An Assessment of Drug-Haematin Binding as a Mechanism for Inhibition of Haematin Polymerisation by Quinoline Antimalarials

Dorn, Arnulf; Vippagunta, Sudha R.; Matile, Hugues; Jaquet, Catherine; Vennerstrom, Jonathan L.; Ridley, Robert G.

doi:10.1016/s0006-2952(97)00510-8

Cited by 298 publications

(289 citation statements)

References 55 publications

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“…11 The positive correlation between pyronaridine, amodiaquine, quinine, and halofantrine responses may be explained by the role of quinoline blood schizonticides in the inhibition of hematin polymerization. 32 However, other studies showed that the acquisition of reduced halofantrine susceptibility was accompanied by similar shifts in sensitivity to quinine, mefloquine, and other antimalarial agents containing the methanolic function, but increased susceptibility to chloroquine. This suggests that the methanolic functional group is essential for activity or is of importance in the resistance mechanism, 33 resistance to halofantrine, quinine, and mefloquine is related to reduced drug accumulation within the parasite, and that this can be achieved without overexpression of Pgh 1.…”

Section: Resultsmentioning

confidence: 98%

“…31 In addition, Dorn and others have demonstrated a correlation for pyronaridine, chloroquine, amodiaquine, quinine, and halofantrine between the inhibition of hematin polymerization in vitro and inhibition of P. falciparum growth in culture, which confirms hematin polymerization as the likely target of quinoline blood schizonticides. 32 The high activity of pyronaridine against chloroquineresistant parasites may be due to a higher affinity of pyronaridine for the enzyme heme polymerase, higher binding to monomeric hematin, or a lower affinity for the putative chloroquine efflux pump.…”

Section: Resultsmentioning

confidence: 99%

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In vitro susceptibility of African isolates of Plasmodium falciparum from Gabon to pyronaridine.

Pradines

Mamfoumbi²,

Parzy³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. The in vitro activity of pyronaridine was evaluated against 62 isolates of Plasmodium falciparum from Libreville, Gabon using an isotopic, drug susceptibility microtest and was compared with amodiaquine, chloroquine, quinine, and halofantrine activities. The mean 50% inhibitory concentration (IC 50 ) values of the 62 isolates from Gabon to pyronaridine was 3.0 nM (95% confidence interval [CI] ϭ 2.1-3.9). Pyronaridine was less potent against chloroquine-resistant isolates than chloroquine-susceptible isolates but more potent than chloroquine against chloroquine-resistant parasites. The cut-off value for in vitro reduced susceptibility to pyronaridine was an IC 50 Ͼ 15 nM. Two isolates (3%) showed an IC 50 Ͼ 15 nM. A significant positive correlation was found between the activities of pyronaridine and chloroquine (r 2 ϭ 0.26, P Ͻ 0.001), pyronaridine and quinine (r 2 ϭ 0.36, P Ͻ 0.001), pyronaridine and amodiaquine (r 2 ϭ 0.55, P Ͻ 0.001), and pyronaridine and halofantrine (r 2 ϭ 0.50, P Ͻ 0.001). This correlation suggests in vitro cross-resistance or at least in vitro cross-susceptibility, which is not necessarily predictive of crossresistance in vivo. The present in vitro findings require comparison with those of clinical studies.The only current options for reducing the morbidity and mortality of malaria, especially in Africa, are chemoprophylaxis and chemotherapy. Therefore, the increasing prevalence of strains of Plasmodium falciparum resistant to chloroquine and other antimalarial drugs poses a serious problem for control of malaria.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

In vitro susceptibility of African isolates of Plasmodium falciparum from Gabon to pyronaridine.

Pradines

Mamfoumbi²,

Parzy³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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“…A possible explanation is that mefloquine, which is similar to chloroquine and quinine, appears to interfere with the ability of the parasite to metabolize and use erythrocyte hemoglobin. 26 Mefloquine might bind free heme, thus inhibiting the polymerization of heme or the swelling of food vacuoles. Conversely, mefloquine is believed to act by forming toxic heme complexes that damage parasitic food vacuoles.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Effects of Pepstatin A and Mefloquine on the Growth of Babesia Parasites

Munkhjargal¹,

AbouLaila²,

Terkawi³

et al. 2012

The American Society of Tropical Medicine and Hygiene

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Abstract. We evaluated the inhibitory effects of pepstatin A and mefloquine on the in vitro and in vivo growths of Babesia parasites. The in vitro growth of Babesia bovis, B. bigemina, B. caballi, and B. equi was significantly inhibited (P 0.05) by micromolar concentrations of pepstatin A (50% inhibitory concentrations = 38.5, 36.5, 17.6, and 18.1 μM, respectively) and mefloquine (50% inhibitory concentrations = 59.7, 56.7, 20.7, and 4 μM, respectively). Furthermore, both reagents either alone at a concentration of 5 mg/kg or in combinations (2.5/2.5 and 5/5 mg/kg) for 10 days significantly inhibited the in vivo growth of B. microti in mice. Mefloquine treatment was highly effective and the combination treatments were less effective than other treatments. Therefore, mefloquine may antagonize the actions of pepstatin A against babesiosis and aspartic proteases may play an important role in the asexual growth cycle of Babesia parasites.

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“…Chloroquine and other quinolines accumulate to high concentrations in the acid food vacuole because of their weak base properties. They apparently act by non-covalently binding to the soluble heme molecule and inhibiting its sequestration into a harmless microcrystalline form known as hemozoin, or malaria pigment [118][119][120]. Resistance to chloroquine is a result of amino acid changes in the PfCRT protein, a putative transporter located in the food vacuole membrane [80,121,122].…”

Section: Chloroquinementioning

confidence: 99%

Proteomic Approaches to Studying Drug Targets and Resistance in Plasmodium

Cooper

Carucci²

2004

CDTID

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Ever increasing drug resistance by Plasmodium falciparum , the most virulent of human malaria parasites, is creating new challenges in malaria chemotherapy. The entire genome sequences of P. falciparum and the rodent malaria parasite, P. yoelii yoelii are now available. Extensive genome sequence data from other Plasmodium species including another important human malaria parasite, P. vivax are also available. Powerful research techniques coupled to genomic resources are needed to help identify new drug and vaccine targets against malaria. Applied to Plasmodium, proteomics combines high-resolution protein or peptide separation with mass spectrometry and computer software to rapidly identify large numbers of proteins expressed from various stages of parasite development. Proteomic methods can be applied to study sub-cellular localization, cell function, organelle composition, changes in protein expression patterns in response to drug exposure, drug-protein binding and validation of data from genomic annotation and transcript expression studies. Recent high-throughput proteomic approaches have provided a wealth of protein expression data on P. falciparum, while smaller-scale studies examining specific drug-related hypotheses are also appearing. Of particular interest is the study of mechanisms of action and resistance of drugs such as the quinolines, whose targets currently may not be predictable from genomic data. Coupling the Plasmodium sequence data with bioinformatics, proteomics and RNA transcript expression profiling opens unprecedented opportunities for exploring new malaria control strategies. This review will focus on pharmacological research in malaria and other intracellular parasites using proteomic techniques, emphasizing resources and strategies available for Plasmodium.

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An Assessment of Drug-Haematin Binding as a Mechanism for Inhibition of Haematin Polymerisation by Quinoline Antimalarials

Cited by 298 publications

References 55 publications

In vitro susceptibility of African isolates of Plasmodium falciparum from Gabon to pyronaridine.

In vitro susceptibility of African isolates of Plasmodium falciparum from Gabon to pyronaridine.

Inhibitory Effects of Pepstatin A and Mefloquine on the Growth of Babesia Parasites

Proteomic Approaches to Studying Drug Targets and Resistance in Plasmodium

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