Antimalarial drug discovery: old and new approaches
Department of Medicine, University of California, San Francisco, CA 94143, USA
(e-mail: rosnthl{at}itsa.ucsf.edu)
Accepted 2 July 2003
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Summary |
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Key words: malaria, Plasmodium falciparum, drugs, chemotherapy, drug discovery, resistance
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Introduction |
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Considering increasing resistance to available agents, there is broad
consensus that there is a need to develop new antimalarial drugs
(Ridley, 2002). Antimalarial
drug development can follow several strategies, ranging from minor
modifications of existing agents to the design of novel agents that act
against new targets. Increasingly, available agents are being combined to
improve antimalarial regimens. This review will discuss multiple approaches to
antimalarial drug discovery, emphasizing the varied strategies that have led
to available drugs and that are likely to provide important new drugs in the
future. Additional detailed reviews of antimalarial chemotherapy and potential
new targets for drug discovery have been published recently
(Olliaro and Yuthavong, 1999
;
Ridley, 2002
;
Rosenthal, 2001a
).
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Unique aspects of antimalarial drug discovery |
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Approaches to antimalarial chemotherapy |
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Some older agents, which are now significantly limited by drug resistance,
may nonetheless remain effective in combination. Presumably, the prevalence of
resistance to each agent is low enough such that resistance to both drugs is
unlikely. Although a combination regimen, sulfadoxine/pyrimethamine loses
efficacy quickly once resistance is seen; in this case, efficacy is dependent
on synergism, so is lost once resistance develops to either drug. However, the
combination of sulfadoxine/pyrimethamine with amodiaquine, a chloroquine
analog that remains active against many chloroquine-resistant parasites,
provides two effective long-acting drugs. Importantly, this combination
regimen uniquely provides two available and inexpensive drugs, although both
components are already limited by drug resistance in many areas and safety
concerns (with rare but severe toxicity with long-term prophylactic use).
Despite these concerns, the combination of amodiaquine and
sulfadoxine/pyrimethamine showed excellent antimalarial efficacy in regions of
East Africa, with fairly high levels of resistance to each individual agent
(Dorsey et al., 2002;
Schellenberg et al., 2002
;
Staedke et al., 2001
). Another
intriguing possibility is the reuse of chloroquine, ideally in combination
regimens, in areas where it has not been used for an extended period;
chloroquine sensitivity was recently shown to reemerge in Malawi after its use
was curtailed for about a decade (Kublin
et al., 2003
).
Artemisinin analogs, in particular artesunate and artemether, have recently
shown great promise as rapidly acting and potent antimalarials, but the short
half-lives of these compounds lead to many late recrudescences after therapy,
suggesting that combination therapies are necessary to fully exploit the
potency of this class. Artesunate has been studied in combination with both
sulfadoxine/pyrimethamine (von Seidlein et
al., 2000) and amodiaquine
(Adjuik et al., 2002
) in
Africa, with good efficacy, although underlying resistance to the two
artesunate partners may lead to unacceptable rates of late recrudescence in
many areas, as seen with artesunate/sulfadoxine/pyrimethamine in Uganda
(Dorsey et al., 2002
).
Combinations of artemisinins with longer-acting drugs without underlying
resistance may prove to be optimal antimalarial agents. In Thailand, where
drug resistance is particularly severe, the combination of artesunate and
mefloquine has proven to be highly effective, even in areas where mefloquine
resistance was previously seen to be quite common
(Price et al., 1997
).
Artemether has been combined with lumefantrine, a new agent related to
halofantrine, to provide a highly effective therapy
(Lefevre et al., 2001
).
Atovaquone, an agent first marketed for Pneumocystis pneumonia, has
been combined with proguanil, an old dihydrofolate reductase (DHFR) inhibitor,
to provide synergistic antimalarial activity
(Canfield et al., 1995
) and
action even against parasites resistant to individual agents in the
combination (Vaidya, 2001
).
Artesunate/mefloquine, artemether/lumefantrine and atovaquone/proguanil are
all quite expensive, do not include components with similar pharmacokinetics,
may have toxicity concerns (especially for mefloquine) and, in some cases, do
not have ideal dosing regimens (for artemether/lumefantrine, twice-daily
dosing with a fatty meal). Thus, these combination regimens offer promise for
some indications but may not be ideal for widespread use in many areas, in
particular Africa.
An interesting new approach to antimalarial drug development is
chlorproguanil/dapsone, which combines a close analog of proguanil with
dapsone, an old dihydropteroate synthase (DHPS) inhibitor that has been widely
used to treat leprosy. Chlorproguanil/dapsone has been specifically devised
for the treatment of malaria in Africa, where resistance to chloroquine is
very common and resistance to sulfadoxine/pyrimethamine is increasing.
Although the new regimen shares the targets of sulfadoxine/pyrimethamine, it
is generally effective against sulfadoxine/pyrimethamine-resistant parasites,
as the common DHFR and DHPS mutations that mediate this resistance do not lead
to clinical resistance to chlorproguanil/dapsone, and additional mutations
that lead to higher level antifolate resistance (and resistance to
chlorproguanil/dapsone) are rare in Africa
(Kublin et al., 2002;
Mutabingwa et al., 2001
;
Nzila et al., 2000
). Another
key advantage of chlorproguanil/dapsone is a relatively short half-life, which
appears to be long enough to provide effective therapy with 3-day daily dosing
but is not so long as to readily select for resistance. Chlorproguanil/dapsone
will probably be available for the treatment of malaria very soon. However,
its optimal use may be as a three-drug combination. The combination of
chlorproguanil/dapsone and artesunate may be ideal, combining the rapid
potency of artesunate with the slower curative efficacy of
chlorproguanil/dapsone, but definitive studies of this combination are still
needed.
Development of analogs of existing agents
Another approach to antimalarial chemotherapy is to improve upon existing
antimalarials by chemical modifications of these compounds. This approach does
not require knowledge of the mechanism of action or the biological target of
the parent compound. Indeed, this approach was responsible for the development
of many existing antimalarials. For example, chloroquine, primaquine and
mefloquine were discovered through chemical strategies to improve upon quinine
(Stocks et al., 2001). More
recently, 4-aminoquinolines that are closely related to chloroquine appear to
offer the antimalarial potency of the parent drug, even against
chloroquine-resistant parasites (Kaschula
et al., 2002
; Raynes et al.,
1999
). A related compound, pyronaridine, was developed in China
and is now undergoing extensive clinical trials in other areas
(Ringwald et al., 1996
). An
8-aminoquinoline, tafenoquine, offers improved activity against hepatic-stage
parasites over that of the parent compound, primaquine
(Walsh et al., 1999
), and is
effective for antimalarial chemoprophylaxis
(Lell et al., 2000
). Since
halofantrine use is limited by toxicity, the analog lumefantrine was developed
and is now a component of the new combination co-artemether
(artemether/lumefantrine; van Vugt et al.,
2000
). New folate antagonists
(Tarnchompoo et al., 2002
) and
new endoperoxides related to artemisinin
(Posner et al., 2003
;
Vennerstrom et al., 2000
) are
also under study.
Natural products
Plant-derived compounds offer a third approach to chemotherapy.
Importantly, this approach can benefit from knowledge of medicinal plants
among natives of malarious regions, where the appreciation of the use of plant
products to treat febrile illnesses has grown over many generations.
Therefore, as a great improvement over random screening, a plant product with
specific clinical activity can be the starting point for a medicinal chemistry
effort. Natural products are the sources of the two most important drugs
currently available to treat severe falciparum malaria, quinine and
derivatives of artemisinin. In the case of artemisinin, relatively simple
chemical modifications of the natural product parent compound have led to a
series of highly potent antimalarials that are playing an increasingly
important role in the treatment of malaria
(Meshnick, 2001). However, the
cost of these compounds may be limiting, and so efforts to design fully
synthetic endoperoxides that are less expensive to produce are an important
priority (Posner et al., 2003
;
Vennerstrom et al., 2000
).
Extensive evaluations of natural products as potential new therapies for many
human diseases are underway (Tagboto and
Townson, 2001
). It is important that such trials include the
evaluation of the antimalarial activity of plant extracts and potential drugs
purified from these extracts. As with both the quinolines and artemisinins, it
is likely that antimalarial natural products will be the parent compounds for
the semi-synthetic or fully synthetic production of new drugs.
Compounds active against other diseases
A fourth approach to antimalarial chemotherapy is to identify agents that
are developed or marketed as treatments for other diseases. These compounds
might act against orthologs of their targets in other systems or by different
mechanisms against malaria parasites. Considering the difficulties of funding
antimalarial drug discovery, the advantage of these compounds is that,
whatever their mechanism, they have already been developed for a human
indication, so will be quite inexpensive to develop as antimalarials. However,
costs of production for drugs vary greatly, and some new agents, especially
those developed for diseases of wealthy nations such as cancer, may be too
expensive to produce as antimalarials, even if they do not require extensive
development expenses. In many cases, however, drugs may be quite inexpensive
to produce and may be available as inexpensive antimalarials, especially after
patents have expired, as has been the case with some antibiotics.
Folate antagonists, tetracyclines and other antibiotics were developed for
their antibacterial properties and were later found to be active against
malaria parasites (Clough and Wilson,
2001). Atovaquone was initially identified as an antimalarial, but
its development was expedited by the discovery of its activity against
Pneumocystis. More recently, its potential as an antimalarial (as a
component of the combination drug Malarone) has been re-explored, and it was
found to have marked antimalarial synergy with proguanil
(Canfield et al., 1995
).
Malarone was subsequently shown to be effective in the treatment and
chemoprophylaxis of malaria, and it is now approved for both of these
indications (Hogh et al.,
2000
). Iron chelators, which are used to treat iron overload
syndromes, have documented antimalarial efficacy
(Loyevsky and Gordeuk, 2001
).
These examples suggest that it is appropriate to screen new antimicrobial
agents and other available compounds as antimalarial drugs. This approach is
facilitated by the presence of high-throughput assays for potential
antimalarials. As suggested by the recent development of Malarone, the
consideration of compounds with activity against other more economically
attractive microbial targets may provide a relatively inexpensive means of
identifying new antimalarials. In the case of protein farnesyl transferases,
development efforts have not yet led to viable anticancer therapies, but
nonetheless have expedited the consideration of these targets for antimalarial
chemotherapy (Gelb et al.,
2003
).
Drug resistance reversers
Combining previously effective agents with compounds that reverse parasite
resistance to these agents offers another approach to chemotherapy. Many drugs
have been shown to reverse the resistance of P. falciparum to
chloroquine in vitro, most notably the antihypertensive verapamil
(Martin et al., 1987) and the
antidepressant desipramine (Bitonti et al.,
1988
). In many cases, unacceptably high concentrations of the
resistance reversers are needed for their effects, but combinations of two or
more of these agents at pharmacological concentrations may provide clinically
relevant resistance reversal, as suggested by studies with verapamil,
desipramine and trifluoperazine (van
Schalkwyk et al., 2001
). The commonly used and inexpensive
antihistamine chlorpheniramine reversed resistance at safe dosing levels,
although the common side-effect of drowsiness might limit acceptance of this
therapy (Sowunmi et al.,
1997
). Efforts to design new reversers of chloroquine resistance
are underway (Alibert et al.,
2002
; Batra et al.,
2000
). Thus, although chloroquine appears to already have failed
as a first-line antimalarial in most of the world, this inexpensive,
rapidacting, well-tolerated antimalarial may be resurrected by combination
with effective resistance reversers.
Compounds active against new targets
Arguably the most innovative approach to chemotherapy is the identification
of new targets and subsequent discovery of compounds that act on these
targets. Progress towards the characterization of the biology of malaria
parasites has been stimulated by the development of technology to disrupt
plasmodial genes, although this process remains laborious and inefficient, and
the sequencing and annotation of the P. falciparum genome. The
readily accessible genome sequence facilitates genomic approaches to drug
discovery, although the more difficult and risky biochemical and
parasitological validation of putative drug targets remains essential and
typically limits progress. New targets for antimalarial therapy will be
considered based on their locations within the malaria parasite
(Table 2).
Cytosolic targets
The cytosol is the location of numerous metabolic pathways, with hundreds
of enzymes that are probably essential, and thus potential drug targets.
However, many of these pathways are evolutionarily well conserved, such that
parasite and host targets are quite similar, and so the identification of
compounds that selectively inhibit parasite enzymes may be difficult.
One pathway that has proven to be a valuable target is folate metabolism,
as discussed above (Plowe,
2001). Indeed, despite similarities in targets, extensive study
has identified antifolates that effectively treat both bacterial and protozoan
infections with minimal toxicity. This approach has also benefited from the
availability of compounds developed against other diseases, in this case
bacterial infections. Unfortunately, resistance to individual DHFR and DHPS
inhibitors, including pyrimethamine, proguanil and sulfas, leads to a marked
loss in efficacy of even combination regimens
(Plowe, 2001
).
Sulfadoxine/pyrimethamine is inexpensive and it has replaced chloroquine as
first-line therapy for malaria in a number of countries in Africa. However,
resistance to this agent is already common in many areas, including parts of
Africa, and resistance appears to develop quickly, at least in some settings,
with widespread use. The new combination of chlorproguanil/dapsone will
probably be highly effective in Africa, but not some other areas, due to
differences in the P. falciparum DHFR and DHPS mutation patterns in
different parts of the world, but it remains to be seen how quickly this new
drug will select for resistance if it is used alone to treat malaria, as will
probably soon be the case. Attempts are now underway to develop improved DHFR
inhibitor antimalarials, including biguanides related to proguanil
(Kinyanjui et al., 1999
). In
addition, inhibitors of other folate pathway enzymes may be effective
antimalarials. For example, 5-fluoroorotate exerts antimalarial activity
via the inhibition of thymidylate synthase
(Rathod et al., 1992
).
Glycolysis is another cytosolic pathway of interest. Malaria parasites are
dependent on this pathway for energy production. P. falciparum
lactate dehydrogenase has been characterized structurally, and its unique
binding site for the NADH cofactor offers opportunities for the design of
selective inhibitors (Dunn et al.,
1996). Selective inhibitors of P. falciparum lactate
dehydrogenase have been identified (Deck
et al., 1998
) and some compounds have demonstrated in
vitro antimalarial activity
(Razakantoanina et al.,
2000
).
Purine salvage and pyrimidine synthetic pathways also offer potential drug
targets. Malaria parasites cannot synthesize purines and rely on salvage of
host purines for nucleic acid synthesis. The principal source of purines in
P. falciparum appears to be hypoxanthine, and hypoxanthine-guanine
phosphoribosyltransferase (HGPRT) has been considered as a potential drug
target (Keough et al., 1999).
Other enzymes in purine salvage may offer useful targets, considering both
unique features of the parasite enzymes and the essential role of purine
salvage for the parasites, but not humans. In contrast to the case with
purines, malaria parasites cannot salvage pyrimidines and are thus reliant on
pyrimidine synthesis. Differences between pyrimidine synthetic enzymes of
parasites and humans offer potential for exploitation as drug targets.
Pyrimidine synthesis also relies on mitochondrial electron transport, linking
these targets to those in the mitochondrion (see below).
Parasite membrane targets
Parasite phospholipid metabolism is one potential target. Intraerythrocytic
malaria parasites undergo extensive phospholipid synthesis to produce the
membranes necessary to enclose the parasitophorous vacuole, cytosol and
multiple subcellular compartments. The most abundant lipid in plasmodial
membranes is phosphatidylcholine. Synthesis of phosphatidylcholine requires
host choline, and blockage of choline transport has been identified as a
promising therapeutic strategy (Vial and
Calas, 2001). Extensive medicinal chemistry efforts have
identified compounds that exert profound antimalarial effects, probably by
inhibition of choline transport. A lead compound, G25, inhibited the
development of cultured P. falciparum parasites at concentrations
that were 1000-fold below those toxic to mammalian cells
(Calas et al., 2000
;
Wengelnik et al., 2002
). G25
was also effective in vivo against mice infected with rodent malaria
parasites and primates infected with Plasmodium cynomolgi (a model
for Plasmodium vivax) and P. falciparum. Importantly, the
compound was remarkably potent in the primate models, with activity at doses
far below 1 mg kg-1 day-1, although potency with oral
dosing was well below that with parenteral dosing.
Other membrane targets are transport pathways that are unique to malaria
parasites. Intraerythrocytic parasites markedly alter erythrocyte transport
pathways. Our understanding of parasite transport mechanisms remains
incomplete, but it is likely that differences between host and parasite
mechanisms offer possibilities for selective antimalarial drugs
(Haldar and Akompong, 2001;
Kirk, 2001
). One possibility
is to take advantage of selective transport of cytotoxic compounds into P.
falciparum-infected erythrocytes. A strategy currently being investigated
is the use of dinucleoside phosphate dimers conjugated to antimalarial
compounds to improve selective access to parasite targets
(Gero et al., 2003
).
Food vacuole targets
Malaria parasites contain acidic food vacuoles in which erythrocyte
hemoglobin is hydrolyzed. In P. falciparum trophozoites, a single
large food vacuole is present. The food vacuole appears to be the site of
action of a number of existing antimalarials and also offers opportunities for
therapies directed against new targets
(Banerjee and Goldberg, 2001).
In the food vacuole, hemoglobin is degraded into heme, which is polymerized
into insoluble hemozoin pigment and globin, which is hydrolyzed to individual
amino acids. Antimalarial drugs appear to act by preventing hemozoin
formation, producing free radicals in the food vacuole or, in the case of
experimental compounds, preventing globin hydrolysis.
The 4-aminoquinoline chloroquine appears to act by blocking the formation
of hemozoin from heme molecules once they are liberated from hemoglobin
(Sullivan, 2002).
Antiparasitic effects are presumably engendered by the toxicity of free heme,
possibly by disruption of membranes. It is unclear if other chemically related
antimalarials act in a similar fashion. Although chloroquine use is now
severely compromised by drug resistance, it is important to note that the
>50-year history of successful use of this drug, with only a slow
development of resistance, may be due to its nonenzymatic mechanism of action.
Many available and experimental antimalarials inhibit specific enzymes, but
this approach is likely to routinely suffer from rapid selection of parasites
with mutations in target enzymes that mediate drug resistance, as is the case
with antifolates. With chloroquine, resistance developed only very slowly. It
is now clear that resistance is due primarily to mutations in a putative
transporter, PfCRT, and that, although a single mutation mediates resistance
in vitro, multiple mutations were necessary to select for clinical
resistance (Fidock et al.,
2000
). Although chloroquine-resistant parasites are now common in
almost all malarious areas, it seems reasonable to develop other compounds
that attack heme polymerization. In this regard, major efforts to synthesize
improved quinoline or related compounds as antimalarials are underway
(De et al., 1998
; Stocks et
al., 2001
,
2002
).
The food vacuole also appears to be the target of artemisinin
antimalarials. As noted above, this new class of compounds offers very potent
activity without, to date, any reported drug resistance. Artemisinins contain
an endoperoxide bridge that is essential for antimalarial activity and that
appears to undergo an iron-catalyzed decomposition into free radicals
(Meshnick, 2001). The
compounds apparently exert antimalarial effects via free-radical
damage, possibly by alkylation of plasmodial proteins
(Asawamahasakda et al., 1994
;
Bhisutthibhan et al., 1998
),
although the specific drug targets are uncertain. As is the case with other
compounds active in the food vacuole, a key to the selective antimalarial
toxicity of artemisinins may be the specific accumulation of the drug in this
parasite organelle. Artemisinin analogs are already proven antimalarials but
they are fairly expensive to produce, in part because they are semi-synthetic
plant products. Extensive efforts are underway to develop fully synthetic
peroxides and related compounds as antimalarials
(Borstnik et al., 2002
;
Vennerstrom et al., 2000
).
Globin hydrolysis appears to be mediated by a number of classes of
proteases, including food vacuole aspartic (plasmepsins;
Banerjee et al., 2002),
cysteine (falcipains; Shenai et al.,
2000
; Sijwali et al.,
2001
) and metalloproteases (falcilysin;
Eggleson et al., 1999
), and at
least one cytosolic metalloaminopeptidase
(Gavigan et al., 2001
). These
enzymes all offer potential targets for chemotherapy
(Rosenthal, 2001b
). In the
case of the plasmepsins and falcipains, the repertoire of proteases that
mediate hemoglobin hydrolysis is now known to be more complicated than
originally envisioned, as biochemical studies and the availability of the full
P. falciparum genome sequence have identified additional members of
these families. Four plasmepsins are believed to participate in hemoglobin
hydrolysis in the food vacuole (Banerjee et
al., 2002
). It has been argued that plasmepsin II and perhaps
additional plasmepsins mediate initial cleavages of hemoglobin, allowing
additional processing by other proteases, but the specific roles of these or
any other proteases in the process remain uncertain. Plasmepsin inhibitors
have demonstrated antimalarial effects
(Francis et al., 1994
;
Haque et al., 1999
;
Jiang et al., 2001
;
Moon et al., 1998
;
Nezami et al., 2002
;
Noteberg et al., 2003
;
Silva et al., 1996
) but these
have not clearly correlated with inhibition of hemoglobin hydrolysis. Cysteine
protease inhibitors appear to act by inhibiting falcipain-2 and falcipain-3,
the principal cysteine protease mediators of hemoglobin hydrolysis
(Shenai et al., 2000
;
Sijwali et al., 2001
).
Falcipain inhibitors have been shown to prevent hemoglobin hydrolysis, block
parasite development and cure murine malaria
(Batra et al., 2003
;
Rosenthal, 2001b
; Rosenthal et
al., 1991
,
1993
,
1996
,
2002
;
Shenai et al., 2003
;
Singh and Rosenthal, 2001
).
Importantly, the antimalarial activity of cysteine protease inhibitors is
accompanied by a block in parasite hydrolysis of hemoglobin, with the
accumulation of intact hemoglobin in the food vacuole. This morphological
abnormality confirms the specific action of these compounds on falcipain
targets. Of interest, cysteine and aspartic protease inhibitors exert
synergistic antimalarial effects in vitro and in vivo
(Semenov et al., 1998
). These
results suggest that an optimal protease inhibitor antimalarial might include
inhibitors of both classes of proteases.
Mitochondrial targets
One new antimalarial has a mitochondrial target. Atovaquone acts against
ubiquinol-cytochrome c oxidoreductase (complex III), inhibits
electron transport and collapses mitochondrial membrane potential, which is
required for a number of parasite biochemical processes
(Vaidya, 2001). The drug has
potent antimalarial activity but suffers from rapid selection of resistant
parasites with mutations in the target enzyme, and so is inappropriate as
monotherapy. Atovaquone proved to be surprisingly effective in combination
with the antifolate proguanil, and this combination is now marketed as
Malarone, an effective, but very expensive, drug for both chemoprophylaxis
(Hogh et al., 2000
) and
therapy (Radloff et al., 1996
)
of falciparum malaria. The combination probably benefits from synergistic
action of atovaquone and proguanil rather than the antifolate activity of the
metabolite cycloguanil, and for this reason it is more effective than would
have been predicted in areas with high levels of antifolate resistance
(Vaidya, 2001
).
Apicoplast targets
The apicoplast has recently been identified as a chloroplast-like organelle
of apicomplexan parasites (Kohler et al.,
1997). The apicoplast apparently resulted from endosymbiosis,
leading to an organelle that maintains certain specific functions, probably
including fatty acid, heme and amino acid metabolism
(Roos et al., 2002
). Like the
mitochondrion, the apicoplast has a separate, prokaryote-like genome, and this
fact probably explains the antimalarial effects of a number of antibacterial
compounds that otherwise do not attack eukaryotes. However, most apicoplast
proteins are encoded in the nucleus and then transported to the apicoplast by
a specific mechanism involving two amino-terminal targeting sequences
(Foth et al., 2003
;
Waller et al., 1998
).
As noted above, a number of antibacterial compounds are effective, albeit
slow-acting, antimalarials (Clough and
Wilson, 2001). These compounds probably act by targeting
apicoplast and/or mitochondrial processes that are similar to those in
bacteria (Ralph et al., 2001
).
Tetracyclines, clindamycin, macrolides and chloramphenicol inhibit different
steps of prokaryote-like protein synthesis. Quinolone antibiotics inhibit DNA
gyrase, and rifampin inhibits RNA polymerase, again with specificity to
prokaryote-like activity. It is not clear why all of these compounds appear to
exert only slow antimalarial activity. It seems most likely, based in part on
studies with the related protozoan Toxoplasma, that apicoplast
toxicity primarily impacts on the life cycle after that which is initially
incubated with these drugs (Fichera and
Roos, 1997
). In some cases, mitochondrial toxicity may also play a
role. Despite the slow action of antibacterial compounds as antimalarials,
some, including tetracyclines and clindamycin, are already well-validated as
effective antimalarial agents, and additional study of related drugs is
warranted.
Apicoplast biology includes a number of biochemical pathways that are
present in bacteria, plants and apicomplexan parasites but are absent in the
human host and thus provide obvious opportunities for chemotherapy
(Ralph et al., 2001;
Roos et al., 2002
). The type
II fatty acid biosynthesis pathway is absent in humans, but genes encoding
homologs of bacterial enzymes from this pathway are present in the P.
falciparum genome and contain putative apicoplast coding signals
(Waller et al., 1998
). One
type II fatty acid biosynthesis subunit, ß-ketoacyl-acyl-carrier protein
synthase (FabH), is the target of the antibiotic thiolactomycin, and this
antibiotic was active against cultured malaria parasites
(Waller et al., 1998
). Another
subunit, enoyl-acyl-carrier protein reductase (FabI), is also encoded by
P. falciparum and is the target of the antibacterial triclosan
(Surolia and Surolia, 2001
).
Triclosan demonstrated activity against cultured P. falciparum
parasites and against murine malaria, inhibited the target enzyme and blocked
parasite fatty acid synthesis, validating this target.
Isopentenyl diphosphate, the precursor for isoprenoids, is synthesized in
plants and animals via the mevalonate pathway, but an alternative
pathway, known as the 1-deoxy-D-xylulose 5-phosphate (DOXP) or
non-mevalonate pathway, is present in bacteria and chloroplasts. Genes
encoding two enzymes in this pathway, DOXP reductoisomerase and DOXP synthase,
are encoded by P. falciparum and contain putative apicoplast
targeting signals (Jomaa et al.,
1999). The antibiotic fosmidomycin inhibited the activity of
recombinant DOXP reductoisomerase, inhibited the growth of cultured P.
falciparum parasites and cured murine malaria
(Jomaa et al., 1999
).
Fosmidomycin was previously developed as an antibacterial, so it could quite
quickly be brought to human trials for malaria. In an initial trial of safety
and efficacy for uncomplicated malaria, fosmidomycin was well tolerated and
demonstrated 100% initial cure rates (Lell
et al., 2003
). However, the use of fosmidomycin as monotherapy
will be limited by the apparent need for frequent and prolonged dosing and the
common occurrence of recrudescence after therapy. The inclusion of this
compound or other inhibitors of apicoplast processes in combination
antimalarial regimens may be appropriate.
The DOXP pathway provides precursors for protein farnesylation. Inhibitors
of protein farnesyltransferases have been studied as potential cancer
therapies. Plasmodial farnesyl transferase activity has unique biochemical
features (Chakrabarti et al.,
2002), and inhibitors of this process have in vitro
antimalarial activity (Chakrabarti et al.,
2002
; Ohkanda et al.,
2001
).
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Conclusion |
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References |
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