ArticleCell host & microbe2013
Na(+) regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials.
Article in Cell host & microbe, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 122 papers.
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Who cites it
122 citing papers in PubMed, 238 citations in OpenAlex.
- A human microdose study of the antimalarial drug GSK3191607 in healthy volunteers.British journal of clinical pharmacology · 2018Trial
- Estimation of the In Vivo MIC of Cipargamin in Uncomplicated Plasmodium falciparum Malaria.Antimicrobial agents and chemotherapy · 2017Trial
- A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel antimalarial Spiroindolone KAE609 (Cipargamin) to assess its safety, tolerability, and pharmacokinetics in healthy adult volunteers.Antimicrobial agents and chemotherapy · 2014Trial
- Spiroindolone KAE609 for falciparum and vivax malaria.The New England journal of medicine · 2014Trial
- Review
- Article
- Deciphering Membrane Protein Complexes in Plasmodium falciparum Gametocytes via Integrative Structural Systems Biology.Molecular & cellular proteomics : MCP · 2026Article
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- Impacts of Cipargamin on NaMembranes · 2025Article
- Endogenous structure of antimalarial target PfATP4 reveals an apicomplexan-specific P-type ATPase modulator.Nature communications · 2025Article
- Identification of α-Azacyclic Acetamide-Based Inhibitors ofACS infectious diseases · 2025Article
- MappingbioRxiv : the preprint server for biology · 2025Article
- PfATP2 is a flippase on the Plasmodium falciparum surface that is important for growth and influences parasite sensitivity to antiplasmodial compounds.PLoS pathogens · 2025Article
- An all-in-one pipeline for the in vitro discovery and in vivo testing of Plasmodium falciparum malaria transmission blocking drugs.Nature communications · 2025Article
- Emerging Molecular Mechanisms in Malaria Pathogenesis and Novel Therapeutic Approaches: A Focus onBiomolecules · 2025Review
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- Insights into platelet factor 4-derived peptide macrocycles; the mechanistic basis of their rapid and selective antiplasmodial actions.Cellular and molecular life sciences : CMLS · 2025Article
- A review of natural products as a source of next-generation drugs against apicomplexan parasites.npj antimicrobials and resistance · 2025Review
- A Soluble Expression Construct of the Isolated Catalytic Domain of Plasmodium falciparum ATP4 Exhibits ATPase Activity Independent of a γ-Phosphate Receiving Aspartate.Molecular microbiology · 2025Article
62 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 4 institutions in 3 countries.
Funding
Abstract
The malaria parasite Plasmodium falciparum establishes in the host erythrocyte plasma membrane new permeability pathways that mediate nutrient uptake into the infected cell. These pathways simultaneously allow Na(+) influx, causing [Na(+)] in the infected erythrocyte cytosol to increase to high levels. The intraerythrocytic parasite itself maintains a low cytosolic [Na(+)] via unknown mechanisms. Here we present evidence that the intraerythrocytic parasite actively extrudes Na(+) against an inward gradient via PfATP4, a parasite plasma membrane protein with sequence similarities to Na(+)-ATPases of lower eukaryotes. Mutations in PfATP4 confer resistance to a potent class of antimalarials, the spiroindolones. Consistent with this, the spiroindolones cause a profound disruption in parasite Na(+) homeostasis, which is attenuated in parasites bearing resistance-conferring mutations in PfATP4. The mutant parasites also show some impairment of Na(+) regulation. Taken together, our results are consistent with PfATP4 being a Na(+) efflux ATPase and a target of the spiroindolones.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.