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

Abstract

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.

A Nature-Inspired Betalainic Probe for Live-Cell Imaging of Plasmodium-Infected Erythrocytes

“…[9] A single type of broad-specificity channel, variously called the new permeation pathway (NPP), the nutrient channel, or the plasmodial surface anion channel, is responsible for the increased permeability of low molecular weight solutes, both charged and uncharged, with a strong preference for anions. [10].…”

Development of Plasmodium falciparum Protease Inhibitors in the Past Decade (2002–2012)

“…For instance, there are different biosynthesis pathways today used as targets for the discovery of antimalarial drugs such as the folate biosynthesis pathway [11][12][13]. The second target category includes pathways which mediate the uptake of nutrients into cells and the generation and maintenance of transmembrane electrochemical gradients, for instance, the plasmodial surface anion channel (PSAC) [14][15][16]. Other examples which fall within this target category are enzymes whose substrates are involved in intracellular signal transduction, for instance, farnesyltransferase [17][18][19].…”

Effect of Solanum nudum steroids on uninfected and Plasmodium falciparum-infected erythrocytes

“…The changes in parasitised red blood cells (pRBCs) are intimately connected to Plasmodium biology and are involved in nutrient acquisition through new permeability pathways (NPPs), which become apparent in trophozoite stages approximately 12-15 h post-invasion of the merozoite into the red blood cells (RBC) (Kirk 2001). The NPPs allow metabolic and biosynthetic substrate uptake of inorganic and organic ions, amino acids, sugars and nucleosides (Kirk 2001, Staines et al 2004b, Bokhari et al 2008 ; currently, parasite-induced permeability pathways are considered attractive chemotherapeutic targets (Staines et al 2005, Kelly et al 2007, Lopez & Segura 2008.…”