The Functioning of Na+-ATPases from Protozoan Parasites: Are These Pumps Targets for Antiparasitic Drugs?

Abstract

The ENA ATPases (from exitus natru: the exit of sodium) belonging to the P-type ATPases are structurally very similar to the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA); they exchange Na+ for H+ and, therefore, are also known as Na+-ATPases. ENA ATPases are required in alkaline milieu, as in the case for Aspergillus, where other transporters cannot mediate an uphill Na+ efflux. They are also important for salt tolerance, as described for Arabidopsis. During their life cycles, protozoan parasites might encounter a high pH environment, thus allowing consideration of ENA ATPases as possible targets for controlling certain severe parasitic diseases, such as Chagas’ Disease. Phylogenetic analysis has now shown that, besides the types IIA, IIB, IIC, and IID P-type ATPases, there exists a 5th subgroup of ATPases classified as ATP4-type ATPases, found in Plasmodium falciparum and Toxoplasma gondii. In malaria, for example, some drugs targeting PfATP4 destroy Na+ homeostasis; these drugs, which include spiroindolones, are now in clinical trials. The ENA P-type (IID P-type ATPase) and ATP4-type ATPases have no structural homologue in mammalian cells, appearing only in fungi, plants, and protozoan parasites, e.g., Trypanosoma cruzi, Leishmania sp., Toxoplasma gondii, and Plasmodium falciparum. This exclusivity makes Na+-ATPase a potential candidate for the biologically-based design of new therapeutic interventions; for this reason, Na+-ATPases deserves more attention.

Uncovering the antimalarial potential of toad venoms through a bioassay-guided fractionation process

“…The cation ATPase Pf P-type ATP 4 helps maintain the parasites Na + homeostasis through Na + ions efflux accompanied by an influx of H + . The inhibition of this pump leads to an accumulation of Na + within the parasitophorous vacuole that could disrupt the finely tuned ion equilibrium of the parasites and lead to their death ( Spillman and Kirk, 2015 ; Spillman et al, 2013 ; Flannery et al, 2015 ; Dick et al 2020 ; Gilson et al, 2019 ).…”

Down the membrane hole: Ion channels in protozoan parasites

“…Curiously, ouabain-sensitive Na + /K + ATPases, extremely abundant in mammalian cells, do not seem to play a significant role in ion homeostasis in protozoans; instead, Na + pumps are ubiquitously expressed. In Plasmodium falciparum PfATP4, initially described as a Ca 2+ pump [ 65 ], was later demonstrated to be a plasma membrane Na + efflux pump [ 66 , 67 ] associated with resistance to antimalarials [ 68 , 69 ]. TgATP4, a homolog found in Toxoplasma gondii , controls the cytosolic concentration of Na + [ 70 ].…”

Transporter-Mediated Solutes Uptake as Drug Target in Plasmodium falciparum

“…Tests of NITD609 in culture on several field isolates of P. falciparum and P. vivax , including drug resistant and susceptible isolates, resulted in the same inhibitory potential in the low nanomolar range ( Rottmann et al, 2010 ). The drug further inhibits gametocyte and oocyst development, acts faster than artemisinins, could cure in vivo infections with P. berghei in a single dose (100 mg/kg), and possesses favorable pharmacokinetic and pharmacodynamic properties ( Rottmann et al, 2010 ; Dick et al, 2020 ). NITD609 already concluded the first phase 2 clinical trial with another phase 2 trial planned for March 14, 2022 ( Novartis Pharmaceuticals 2022 ); accessed 18/02/2022).…”