Quinine, originally extracted from cinchona bark in the early 1800s, along with its dextroisomer quinidine, is still one of the most important drugs for the treatment of uncomplicated malaria, and often the drug of last resort for the treatment of severe malaria. Chloroquine (CQ), a 4-aminoquinoline derivative of quinine, has been the most successful, inexpensive, and therefore the most widely used antimalarial drug since the 1940s. However, its usefulness has rapidly declined in those parts of the world where CQ-resistant strains of P. falciparum and P. vivax have emerged and are now widespread. Amodiaquine, an analogue of CQ, is a pro-drug that relies on its active metabolite monodesethylamodiaquine, and is still effective in areas of Africa, but not in regions of South America. Other quinine-related, commonly used drugs include mefloquine, a 4-quinoline-methanol derivative of quinine, and the 8-aminoquinoline derivative, primaquine; the latter is specifically used for eliminating relapse causing, latent hepatic forms (hypnozoites) of P. vivax. Halofantrine and lumefantrine, both structurally related to quinine, were found to be effective against multidrug-resistant falciparum malaria [17,19,20]. While lumefantrine, in combination with an artemisinin derivative, artemether (Coartem), is recommended by the WHO for treating uncomplicated falciparum malaria, halofantrine generally is not recommended because of serious side effects and extensive cross-resistance with mefloquine [21].

Antifolate drugs include various combinations of dihydrofolate reductase enzyme (DHFR) inhibitors, such as pyrimethamine, proguanil, and chlorproguanil, and dihydropteroate synthase enzyme (DHPS) inhibitors, such as sulfadoxine and dapsone. With rapidly growing sulfadoxine-pyrimethamine (SP) resistance, a new combination drug, Lapdap (chlorproguanil-dapsone), was tested in Africa in the early 2000s, but was withdrawn in 2008 because of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase enzyme (G6PD) deficiency [22].

Artemisinin drugs, which originated from the Chinese herb qing hao (Artemisia annua), belong to a unique class of compounds, the sesquiterpene lactone endoperoxides [18]. The parent compound of this class is artemisinin (quinghaosu), whereas dihydroartemisinin (DHA), artesunate, artemether, and β-arteether are the most common derivatives of artemisinin; DHA is the main bioactive metabolite of all artemisinin derivatives (artesunate, artemether, β-arteether, etc.), and is also available as a drug itself [17,18,20].

Since 2001, the WHO has recommended the use of artemisinin-based combination therapies (ACTs) for treating falciparum malaria in all countries where resistance to monotherapies or non-artemisinin combination therapies (e.g., SP) is prevalent [23]. The rationale for the use of ACTs is based on the facts that artemisinin derivatives are highly potent and fast acting, and that the partner drug in ACT has a long half-life, which allows killing the parasites that may have escaped the artemisinin inhibition. Thus, it is thought that ACTs will delay the onset of resistance by acting as a “double-edged sword” [18,24,25]. ACTs, such as artemether-lumefantrine, artesunate-amodiaquine, and artesunate-mefloquine are being used in China, Southeast Asia, many parts of Africa, and some parts of South America [17,18,20]. Introduction of ACTs has initiated noticeable reduction in malaria prevalence in these endemic regions of the world [18]. Although the mechanism(s) of action is poorly understood (described below), the current high level of interest in artemisinin drugs is due to their well-recognized pharmacological advantages: These drugs act rapidly upon asexual blood stages of CQ-sensitive as well as CQ-resistant strains of both P. falciparum and P. vivax, and reduce the parasite biomass very quickly, by about 4-logs for each asexual cycle. In addition, these drugs are gametocytocidal. Thus, through rapid killing of asexual blood stages and developing gametocytes, artemisinin drugs significantly limit the transmission potential of the treated infections. These drugs have large therapeutic windows, and based on extensive human use, they appear to be safe, even in children and mid/late pregnant women. Furthermore, there is no reported “added toxicity” when these drugs are used in combination with other types of antimalarial compounds.

In addition to these three main classes of compounds, the antibiotic tetracycline and its derivatives, such as doxycycline, are consistently active against all species of malaria, and in combination with quinine, are particularly useful for the treatment of severe falciparum malaria [17]. Until recently, a combination of atovaquone, a hydroxynaphthoquinone, and proguanil (Malarone) was considered to be effective against CQ- and multidrug-resistant falciparum malaria; atovaquone resistance has recently been noticed in Africa [26]. Piperaquine, another member of the 4-aminoquinoline group, in combination with DHA (Artekin), holds the promise of being successful in CQ-resistant endemic areas of Southeast Asia [17,18,20].

Recently, a drug replacement/rotation approach has been suggested to stem the tide of resistance by changing the “playing field” for malaria parasites [47,48]. This approach is based on the understanding that the drug-resistant mutant forms are likely to be less fit than their wild-type strains in the absence of drug selection [49]. It has been shown that when CQ was withdrawn from Malawi, where a high level of CQR prevailed, CQ sensitivity returned [50]. The return of CQ-sensitive falciparum malaria in Malawi took almost 10 years, and was associated with a re-expansion of pfcrt-76K allele-carrying diverse, sensitive parasites [51,52]. Similar association between cessation of CQ use and decrease in pfcrt-76T allele-carrying resistant parasites has been observed in Kenya [53] as well as in China [54,55]. However, it is estimated that in these areas, sensitivity to CQ may take many more years to return to a level where the drug could be used effectively again [53,54].

Regarding SP, it has been shown that in the Amazon region of Peru, the frequencies of the mutant pf-dhfr and pf-dhps alleles, conferring SP resistance, declined significantly 5 years after the drug was replaced [48]. This, however, was not the case in Venezuela [56] and Cambodia [57], where the SP resistance-conferring alleles have remained at a high frequency 8 years and 2 decades, respectively, after the replacement of SP. It appears that the outcome of the drug replacement/rotation approach is not universal but malaria-endemic region dependent; a number of diverse ecological and epidemiological factors are likely to play a role in determining the outcome of this approach. In addition, the logistics, including the cost component, of this approach may pose challenges for some countries.

Improving the use of existing antimalarial drugs by designing new combinations is another potential approach to combat resistance. CQ entered widespread usage in the 1940s [19]. In spite of widespread resistance, this drug is still widely available because it is inexpensive and relatively non-toxic. In a thought-provoking article, Ginsburg [58] suggested that differential use of CQ in holoendemic areas that precludes children and pregnant women could still confer an efficacious protection for semi-immune adults, and more efficient treatment protocols could be devised to treat even patients infected with CQ-resistant parasite strains. According to the author [58], since the antimalarial activity of CQ is pleiotropic, drug resistance may be due to different mechanisms, each amenable to reversal by drug combination. Since the pivotal study by Martin and colleagues [59], which showed that CQR in P. falciparum was partly reversible by verapamil, it has been envisioned that the usefulness of CQ can be rescued by attempting to reverse the resistance—By co-administering CQ with another drug that chemosensitizes the parasite to its effect [60-64]. Among more than 40 such compounds, only one, chlorpheniramine, a histamine H1 receptor antagonist, in combination with CQ has been tested in patients with some success [58,60]. Of further interest, primaquine and antiretroviral protease inhibitors (PIs) saquinavir, ritonavir, and indinavir, may act as CQR reversers [60]. Fluoxetine, an antidepressant of the selective serotonin reuptake inhibitor class, has been shown to reverse both CQ and mefloquine resistance, while ketoconazole, a synthetic antifungal drug of the imidazole class, has been shown to reverse mefloquine resistance in a monkey model [60]. In addition, novel compounds that are more potent and less toxic than the archetypal CQR reverser verapamil are under investigations [60]. Thus, the reports of new resistance reversers over the last few years have generated considerable interest, and may lead to an effective stopgap therapy for drug-resistant malaria.

Use of combination therapy is currently mandated by the WHO [23]. With widespread high-level CQR, SP, as a 2-drug combination, was a successful first-line treatment in Africa for almost two decades. Currently, our hope rests mainly upon ACTs and atovaquone-proguanil (Malarone). As mentioned before, it is of concern that some of these combinations have started showing signs of failure. A further approach to minimize/delay the development of drug resistance in malaria is to apply combinations of three or more drugs (“multiple-drug therapy”), as is practiced for treating HIV/AIDS and tuberculosis. Attempts at combining existing drugs with CQ (e.g., CQ-SP) have proved less successful, whereas amodiaquine-SP has shown encouraging clinical activity [65]. Recently, a triple combination of artesunate-Lapdap, despite the side effects associated with Lapdap, is under evaluation for the treatment of uncomplicated falciparum malaria in Africa [66]. A limitation of this approach is the increased possibility of drug-drug interactions or the need for a reformulation of the drugs, both of which can prove costly and time-consuming to resolve. Furthermore, given that only a handful of effective antimalarial drugs are now left, this approach seems less promising.

With any drug, one of the major limitations is side effects. Mefloquine was first synthesized in 1969 primarily for the purpose of chemoprophylaxis in the U.S. military following the then recently discovered threat of CQ-resistant falciparum malaria. The drug has been in use as monotherapy and as combination therapy with either SP or artesunate. However, due to increasing incidences of resistance, particularly in the areas of multidrug resistance [67,68], newer information about toxicity [69,70], and the potential for severe neuropsychiatric adverse events among US military personnel [71], doxycycline is considered as a replacement for mefloquine chemoprophylaxis [72]. Although doxycycline has scanty side effects, a major limitation is that in prophylactic therapy, it must be taken daily leading to high non-compliance. Therefore, a new investigational drug, tafenoquine, an analogue of primaquine, related to mefloquine, was introduced in 1990s [73,74]. Although like primaquine, tafenoquine causes hemolysis in patients with G6PD deficiency, the drug has the potential advantage of a shorter treatment course, and therefore increased patient compliance, and higher therapeutic index than primaquine [73-75]. Thus, the interest in tafenoquine has been continued and efforts are directed at ameliorating side effects, so that this new efficacious compound can be used for malaria prevention as well as treatment [76-78].

It is known that some antimalarial drugs have moderate anti-HIV activities [79,80]. However, recent studies have also demonstrated that certain antiretroviral agents can inhibit malaria parasite growth. Skinner-Adams et al. [81] showed that antiretroviral PIs saquinavir, ritonavir, and indinavir were effective against P. falciparum. Subsequently, other antiretroviral PIs were also shown to exhibit potent antimalarial activity [82,83]. The current working hypothesis for the antimalarial activity of antiretroviral PIs is that these compounds inhibit one or more of the parasite's aspartic proteases (termed plasmepsins), located on the food/digestive vacuole or non-digestive vacuole [84-86].

Recently, we found that a non-nucleoside reverse transcriptase inhibitor, TMC-125, which had been shown to be highly active against HIV [87], demonstrated potent activity against P. falciparum [88]. It is theorized that this compound targets the parasite enzyme PfTERT, a catalytic reverse transcriptase component of telomerase, expressed in asexual blood-stage parasites that have begun DNA synthesis [89]. There appears to be only one gene for TERT in P. falciparum [89], P. vivax [90], and P. knowlesi [89], containing some highly conserved regions across species [89,90]. Since telomerase activity is likely to be necessary during blood-stage parasite proliferation, it is hoped that screening other reverse transcriptase inhibitors, or designing specific anti-telomerase compounds may lead to novel antimalarial drugs with potent activity against multiple-species infections.

The potential for crossover between malaria and HIV treatments is undoubtedly intriguing, as most of the malaria-endemic areas also bear the brunt of the HIV pandemic. However, at a time when access to antiretroviral drugs is increasing, and new combinations of antimalarial drugs, particularly ACTs, are being evaluated, it is important that potential interactions between therapies for these 2 infections are also understood [79,80,91]. In this regard, it is important to mention that human drug-metabolizing enzymes CYP2B6 (phase I metabolism) and UGT2B7 (phase II metabolism) play important roles in the metabolism of antiretroviral drugs efavirenz, nevirapine, and zidovudine, as well as antimalarial artemisinin drugs, including their active metabolite DHA [92-94]. Functional polymorphisms in CYP2B6 and UGT2B7 are highly prevalent in the regions where HIV/AIDS and malaria co-occur [93-95]. Phenotypic consequences of polymorphisms in these enzyme genes on the pharmacokinetics and effectiveness of artemisinin drugs are yet to be determined, and comprehensive studies evaluating the potential interactions between these antiretroviral and antimalarial drugs in individuals with or without polymorphisms are needed.

A new area in antimalarial drug discovery is the exploration of anti-cancer drugs that target cellular programs such as cell proliferation, cell differentiation, and cell death [88,96,97]. The interesting revelation that artesunate is effective against certain types of cancer, and may target one or more of these cellular programs [98-100], also lends credence to this path of investigation. Our recent study has shown that two anti-cancer compounds, SU-11274 and Bay 43-9006, exhibit potent activities (IC₅₀ values <1 μM) against P. falciparum [88]. In humans, SU-11274 acts as a specific inhibitor of the MET receptor tyrosine kinase activity [101]. Bay 43-9006, a dual-action inhibitor, targets the RAF/MEK/ERK signaling pathway in tumor cells, and receptor tyrosine kinases VEGFR/PDGFR in tumor vasculature [102]. The specific targets for SU-11274 and Bay 43-9006 activities against P. falciparum are not clear yet, but with the analysis of Plasmodium spp. genomes, plasmodial protein kinases (“Plasmodium kinome”) are emerging as highly promising targets for such compounds [103,104]. In addition, inhibition of protein kinases of the human host is being viewed as another major parasiticidal strategy [97,103,105]. Recently, Doerig and colleagues [97] showed that the host PAK-MEK signaling pathway was selectively activated in P. falciparum-infected red blood cells. Selective inhibitors of PAK (IPA-3, IC₅₀ value 2 μM) and MEK (U0126 [IC₅₀ value 3 μM], PD184352 [IC₅₀ value 7 μM]) inhibited the parasite proliferation. Moreover, the MEK inhibitors showed in vitro parasiticidal effects on hepatocyte and erythrocyte stages of the rodent malaria parasite P. berghei, indicating conservation of this subversive strategy in plasmodia [97].

As also discussed by Doerig and colleagues [97], several kinase-inhibiting drugs are now used clinically, mostly in a variety of cancers, with many more in different stages of clinical trials. Evaluating these inhibitors for antimalarial properties would considerably reduce the overall discovery/development cost and accelerate the process. A potential problem associated with most of these inhibitors is toxicity, as they tend to have small therapeutic indices. Most fatalities in malaria occur in children under 5, which emphasizes the need for not only highly efficacious but also very safe drugs. Although the kinase-inhibiting anti-cancer drugs have toxic effects, using them in malaria chemotherapy would require much shorter treatment periods, hopefully limiting the problem of toxicity. It would also be of interest to see whether these drugs can be used in combination with artemisinin drugs, which show no “added toxicity”, and whether such a combination helps in reducing the effective parasiticidal concentration of these drugs, thus reducing their toxicity.

One method to synthesize new antimalarial drugs is to start with the chemical framework of existing antimalarial drugs; the 4- and 8-aminoquinolines and artemisinin drugs are the two common examples of this approach [106]. Recently, a variety of 4-aminoquinoline derivatives (thiourea, triazine, and bisquinoline) have been found to be highly active against P. falciparum in vitro, and against P. yoelii or P. berghei in mice [107-109]. Synthesis/screening of 4-position modified quinoline-methanol compounds is anticipated to yield an efficacious and less toxic replacement for mefloquine [110-112]. In addition to 4-aminoquinoline analogs, extensive derivatization approaches followed by better understanding of structure-activity relationships and biotransformation mechanisms of toxicity have also provided 8-aminoquinoline analogs with better pharmacologic and reduced toxicologic profiles [113].

Derivatives of artemisinin, particularly the water-soluble and efficacious artesunate, are another obvious choice for the synthesis of new compounds [20,114]. Although highly potent and fast acting, the currently available semisynthetic artemisinin derivatives are prone to hydrolysis, resulting in a short biological half-life and the generation of potentially toxic DHA [115,116]. Therefore, extensive efforts have been made to synthesize new derivatives of artemisinin and chemically-related compounds, which are more stable and exhibit potent in vitro [117,118] and in vivo [119-122] antimalarial activities. The in vitro activity of these new derivatives did not indicate any apparent cytotoxicity [118].

Thus, it appears that derivatization is one possible approach to prolong the clinical usefulness of aminoquinoline and artemisinin classes of compounds. However, as a potential limitation of this approach, toxicity and cross-resistance with the parent compound may still occur in some of the derivatives [123].

Burgess et al. reported a highly innovative hybrid molecule that combines the pharmacophore of an active 4-amino-7-chloroquinoline antimalarial with a resistance-reversing group based on imipramine [124]. The compound was found to be highly active against both CQ-sensitive and CQ-resistant strains of P. falciparum in vitro, and against P. chabaudi in mice, with no obvious signs of toxicity. The authors named this class “reversed chloroquine (RCQ)”. Further studies showed that linking any of several reversal-agent-like moieties to a 4-amino-7-chloroquinoline yielded good parasiticidal activity [125]. Structure-activity relationship investigation indicated that RCQ molecules inhibit hemozoin formation in the parasite's digestive vacuole in a manner similar to that of CQ [126].

Recently, in a deliberate rational design of antimalarials acting specifically on multiple targets, several hybrid molecules have been developed in what has been termed “covalent bitherapy” [127]. One interesting report described the synthesis of a novel artemisinin-quinine hybrid with potent antimalarial activity [128]. Artemisinin was reduced to DHA and coupled to a carboxylic acid derivative of quinine via an ester linkage. This novel hybrid molecule had potent activity against CQ-sensitive and CQ-resistant strains of P. falciparum in vitro. The activity was superior to that of artemisinin alone, quinine alone, or a 1:1 mixture of artemisinin and quinine [128]. Another example is a trioxane motif of sesquiterpene lactone artemisinin covalently linked to a quinoline entity of an aminoquinoline (e.g., CQ), to form new modular molecules referred to as trioxaquines [127]. The trioxaquines had more improved antimalarial activity than their individual components, indicating a potential additive/synergistic effect of the hybrids, as well as good oral bioavailability and low toxicity [127]. Such hybrid molecules have the potential to delay or circumvent the development of resistance and reduce the risk of drug-drug adverse interactions, the latter often seen with multiple-drug therapies. The antimalarial activities, combined with a good drug profile (preliminary absorption, metabolism, and safety parameters) seem favorable for the selection of hybrid molecules for development as drug candidates [129].

One of the major thrust areas for antimalarial drug discovery is to screen diverse chemical libraries using high-throughput assays. In recent years, impressive efforts by several drug-screening groups at pharmaceutical companies and academic institutions have generated a plethora of compounds, which may serve as new starting points for potential antimalarial drugs with novel mechanisms. Here, we summarize five such studies (Table 1).

The life cycle of malaria parasites is very tightly regulated, since it passes through a succession of developmental stages that vary in terms of proliferation and differentiation. The successful completion of such a complex life cycle requires a strict control of the cellular machinery that carries out phosphorylation, transcriptional control, post-transcriptional control, and protein degradation. These mechanisms most likely involve fine interactions among various cell-cycle proteins (particularly kinases), which may represent strategic targets for pharmacological interventions [96,104,176].

There are a large number and variety of kinases (“Plasmodium kinome”), many of which are clearly distinct from human protein kinases, and thus are considered as targets of choice for antimalarial drug development [176,177]. A serine/threonine protein kinase, casein kinase 2α (PfCK2α), crucial for asexual blood-stage parasites, has been identified as a potential target for antimalarial chemotherapeutic intervention [178]. Among cyclin-dependent protein kinases, Pfmrk is the most attractive target for antimalarial drug development; a variety of inhibitors selectively inhibit Pfmrk at sub-micromolar concentrations [179-181]. Calcium-dependent protein kinase 1 (PfCDPK1), essential for parasite survival, can be inhibited by small-molecule compounds at nanomolar concentrations [182,183]. An orphan protein kinase PfPK7, significant for asexual stage development in humans and oocyst production in mosquitoes, has recently been identified as a lead target [184-187]. In addition, mitogen-activated protein kinase 2 (PfMAP-2), essential for completion of the asexual cycle 188, NIMA-related protein kinase Pfnek-2, predominantly expressed in, and required for transmission of, gametocytes [189], and cAMP-dependent protein kinase (PfPKA), essential for parasite growth and survival [190], hold the promise of being selective and effective targets for the development of new antimalarial drugs.

Histone acetylation plays key roles in regulating gene transcription in both prokaryotes and eukaryotes, the acetylated form inducing gene expression while deacetylation silences genes. A number of HDAC inhibitors are currently in clinical trials, alone or in combination, for the treatment of a variety of cancers, parasitic/infectious diseases, and hemoglobinopathies [191,192]. Plasmodium falciparum has at least five putative HDACs, which play a major role in transcriptional regulation of the parasite life cycle [193]. Among these, PfHDAC1 in particular is considered as a promising new antimalarial drug target. A variety of PfHDAC1 inhibitors showed potent in vitro antimalarial activity (IC₅₀ values in nM range) against CQ-sensitive and CQ-resistant strains of the parasite, and several of the inhibitors were significantly more toxic to the parasites than to mammalian cells [194,195]. Furthermore, an HDAC inhibitor WR301801 (YC-2-88) exhibited cures in P. berghei-infected mice at a dose of 52 mg/kg/day orally, when combined with subcurative doses of CQ [196]. Recently, using a modified schizont maturation assay, certain HDAC inhibitors were found to exert potent activity (at nM concentrations) against multidrug-resistant clinical isolates of both P. falciparum (n = 24) and P. vivax (n = 25) from Papua, Indonesia, suggesting that these inhibitors may be promising candidates for antimalarial therapy in geographical locations where both species are endemic [197].

Erythrocytic stages of P. falciparum seem to maintain an active mitochondrial electron transport chain to serve just one metabolic function: regeneration of ubiquinone required as the electron acceptor for DHODH, an essential enzyme for de novo pyrimidine biosynthesis [198]. For this very reason, PfDHODH is also receiving increasing attention as a new target for antimalarial drug discovery [199,200]. A variety of potent inhibitors of PfDHODH showing strong selectivity for the malarial enzyme over that from the human host have been designed and synthesized, and identified by high-throughput screening [201-204]. Potent activity against Plasmodium spp. parasites in vitro at nM concentrations, with good correlation between activity against the parasites and the enzyme from the parasites has been observed for a number of these inhibitors [201,205]. Lead optimization of a triazolopyrimidine-based series of inhibitors has identified Genz-667348, which is orally bioavailable, with prolonged plasma exposure, and cures P. berghei infection in mice at a total dose of 100 mg/kg/day [201]. Further refinement of the structure-activity relationship within this series is underway, with 2 recent analogs of Genz-667348 undergoing further testing to determine if they represent suitable candidates for preclinical development [201].

In addition, new compounds may participate in the combat against falciparum malaria not by directly killing but preventing the parasite from causing severe forms of the disease. One way to achieve this is to inhibit the parasite's ability to sequester. Sequestration occurs because parasite-derived adhesins, expressed on the surface of mature infected erythrocytes, bind to receptors on human cells (often referred to simply as cytoadherence or cytoadhesion). Organ-specific sequestration in brain and placenta play an important role in the pathogenesis of cerebral and placental malaria, respectively [5,206]. Plasmodium falciparum-infected erythrocytes have been shown to have the potential for binding to a diverse array of endothelial receptors; however, only two of these receptors, CD36 and intracellular adhesion molecule 1 (ICAM1), have been studied in detail [206]. Chondroitin sulfate A (CSA) has been consistently identified as the dominant placental adhesion receptor [5].

In recent years, some progress has been made in inhibiting cytoadherence that is mediated by these receptors. CD36-mediated cytoadherence can be inhibited in vitro by antiretroviral PIs ritonavir and saquinavir [207], and polysaccharides derived from seaweed (carrageenans) [208]. A randomized clinical trial of Thai patients with uncomplicated malaria showed that levamisole, an antihelminth drug, known to block cytoadherence to CD36, when used as an adjunctive therapy with quinine and doxycycline, resulted in increased numbers of early-mid trophozoites in the peripheral blood [209]. It was suggested that levamisole prevented the sequestration of these parasites as they matured from ring stages following treatment [209]. Using the crystal structure of ICAM1, Dormeyer and colleagues [210] found that (+)-epigalloylcatechin gallate, a naturally occurring polyphenol compound in green tea, inhibited cytoadherence to ICAM1 in a dose-dependent manner with two variant ICAM 1-binding parasite lines. Using CSA-expressing CHO-K1 cells and ex vivo human placental tissue, Andrews et al. [211] showed that two carrageenans and a cellulose sulfate (CS10) were able to inhibit cytoadhesion to CHO-K1 cells as well as human placental tissue; the inhibitory effect on CHO-K1 cells was dose-dependent.

Inhibition of cell adhesion processes is becoming increasingly interesting in the discovery of novel therapeutics [212]. Although our understanding of the molecular mechanisms of parasite adhesion is still incomplete, and many questions remain unanswered [206], the discoveries outlined above open up the possibility of developing therapeutic interventions aimed at blocking or reversing parasite adhesion.