In vitro stage-specific sensitivity of Plasmodium falciparum to quinine and artemisinin drugs

Skinner, Tina S.; Manning, Linda S.; Johnston, Wayne A.; Davis, Timothy M. E.

doi:10.1016/0020-7519(96)89380-5

Cited by 116 publications

(91 citation statements)

References 25 publications

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“…More work is needed to gain insight into the molecular basis of BIX-01294-induced rapid parasite death. This activity profile is in contrast to the large majority of important antimalarial compounds, which show clear stage-specific activity (40,41), or antibiotics, which require exposure during multiple cycles to kill parasites (42). Presently, the only exceptions to this rule are the semisynthetic artemisinin derivatives that form the basis of currently administered combined therapies (43).…”

Section: Discussionmentioning

confidence: 92%

Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms inPlasmodium falciparum

Malmquist

Moss

Mécheri

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

122

116

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Epigenetic factors such as histone methylation control the developmental progression of malaria parasites during the complex life cycle in the human host. We investigated Plasmodium falciparum histone lysine methyltransferases as a potential target class for the development of novel antimalarials. We synthesized a compound library based upon a known specific inhibitor (BIX-01294) of the human G9a histone methyltransferase. Two compounds, BIX-01294 and its derivative TM2-115, inhibited P. falciparum 3D7 parasites in culture with IC 50 values of ∼100 nM, values at least 22-fold more potent than their apparent IC 50 toward two human cell lines and one mouse cell line. These compounds irreversibly arrested parasite growth at all stages of the intraerythrocytic life cycle. Decrease in parasite viability (>40%) was seen after a 3-h incubation with 1 µM BIX-01294 and resulted in complete parasite killing after a 12-h incubation. Additionally, mice with patent Plasmodium berghei ANKA strain infection treated with a single dose (40 mg/kg) of TM2-115 had 18-fold reduced parasitemia the following day. Importantly, treatment of P. falciparum parasites in culture with BIX-01294 or TM2-115 resulted in significant reductions in histone H3K4me3 levels in a concentration-dependent and exposure time-dependent manner. Together, these results suggest that BIX-01294 and TM2-115 inhibit malaria parasite histone methyltransferases, resulting in rapid and irreversible parasite death. Our data position histone lysine methyltransferases as a previously unrecognized target class, and BIX-01294 as a promising lead compound, in a presently unexploited avenue for antimalarial drug discovery targeting multiple life-cycle stages.chromatin | global health | chemical genetics M alaria continues to claim >1 million lives annually, particularly in the vulnerable populations of pregnant women and children <5 y of age (1, 2). Although artemisinin-based combination therapies have helped rescue the world's antimalarial armamentarium, the parasite's ability to develop resistance continues to outpace our ability to control this devastating disease (3). Effective malaria drug discovery efforts must therefore include both the development of improved antimalarials from existing compounds and the discovery of new parasite drug targets and novel small-molecule inhibitors.Epigenetic control of gene regulation in Plasmodium falciparum, the main causative agent of human malaria, has received considerable attention originally due to the apparent lack of recognizable transcription factors in the parasite genome (4). Although the recent discovery of a family of apicomplexan AP2 transcription factors (5, 6) has partly fulfilled the search for more traditional transcription factors, epigenetic gene regulation, particularly at the level of histone posttranslational modifications, has proven to play a significant role in P. falciparum virulence gene regulation. For example, expression of variant surface antigen gene families (7) and ligands involved in parasite red bl...

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Section: Discussionmentioning

confidence: 92%

Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms inPlasmodium falciparum

Malmquist

Moss

Mécheri

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

122

116

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“…Our data suggest that the release of haem from haemoglobin would be initiated in the ring stage of parasite growth and would be available as a source of an iron-based activator. This might well underlie the finding that artemisinin is highly active against ring-stage parasites (Skinner et al, 1996).…”

Section: Implications For Antimalarial Drug Actionmentioning

confidence: 95%

Digestive-vacuole genesis and endocytic processes in the early intraerythrocytic stages of Plasmodium falciparum

Bakar

Klonis

Hanssen

et al. 2010

Journal of Cell Science

172

209

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SummaryThe digestive vacuole of the malaria parasite Plasmodium falciparum is the site of haemoglobin digestion and haem detoxification, and is the target of chloroquine and other antimalarials. The mechanisms for genesis of the digestive vacuole and transfer of haemoglobin from the host cytoplasm are still debated. Here, we use live-cell imaging and photobleaching to monitor the uptake of the pH-sensitive fluorescent tracer SNARF-1-dextran from the erythrocyte cytoplasm in ring-stage and trophozoite-stage parasites. We compare these results with electron tomography of serial sections of parasites at different stages of growth. We show that uptake of erythrocyte cytoplasm is initiated in mid-ring-stage parasites. The host cytoplasm is internalised via cytostome-derived invaginations and concentrated into several acidified peripheral structures. Haemoglobin digestion and haemozoin formation take place in these vesicles. The ringstage parasites can adopt a deeply invaginated cup shape but do not take up haemoglobin via macropinocytosis. As the parasite matures, the haemozoin-containing compartments coalesce to form a single acidic digestive vacuole that is fed by haemoglobin-containing vesicles. There is also evidence for haemoglobin degradation in compartments outside the digestive vacuole. The work has implications for the stage specificity of quinoline and endoperoxide antimalarials.

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“…2,3 It can completely inhibit parasite growth within 2-4 hours and is the only artemisinin derivative with activity against all asexual blood-stage parasites. 4 The effectiveness of AS has been mostly attributed to its rapid and extensive hydrolysis to DHA. [5][6][7][8] Artemisinins have been used in malaria treatments with monotherapy regimen since 1983.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Profiles of Artesunate After Single Intravenous Doses at 0.5, 1, 2, 4, and 8 mg/kg in Healthy Volunteers: A Phase I Study

Cantilena²,

Leary³

et al. 2009

The American Journal of Tropical Medicine and Hygiene

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Abstract. The pharmacokinetics of good manufacturing process injection of artesunate (AS) were evaluated after single doses at 0.5, 1, 2, 4, and 8 mg/kg with a 2-minute infusion in 40 healthy subjects. Drug concentrations were analyzed by validated liquid chromatography and mass spectrometry system (LC-MS/MS) procedures. The drug was immediately converted to dihydroartemisinin (DHA), with elimination half-lives ranging 0.12-0.24 and 1.15-2.37 hours for AS and DHA, respectively. Pharmacokinetic model-dependent analysis is suitable for AS, whereas DHA fits both model-dependent and -independent methods. Although DHA concentration was superior to that of AS with a 1.12-1.87 ratio of area under the curve (AUC) DHA/AS , peak concentration of AS was much higher than that of DHA, with a 2.80-to 4.51-fold ratio of peak concentration (C max AS/DHA ). Therefore, AS effectiveness has been attributed not only to its rapid hydrolysis to DHA, but also to itself high initial C max .

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In vitro stage-specific sensitivity of Plasmodium falciparum to quinine and artemisinin drugs

Cited by 116 publications

References 25 publications

Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms inPlasmodium falciparum

Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms inPlasmodium falciparum

Digestive-vacuole genesis and endocytic processes in the early intraerythrocytic stages of Plasmodium falciparum

Pharmacokinetic Profiles of Artesunate After Single Intravenous Doses at 0.5, 1, 2, 4, and 8 mg/kg in Healthy Volunteers: A Phase I Study

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