [2]. The majority of severe disease is due to Plasmodium
falciparum. The two most widely used antimalarial drugs,
chloroquine and sulfadoxine/pyrimethamine, are failing at
an accelerating rate in most malaria-endemic regions owing
to the development of resistance to these agents. Other anti-
malarial drugs such as meoquine, halofantrine, atovaquone,
proguanil, artemether and lumefantrine retain efcacy but
have limitations, one of which is their high cost.
The drugs currently used for malaria come from three
families: the quinolines (quinine, chloroquine, meoquine,

Corresponding author. Tel.: +91 124 2343454.

E-mail address: jyoti.paliwal@ranbaxy.com (J. Paliwal).
primaquine), the antifolates (sulfadoxine, pyrimethamine)
and the artemisinin derivatives [3].
The increasingly serious problemof malaria parasite resis-
tance to currently used antimalarials has led to an urgent need
to develop new and effective antimalarial molecules. This
goal can be achieved in two ways: either by focusing on vali-
dated targets in order to generate new drug candidates; or by
identifying new potential targets for malaria chemotherapy.
The advent of functional genomics and structure-based drug
design should help in the search for newtargets. In this report,
we examine putative novel molecular targets for the rational
design of new antimalarials.
2. Potential targets for new antimalarials
Drug-resistant strains of malaria parasites pose signicant
challenges to drug discovery efforts. This increasing resis-
tance to multiple drugs may be the result of defective DNA
repair or other pathways responsible for genomic stability
[4]. Sequencing of the P. falciparum genome, the emergence
of drug resistance and advances in molecular techniques have
refocused antimalarial drug discovery efforts. Several critical
0924-8579/$ see front matter 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
doi:10.1016/j.ijantimicag.2007.01.002
S. Jana, J. Paliwal / International Journal of Antimicrobial Agents 30 (2007) 410 5
Fig. 1. Schematic representation of novel molecular targets in plasmodia.
RBCM, red blood cell membrane; PVM, parasitophorous vacuole mem-
brane; PPM, parasite plasma membrane.
and unrelated biochemical pathways have been exploited for
drug target identication (Fig. 1; Table 1).
2.1. Targeting parasite membrane biosynthesis
Intraerythrocytic parasites possess different membranes
such as the food vacuolar membrane, the parasite plasma
membrane (PPM) and the parasitophorous vacuole mem-
brane. The amount of lipid in infected erythrocytes is
therefore signicantly higher than that of normal erythro-
cytes. Growing and dividing malaria parasites require large
amounts of phospholipids, which are synthesised from
plasma fatty acids. Phosphatidylcholine (PC) is the major
parasite phospholipid. Most of the PC (7080%) is synthe-
sised by de novo synthesis from choline. In infected red
blood cells (RBCs), choline mobility increases signicantly
via a constitutive choline carrier. This occurs from parasite-
induced overactivity of a constitutive host cell transporter
or parasite-driven synthesis of a new carrier. Molecules are
being designed to target the parasites supply of PC. Quater-
nary ammonium and bis-ammonium quaternary salts with
one long lipophilic alkyl chain and bis-ammonium salts
linked by a long alkyl chain showed high in vitro parasite
inhibition at the nanomolar range [5]. Members of this group
of compounds proved effective in vivo in experimental ani-
mals. A new class of potent antimalarial drugs was identied
that inhibits de novo PCbiosynthesis in the parasite [6]. G25,
a lead compound, potently inhibited in vitro growth of P. fal-
ciparum and Plasmodium vivax. It was also 1000-fold less
toxic to mammalian cell lines and IC
50
values (inhibitory
concentration of 50%) were in the low nanomolar range. A
very low dose of G25 can cure monkeys infected with P.
falciparum and Plasmodium cynomolgi, demonstrating the
therapeutic potential of this class of compounds [7].
2.2. Targeting parasite transporters
There is a profound increase in the permeability of the
host membrane to a wide range of solutes in malaria-infected
erythrocytes. Molecular trafc across the host erythrocyte
membrane undergoes dramatic changes with respect to inten-
sity and the nature of permeating solutes. The induced
permeability pathways are known as new permeability path-
ways (NPPs), which are polyspecic, anion selective and
confer increased permeability to a wide range of charged
and low-molecular-weight solutes. These NPPs are thought
to provide the major entry of some essential nutrients (pan-
tothenate) required by the parasites. They also mediate the
efux of various metabolic waste substances such as lactic
acid from the infected cell [8]. The properties of the parasite-
induced transport systems are signicantly different from
those in normal human cells. Therefore, these transport sys-
Table 1
Novel targets in Plasmodium falciparum
Target Enzyme/process Inhibitor
Membrane biosynthesis Phospholipid biosynthesis G25
Parasite transporters Unique channels Quinolines
Hexose transporter O-3-hexose derivatives
Parasite proteases Plasmepsins, falcipains Leupeptin, pepstatin
Shikimate pathway 5-enolpyruvyl shikimate 3-phosphate synthase Glyphosate
Isoprenoid biosynthesis DOXP reductoisomerase Fosmidomycin
Redox system Thioredoxin reductase 5,8-Dihydroxy-1,4-naphthoquinone
Gamma-GCS Buthionine sulfoximine
Mitochondrial system Cytochrome c oxidoreductase Atovaquone
Purine metabolism HGPRT Immucillin-H
Pyrimidine metabolism Thymidylate synthase 5-Fluoroorotate
Apicoplast Fab H Thiolactomycin
Fab I Triclosan
Cyclin-dependent protein kinases Pfmrk Oxindole derivatives, thiophene sulfonamide
DOXP, 1-deoxy-d-xylulose-5-phosphate; GCS, glutamylcysteine synthetase; HGPRT, hypoxanthineguaninexanthine phosphoribosyltransferase.
6 S. Jana, J. Paliwal / International Journal of Antimicrobial Agents 30 (2007) 410
tems could potentially be exploited as targets for antimalarial
chemotherapy. This could be achieved by designing cytotoxic
drugs that selectively enter the parasite through these induced
transporter routes.
Recently, some of the transporters at the PPM have been
characterised. Kirk et al. [9] suggested that a PPM-located
vacuolar-type proton pump (V-type H
+
pump) extrudes pro-
tons. As a result, there is a gradient of pH across the PPM
that generates inwardly negative membrane potential ().
This pump regulates cellular pH by extruding protons gener-
ated by the metabolic activity of the parasite. Asexual-stage
parasites require a continuous supply of glucose to survive
and multiply, suggesting that the hexose transporter (PfHT)
of P. falciparum is a potential drug target. It is a single copy
gene (pfht) with no close paralogues in the fully sequenced
falciparum genome. Joet et al. [10] reported that O-3-hexose
derivatives inhibit uptake of glucose and fructose by PfHT
in Xenopus oocytes and in a mouse model of Plasmodium
berghei. Exploiting knowledge gained about the transport
processes operating in the infected cell might well enhance
the success of these approaches.
2.3. Targeting parasite proteases
Plasmodia are blood-eating parasites. Proteases have
an important role in parasite survival by hydrolysing a
signicant proportion of the host erythrocyte proteins.
Approximately 80% of the host cell haemoglobin is broken
down into individual amino acids, some of which are used
for parasite protein synthesis [11]. Several Plasmodium pro-
teases that appear to be responsible for vital cleavage of host
proteins have been characterised. The spectrumof proteolytic
activity in the malarial parasite can be conveniently divided
into two functional groups: proteases that are involved in
invasion and rupture of the erythrocyte and proteases that are
involved in haemoglobin degradation [11]. The hostparasite
interactions remain elusive at the molecular level during the
invasion process. It is clear that many surface proteins are
proteolytically modied and that these events are critical
for successful merozoite invasion [12]. The merozoite sur-
face protein MSP-1, the most prominent and relatively well
studied, is involved in the invasion process. The malaria par-
asite P. falciparum invades human RBCs. Before infecting
new erythrocytes, the merozoites must exit their host cell to
enter the blood plasma. It is thought that proteases are basi-
cally involved in this step. Cysteine protease inhibitors are
used to study the mechanism of merozoite release using u-
orescence microscopy and immunoelectron microscopy. The
inhibitors block rupture of the host cell membrane, leading to
clustered merozoite structures. Cysteine protease inhibitors
(e.g. E64, leupeptin and chymostatin) appear to be a valuable
template for the development of new inhibitors specic to
individual plasmodial proteases [13]. These would be use-
ful tools to dissect the molecular mechanisms underlying the
process of merozoite release and consequently to develop
potent antimalarial drugs.
Several plasmepsin and falcipain proteins (aspartic and
cysteine proteases) have been evaluated as candidate drug tar-
gets [14,15]. Examples include uoromethyl ketones, vinyl
sulfones and chalcones, which target the cysteine proteases
[16,17]. The statine, allophenylnorstatine and diphenylurea
derivatives target the aspartic proteases [18]. Detailed bio-
chemical characterisation, recombinant expression and X-ray
crystallographic structural analysis of parasite proteases and
their role in pathogenesis of malaria remain to be carried out.
2.4. Targeting the shikimate pathway
The shikimate pathway in apicomplexan parasites,
including P. falciparum, provides several targets for the
development of new antiparasitic agents. This pathway is
not present in mammals [19]. However, it occurs in the
cytosol of bacteria and fungi and is localised to the chloro-
plast in plants. There are seven enzymes involved in the
shikimate pathway, which catalyse sequential conversion
of erythrose-4-phosphate and phosphoenolpuruvate to cho-
rismate. This molecule is utilised by several pathways
for the synthesis of different critical molecules including
tryptophan, phenylalanine, tyrosine, vitamin K, ubiquinone
and p-aminobenzoic acid (PABA), which is utilised for
folate generation. Glyphosate is a herbicide that inhibits 5-
enolpyruvylshikimate 3-phosphate synthase in the shikimate
pathway [20]. 6-S-uoroshikimate and 6-R-uoroshikimate
have been shown to inhibit P. falciparum growth and have
been shown to be specic to the shikimate pathway [21]. A
single gene encoding the terminal enzyme in the shikimate
pathway has been identied in the genome annotation [22].
The coding DNA sequence of chorismate synthase has been
identied in P. falciparum and has been shown to be located
in the parasite cytosol [23]. Chorismate synthase has been
shown to be required for normal growth and disruption of
expression by RNA interference, which decreases parasite
growth [24]. P. falciparum chorismate synthase is therefore
a validated target for drug discovery.
2.5. Targeting isoprenoid biosynthesis
Plasmodium protein farnesyltransferase (PfPFT) inhi-
bition is being considered as a potential drug target.
PFT inhibitors have been developed for the treatment of
human cancer. These inhibitors act by inhibiting post-
translational modication pathways. A similar concept is
being explored by medicinal chemistry and pharmacokinetics
to develop PFT inhibitors against parasites [25]. Mam-
mals and fungi both depend on mevalonate to generate the
intermediate isopentyl diphosphate molecule. Plasmodium
falciparum as well as bacteria utilise 1-deoxy-d-xylulose-5-
phosphate (DOXP) as a precursor molecule, referred to as
the mevalonate-independent pathway. The plastid-encoded
mevalonate-independent pathway of isoprenoid biosynthesis
has been considered as a potential target for antimalar-
ial chemotherapy [26]. Fosmidomycin and its derivative
S. Jana, J. Paliwal / International Journal of Antimicrobial Agents 30 (2007) 410 7
FR900098 are phosphonic acid derivatives with low toxic-
ity. These compounds inhibit DOXP reductoisomerase. It is
the key enzyme of the DOXP pathway, which is absent in
humans. The drug fosmidomycin demonstrates signicant
antiparasitic activity. This facilitates the explanation of this
pathway for chemotherapeutic intervention [27]. PfPFT inhi-
bition is considered to be lethal as a result of the absence
of protein geranylgeranyl transferase-1 (PGGT-1), which
reverses PFT-inhibited mammalian cells.
2.6. Targeting the redox system
Oxidative stress is an important mechanism for destruc-
tion of malaria and other intracellular parasites. In
intraerythrocytic-stage malaria, parasites encounter reactive
oxygen species produced either by themselves or by the ery-
throcyte or host immune cells. To prevent oxidative stress,
the parasite has its own battery of defence tactics and pro-
duces its own antioxidant enzymes. The malaria parasite
contains three antioxidant enzymes: superoxide dismutase
(SOD), glutathione peroxidase (GPx) and catalase. The para-
sites antioxidant defence could therefore be a potential target
for antimalarial chemotherapeutics. Functional thioredoxin
and glutathione systems have been shown to participate in
antioxidant defence in P. falciparum and both are considered
attractive targets. The key enzymes of P. falciparuminvolved
in redox metabolism are glutathione reductase, glutathione
peroxidase, thioredoxin reductase and thioredoxin peroxire-
doxin [28]. The parasite thioredoxin reductase differs from
the host enzyme, containing a pair of cysteines separated by
four amino acids and lacking a selenocysteine present in the
host enzyme [29]. 5,8-Dihydroxy-1,4-naphthoquinone and
5-nitro-2-furanacrolein are inhibitors of thioredoxin reduc-
tase. Both these compounds have plasmodicidal effects in
vitro [30]. Glutathione S-transferase (GST) catalyses the con-
jugation of glutathione with a wide variety of hydrophobic
compounds and as a result non-toxic products are formed,
which can be readily eliminated. Plasmodium falciparum
possesses only one GSTisoenzyme in contrast to other organ-
isms. Plasmodial GST is a promising target for antimalarial
drug development because it is highly abundant in the para-
site. GST has been shown to act as a ligand for parasitotoxic
hemin. The crystal structure of P. falciparum GST has been
solved and shown to differ considerably from the human
enzyme [31]. This feature could be exploited to search for
specic inhibitors.
2.7. Targeting the mitochondrial system
The mitochondrial DNA sequence of P. falciparum has
been determined. There are two main functions of mitochon-
dria: electron transport and protein synthesis. These appear
to be essential for survival and constitute potential targets for
antimalarial chemotherapy [32]. The malaria parasite mito-
chondrial DNA has a 6 kb genome encoding three proteins:
cytochrome b, and subunit I and III of cytochrome c oxi-
dase, which is a terminal oxidase of the respiratory chain
[33]. Transcripts of the 6 kb element are most abundant in
the late phases of the asexual life cycle. The cytochrome b
gene of the ubiquinolcytochrome c reductase (complex III)
is produced primarily by asexual life stages rather than game-
tocytes. The structural features of the plasmodial cytochrome
b differ from mammalian cytochrome b [34], and these dif-
ferences in mitochondria between malaria parasites and the
host are expected to be a target for chemotherapy.
Atovaquone is a ubiquinone analogue and inhibits
ubiquinone binding to cytochrome b. It is effective against
chloroquine-resistant strains [35]. Its primary site of action
has been biochemically shown to be the ubiquinone oxidation
site of the cytochrome bc1 complex (complex III). The unique
properties of the respiratory chain in mitochondria have yet
to be exploited and the development of a new antimalarial
agent is anticipated.
2.8. Targeting nucleic acid metabolism
Nucleotides are the precursors of DNA and RNA biosyn-
thesis. Nucleic acid metabolism pathways differ between
P. falciparum and the human host. Plasmodia synthesise
purines and pyrimidines by salvage and de novo biosynthetic
pathways, respectively, whilst mammalian cells synthesise
purines de novo and either salvage or synthesise pyrimidine
by a de novo pathway. The two pathways involve a range
of essential enzymes that can be targeted for therapeutic
intervention.
2.8.1. The purine pathway
The malaria parasite lacks the de novo purine biosyn-
thetic pathway and starvation of purines is known
to cause purineless death in cultured cells. The most
extensively studied enzyme of the salvage pathway is
hypoxanthineguaninexanthine phosphoribosyltransferase
(HGPRT). The parasite and human HGPRT share partial
sequence similarity (46%) in the primary structures and differ
in substrate selectivity (xanthine for plasmodia). The struc-
tures give no insight into the origin of this difference. In
humans and parasites, hypoxanthine production is mediated
by phosphorolysis of inosine to hypoxanthine, catalysed by
purine nucleotide phosphorylase (PNP). Immucillin-H is a
transition state analogue that has been shown to kill the par-
asite through inhibition of PNP [36]. Recently, the crystal
structure of P. falciparum PNP complex with immucillin-H
revealed that its active site shows structural differences from
human PNP. Ting et al. [37] demonstrated that 5-methylthio-
immucillin-H kills P. falciparum strain 3D7 cultures. This
inhibition occurs at very low concentrations, where parasite
PNP is selectively inhibited but no inhibition is reported for
human PNP. These results suggest that structure-based design
studies and rapid screening efforts would be helpful for dis-
covering and developing new antimalarials by targeting the
parasite HGPRT and PNP enzymes.
8 S. Jana, J. Paliwal / International Journal of Antimicrobial Agents 30 (2007) 410
2.8.2. The pyrimidine pathway
Malaria parasites derive their pyrimidine nucleotides
through a de novo pathway. They cannot utilise pre-formed
pyrimidine nucleosides. Mammalian cells are capable of de
novo and salvage pathways. The salvage enzymes (uridine
kinase andthymidine kinase) are absent inthe parasite. The de
novo enzymes are carbamoyl phosphate synthase, aspartate
transcarbamylase, dihydroorotase, dihydroorotate dehydro-
genase (DHODase), orotate phosphoribosyl transferase and
orotidine 5

-phosphate decarboxylase [38]. Thymidylate syn-

thase (TS) is linked to dihydrofolate reductase. It is also an
established target for antimalarial chemotherapy. Since TS
is a highly conserved protein, selective inhibitors may be
difcult to design. An alternative strategy could be the com-
bination of an effective TS inhibitor and a nucleoside that
can be utilised by the host. N
5
-N
10
-methylene tetrahydrofo-
late analogues, which inhibit TS without being metabolised
into the nucleotide pool, are considered attractive alternatives
[39]. Such analogues need to be explored further.
2.9. Targeting the apicoplast
By molecular and cell biological analysis it was realised
that apicomplexan parasites, including P. falciparum, harbour
a plastid-like organelle called the apicoplast. This organelle
is derived fromthe engulfment of photosynthetic red algae in
ancient times. The P. falciparum apicoplast genome contains
ca. 35 kb and is much smaller than its plastid ancestor. Most
of the proteins of this organelle are encoded in the nuclear
genome and the proteins are subsequently transported to the
apicoplast. The apicoplast contains unique metabolic path-
ways such as fatty acid, isoprenoid and heme synthesis, which
are not found in the human host [40]. Hence, these parasite-
specic metabolic pathways make an ideal source of drug
targets.
Fatty acid biosynthesis is fundamental to cell growth,
differentiation and homeostasis. All living organisms synthe-
sise fatty acids (except mycoplasmas). Fatty acid synthesis
(FAS) is a major function of the apicoplast. The enzymes
involved in FAS are: acetyl-CoA carboxylase (ACC), mal-
onyl transacetylase (Fab D), -ketoacyl-ACP synthase (Fab
H, B/F), -ketoacyl-ACP reductase (Fab G), -hydroxyacyl-
ACP dehydrase (Fab A/Z) and enoyl-ACP reductase (Fab I).
There is an inherent difference between the fatty acid biosyn-
thesis pathways of the parasite (type II) and the human host
(type I), thus making thema promising target for the develop-
ment of antimalarials. Thiolactomycin is an inhibitor of Fab
H and showed inhibition of P. falciparum growth in in vitro
cultures [41]. This indicates that -ketoacyl-ACP synthase
III (Fab H) has a vital role for apicoplast type II fatty acid
biosynthesis. Recently, enoyl-ACP reductase (Fab I) activ-
ity has also been reported, and triclosan has been shown to
be antiparasitic by inhibition of Fab I [42]. Further stud-
ies to elucidate the functions carried out by this organelle
would aid in selection of the essential enzymes for drug
targeting.
2.10. Targeting the parasite cyclin-dependent protein
kinases (CDKs)
Several kinases from P. falciparum have been identied
that are homologues to the mammalian CDKs. Based on the
conservation of CDKs across species, the plasmodial CDKs
are expected to play a crucial role in parasite growth [43].
The cell cycle of the parasite differs dramatically from the
eukaryotic cell cycle. In eukaryotes, a single round of DNA
replication per cell cycle occurs, resulting in the generation of
two identical daughter cells. During schizogony, the parasite
undergoes multiple rounds of DNA replication and nuclear
division prior to cytokinesis. As a result, a single multinucle-
ate syncytium develops. A single parasite produces between
8 and 32 merozoites. Parasitic cell division must be regulated
in a manner that is different from mammals. Several P. falci-
parumCDKs have been shown with a sequence and structure
similar tothe mammalianhomologues [43]. Therefore, CDKs
have become attractive targets for novel antimalarial thera-
peutics.
HumanCDK7has the highest sequence identity(46%) and
similarity (64%) to Pfmrk. CDK7 has a dual function, act-
ing as the cyclin-dependent kinase-activating kinase and as a
transcription factor to regulate transcription and DNA repair.
The parasite kinase Pfmrk shows a similar two-fold function,
which would render it a highly attractive target for designing
CDK inhibitors [44]. Structural studies would be helpful for
rational design of potent and selective Pfmrk inhibitors as
antimalarial therapeutics.
3. Future perspectives
Malaria parasites have diverse metabolic systems greatly
different from that of the mammalian host by which they
adapt to the specic environment in the host. The key infor-
mation that permits rational approaches to drug design is
knowledge of the aetiology of a given disease or at least
of the biochemical processes that are involved. Despite
considerable advances in our understanding of parasite biol-
ogy and biochemistry, it appears that these organisms often
use novel modes of metabolism, signalling, protein trafck-
ing pathways, cell division and extracellular communication
mechanisms. The proteins involved in these processes often
possess signicant sequence variation and distinct differ-
ences in biochemical or catalytic properties. All proteins of
P. falciparum are often referred to as good targets. Proteins
available frommalaria genome sequencing projects would be
potential drug targets [45]. In addition, rational drug design
using structural information would be possible following
structure elucidation using recombinant protein production
systems. Three-dimensional structure elucidation using X-
ray crystallography would allow us to design drugs based
on a model of the target binding site. The best examples of
these include inhibitors of parasite HGPRT and proteases.
In the absence of protein structural information, quantitative
S. Jana, J. Paliwal / International Journal of Antimicrobial Agents 30 (2007) 410 9
structure activity relationships can be obtained by correlat-
ing the binding strength of ligands to the target molecule with
their structural properties [46]. Computer-assisted molecular
modelling has played an essential role in the design of poten-
tial ligands that are both sterically and chemically compatible
with the binding site of a target molecule.
4. Conclusions
There have been considerable advances in our understand-
ing of the mechanisms of action and resistance to traditional
antimalarial drugs. We principally emphasise putative molec-
ular targets covered based on various aspects of the malaria
parasite. These putative targets could be helpful for the future
development of newantimalarials. The elds of genomics and
proteomics are able to play an important role in the discovery
of new drugs against malaria. There is a large gap between
target identication and validation on the one hand and lead
discovery and optimisation on the other. This gap can be
lled with biochemical studies of the targets and structural
studies of the interaction between the target and the putative
inhibitor. Such studies can provide clues for designing new
compounds. Exploitingknowledge gainedabout the transport
processes operating in the infected cell might be useful for
rational drug design. An understanding of the mechanisms
underlying antimalarial drug resistance should also help us
to circumvent the emergence of resistance to newgenerations
of antimalarials.
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