Channels and transporters as drug targets in the Plasmodium-infected erythrocyte

Kirk, Kiaran

doi:10.1016/j.actatropica.2003.10.002

Cited by 56 publications

(31 citation statements)

References 92 publications

(124 reference statements)

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“…Thus, a novel and promising approach may be to attack the parasite cell from the outside, that is, at the interface with the host. [10] The parasite-host interface is made up of channels and transporters for 1) the establishment of ionic and pH gradients, [10] 2) the import of nutrients and biosynthetic precursors such as glucose [11] and glycerol, [12] and 3) the export of waste metabolites such as lactate. [10] Blockage of such processes should severely affect the parasite by deprivation of its energy supply or by a build-up of cytotoxic metabolites.…”

mentioning

confidence: 99%

Aquaporin Water and Solute Channels from Malaria Parasites and Other Pathogenic Protozoa

Beitz

2006

ChemMedChem

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confidence: 99%

Aquaporin Water and Solute Channels from Malaria Parasites and Other Pathogenic Protozoa

Beitz

2006

ChemMedChem

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“…-Pi importer, PfPiT, that is a close homolog of Pho89p (Table 2) (Saliba et al 2006). Nutrient uptake systems are interesting targets in P. falciparum (Kirk and Saliba 2007;Kirk 2004), where Pi is a vital nutrient whose removal from the growth medium has been shown to reduce P. falciparum proliferation by over 90% (Saliba et al 2006). Our results in yeast show that a Pi supplementation of the growth medium exerts a protective effect to quinine-stressed cells, but the effect of increased Pi on quinine susceptibility in P. falciparum has not yet been investigated.…”

Section: Discussionmentioning

confidence: 99%

A genome-wide screen identifies yeast genes required for protection against or enhanced cytotoxicity of the antimalarial drug quinine

Santos

Sá‐Correia

2011

Mol Genet Genomics

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Quinine is used in the treatment of Plasmodium falciparum severe malaria. However, both the drug's mode of action and mechanisms of resistance are still poorly understood and subject to debate. In an effort to clarify these questions, we used the yeast Saccharomyces cerevisiae as a model for pharmacological studies with quinine. Following on a previous work that examined the yeast genomic expression program in response to quinine, we now explore a genome-wide screen for altered susceptibility to quinine using the EUROSCARF collection of yeast deletion strains. We identified 279 quinine-susceptible strains, among which 112 conferred a hyper-susceptibility phenotype. The expression of these genes, mainly involved in carbohydrate metabolism, iron uptake and ion homeostasis functions, is required for quinine resistance in yeast. Sixty-two genes whose deletion leads to increased quinine resistance were also identified in this screen, including several genes encoding ribosome protein subunits. These well-known potential drug targets in Plasmodium are associated with quinine action for the first time in this study. The suggested involvement of phosphate signaling and transport in quinine tolerance was also studied, and activation of phosphate starvation-responsive genes was observed under a mild-induced quinine stress. Finally, P. falciparum homology searches were performed for a selected group of 41 genes. Thirty-two encoded proteins possess homologs in the parasite, including subunits of a parasitic vacuolar H(+)-ATPase complex, ion and phosphate importers, and several ribosome protein subunits, suggesting that the results obtained in yeast are good candidates to be transposed and explored in a P. falciparum context.

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“…The molecular identity of the channel remains a mystery and there is some controversy as to whether and if the channel is composed of proteins derived from the parasite or simply remodeled from host proteins (Kirk, 2000). But despite this uncertainty there is a clear recognition that the channel is an attractive target for new drug design (Alkhalil, et al, 2004,Desai, 2004,Ginsburg and Stein, 2005,Kirk, 2004,Lisk, et al, 2006. It is hoped that the results reported here will aid in the effort to develop pharmacologic means to block or subvert the channel, leading to discovery of novel antimalarial agents.…”

Section: Discussionmentioning

confidence: 99%

Selective killing of the human malaria parasite Plasmodium falciparum by a benzylthiazolium dye

Kelly

Winter

Braun³

et al. 2007

Experimental Parasitology

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Malaria is an infectious disease caused by protozoan parasites of the genus Plasmodium. The most virulent form of the disease is caused by P. falciparum which infects hundreds of millions of people and is responsible for the deaths of 1 to 2 million individuals each year. An essential part of the parasitic process is the remodeling of the red blood cell membrane and its protein constituents to permit a higher flux of nutrients and waste products into or away from the intracellular parasite. Much of this increased permeability is due to a single type of broad specificity channel variously called the new permeation pathway (NPP), the nutrient channel, and the Plasmodial surface anion channel (PSAC). This channel is permeable to a range of low molecular weight solutes both charged and uncharged, with a strong preference for anions. Drugs such as furosemide that are known to block anion-selective channels inhibit PSAC. In this study we have investigated a dye known as benzothiocarboxypurine, BCP, which had been studied as a possible diagnostic aid given its selective uptake by P. falciparum infected red cells. We found that the dye enters parasitized red cells via the furosemide-inhibitable PSAC, forms a brightly fluorescent complex with parasite nucleic acids, and is selectively toxic to infected cells. Our study describes an antimalarial agent that exploits the altered permeability of Plasmodium-infected red cells as a means to killing the parasite and highlights a chemical reagent that may prove useful in high throughput screening of compounds for inhibitors of the channel.

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Channels and transporters as drug targets in the Plasmodium-infected erythrocyte

Cited by 56 publications

References 92 publications

Aquaporin Water and Solute Channels from Malaria Parasites and Other Pathogenic Protozoa

Aquaporin Water and Solute Channels from Malaria Parasites and Other Pathogenic Protozoa

A genome-wide screen identifies yeast genes required for protection against or enhanced cytotoxicity of the antimalarial drug quinine

Selective killing of the human malaria parasite Plasmodium falciparum by a benzylthiazolium dye

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