Ferriprotoporphyrin IX, phospholipids, and the antimalarial actions of quinoline drugs

Fitch, Coy D.

doi:10.1016/j.lfs.2003.10.003

Cited by 184 publications

(169 citation statements)

References 127 publications

(151 reference statements)

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“…However, once inside the acidic DV, CQ becomes trapped in its doubly protonated and, hence, less membranepermeant form (Ferrari and Cutler, 1991;Homewood et al, 1972;Yayon et al, 1984). CQ is thought to exert its antimalarial effect by binding to haem (Bray et al, 1998;Bray et al, 1999), thereby inhibiting its incorporation into inert haemozoin crystals and leading to the buildup of haem and CQ-haem complexes that kill the parasite (Fitch, 2004;Orjih et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

A verapamil-sensitive chloroquine-associated H+ leak from the digestive vacuole in chloroquine-resistant malaria parasites

Lehane

Hayward

Saliba

et al. 2008

Journal of Cell Science

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Chloroquine resistance in the malaria parasite Plasmodium falciparum has made malaria increasingly difficult to control. Chloroquine-resistant parasites accumulate less chloroquine than their chloroquine-sensitive counterparts; however, the mechanism underlying this remains unclear. The primary site of accumulation and antimalarial action of chloroquine is the internal acidic digestive vacuole of the parasite, the acidity of which is maintained by inwardly-directed H+ pumps, working against the (outward) leak of H+. In this study we have investigated the leak of H+ from the digestive vacuole of the parasite by monitoring the alkalinisation of the vacuole following inhibition of the H+-pumping V-type ATPase by concanamycin A. The rates of alkalinisation observed in three chloroquine-resistant strains were two- to fourfold higher than those measured in three chloroquine-sensitive strains. On addition of chloroquine there was a dramatic increase in the rate of alkalinisation in the chloroquine-resistant strains, whereas chloroquine caused the rate of alkalinisation to decrease in the chloroquine-sensitive strains. The chloroquine-associated increase in the rate of alkalinisation seen in chloroquine-resistant parasites was inhibited by the chloroquine-resistance reversal agent verapamil. The data are consistent with the hypothesis that in chloroquine-resistant parasites chloroquine effluxes from the digestive vacuole, in association with H+, via a verapamil-sensitive pathway.

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Section: Introductionmentioning

confidence: 99%

A verapamil-sensitive chloroquine-associated H+ leak from the digestive vacuole in chloroquine-resistant malaria parasites

Lehane

Hayward

Saliba

et al. 2008

Journal of Cell Science

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“…CQ binds to one or more forms of ferriprotoporphyrin IX (FPIX), a toxic heme metabolite formed in the parasite's DV, and prevents its crystallization into insoluble hemozoin [12]. This leads to parasite death by an as yet undefined mechanism.…”

Section: Introductionmentioning

confidence: 99%

Chloroquine-resistant isoforms of the Plasmodium falciparum chloroquine resistance transporter acidify lysosomal pH in HEK293 cells more than chloroquine-sensitive isoforms

Reeves

Liebelt

Lakshmanan

et al. 2006

Molecular and Biochemical Parasitology

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The emergence of chloroquine-resistant Plasmodium falciparum malaria imperils the lives of millions of people in Africa, Southeast Asia and South America. Chloroquine resistance is associated with mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT). We expressed chloroquine sensitive (HB3) and resistant (Dd2) pfcrt alleles in HEK293 human embryonic kidney cells. PfCRT localized to the lysosomal limiting membrane and was not detected in the plasma membrane. We observed significant acidification of lysosomes containing PfCRT HB3 and Dd2, with Dd2 acidifying significantly more than HB3. A mutant HB3 allele expressing the K76T mutation (earlier found to be key for chloroquine resistance) acidified to the same extent as Dd2, whereas the acidification of a Dd2 allele expressing the T76K "back mutation" was significantly less than Dd2. Thus, the amino acid at position 76 is both an important determinant of chloroquine resistance in parasites and of lysosomal acidification following heterologous expression. PfCRT may be capable of modulating the pH of the parasite digestive vacuole, and thus chloroquine availability. Chloroquine accumulation and glycyl-phenylalanine-2-naphthylamide-induced release of lysosomal Ca 2+ stores were unaffected by PfCRT expression. Cytoplasmic domain mutations did not alter PfCRT sorting to the lysosomal membrane. This heterologous expression system will be useful to characterize PfCRT protein structure and function, and elucidate its molecular role in chloroquine resistance.

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“…and a lipid-rich environment [8][9][10][11]. All of the drugs listed above are able to prevent haemozoin crystal growth, although the exact mechanisms are evidently somewhat different for each class of drug.…”

mentioning

confidence: 99%

An atomic scale mechanism for the antimalarial action of chloroquine from density functional theory calculations

Acharige

Durrant

2014

Transition Met Chem

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Ferriprotoporphyrin IX, phospholipids, and the antimalarial actions of quinoline drugs

Cited by 184 publications

References 127 publications

A verapamil-sensitive chloroquine-associated H+ leak from the digestive vacuole in chloroquine-resistant malaria parasites

A verapamil-sensitive chloroquine-associated H+ leak from the digestive vacuole in chloroquine-resistant malaria parasites

Chloroquine-resistant isoforms of the Plasmodium falciparum chloroquine resistance transporter acidify lysosomal pH in HEK293 cells more than chloroquine-sensitive isoforms

An atomic scale mechanism for the antimalarial action of chloroquine from density functional theory calculations

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