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Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase

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Target not currently curated in GtoImmuPdb

Malaria Pharmacology Ligand  Target has curated data in GtoMPdb

Target id: 2971

Nomenclature: Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase

Abbreviated Name: PfATP4

Family: Transporters (Plasmodium spp.)

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Plasmodium falciparum 3D7 - 1264 ATP4 non-SERCA-type Ca2+ -transporting P-ATPase
Previous and Unofficial Names Click here for help
P-type ATPase4 | Plasmodium falciparum ATPase4
Database Links Click here for help
PlasmoDB
UniProtKB
Whole Organism Assay Data Linked to This Target
Key to terms and symbols Click column headers to sort
Ligand Sp. Assay description Type Action Value Parameter Reference
PA21A092 Small molecule or natural product PfTM90C2B Parasite growth inhibition assay - - 7.9 pEC50 6
pEC50 7.9 (EC50 1.3x10-8 M) [3H]-hypoxanthine incorporation [6]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
PA21A092 Small molecule or natural product PfTM90C2A Parasite growth inhibition assay - - 7.8 pEC50 6
pEC50 7.8 (EC50 1.4x10-8 M) [3H]-hypoxanthine incorporation [6]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
PA21A092 Small molecule or natural product Pf3D7 Parasite growth inhibition assay - - 7.7 pEC50 6
pEC50 7.7 (EC50 1.8x10-8 M) [3H]-hypoxanthine incorporation [6]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
PA21A092 Small molecule or natural product PfFCR3 Parasite growth inhibition assay - - 7.7 pEC50 6
pEC50 7.7 (EC50 1.9x10-8 M) [3H]-hypoxanthine incorporation [6]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
(+)-SJ733 Small molecule or natural product PfDd2 Parasite growth inhibition assay - - 7.7 pEC50 3
pEC50 7.7 (EC50 2x10-8 M) SYBR Green I assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
PA21A092 Small molecule or natural product PfDd2 Parasite growth inhibition assay - - 7.7 pEC50 6
pEC50 7.7 (EC50 2.2x10-8 M) [3H]-hypoxanthine incorporation [6]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
(+)-SJ733 Small molecule or natural product Pf3D7 Parasite growth inhibition assay - - 7.5 pEC50 3
pEC50 7.5 (EC50 3x10-8 M) SYBR Green I assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
PA21A092 Small molecule or natural product PfHB3 Parasite growth inhibition assay - - 7.5 pEC50 6
pEC50 7.5 (EC50 3.2x10-8 M) [3H]-hypoxanthine incorporation [6]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
PA21A092 Small molecule or natural product PfV1/S Parasite growth inhibition assay - - 7.4 pEC50 6
pEC50 7.4 (EC50 3.8x10-8 M) [3H]-hypoxanthine incorporation [6]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
(+)-SJ733 Small molecule or natural product PfK1 Parasite growth inhibition assay - - 7.4 pEC50 3
pEC50 7.4 (EC50 4x10-8 M) SYBR Green I assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
PA21A092 Small molecule or natural product PfNF54 Parasite dual gamete formation assay (DGFA) - - 7.1 – 7.4 pEC50 6
pEC50 7.4 (EC50 3.9x10-8 M) inhibition of gamete formation from mature Stage V male gametocytes [6]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
pEC50 7.1 (EC50 7.4x10-8 M) inhibition of gamete formation from mature Stage V female gametocytes [6]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
(+)-SJ733 Small molecule or natural product PfV1/S Parasite growth inhibition assay - - 7.2 pEC50 3
pEC50 7.2 (EC50 6x10-8 M) SYBR Green I assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin Small molecule or natural product PfNF54 Parasite growth inhibition assay - - 9.3 pIC50 4
pIC50 9.3 (IC50 5x10-10 M) [3H]-hypoxanthine incorporation assay [4]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin Small molecule or natural product PfTM90C2A Parasite growth inhibition assay - - 9.3 pIC50 4
pIC50 9.3 (IC50 5x10-10 M) [3H]-hypoxanthine incorporation assay [4]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin Small molecule or natural product PfK1 Parasite growth inhibition assay - - 9.2 pIC50 4
pIC50 9.2 (IC50 6x10-10 M) [3H]-hypoxanthine incorporation assay [4]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin Small molecule or natural product Pf3D7 Parasite growth inhibition assay - - 9.1 pIC50 4
pIC50 9.1 (IC50 7x10-10 M) [3H]-hypoxanthine incorporation assay [4]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin Small molecule or natural product PfW2 Parasite growth inhibition assay - - 9.1 pIC50 4
pIC50 9.1 (IC50 9x10-10 M) [3H]-hypoxanthine incorporation assay [4]
cipargamin Small molecule or natural product PfTM91C235 Parasite growth inhibition assay - - 9.1 pIC50 4
pIC50 9.1 (IC50 9x10-10 M) [3H]-hypoxanthine incorporation assay [4]
cipargamin Small molecule or natural product PfD6 Parasite growth inhibition assay - - 9.0 pIC50 4
pIC50 9.0 (IC50 1x10-9 M) [3H]-hypoxanthine incorporation assay [4]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin Small molecule or natural product Pf7G8 Parasite growth inhibition assay - - 8.9 pIC50 4
pIC50 8.9 (IC50 1.2x10-9 M) [3H]-hypoxanthine incorporation assay [4]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin Small molecule or natural product PfV1/S Parasite growth inhibition assay - - 8.9 pIC50 4
pIC50 8.9 (IC50 1.4x10-9 M) [3H]-hypoxanthine incorporation assay [4]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
GSK030 Small molecule or natural product Pf Parasite growth inhibition assay - - 7.3 pIC50 1
pIC50 7.3 (IC50 5.2x10-8 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin Small molecule or natural product PfNF54 Parasite early stage (I–II) gametocyte assay - - - - 7
Giemsa-stained blood film counts: dose-dependent, significant inhibition of stage II gametocyte development [7]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
cipargamin Small molecule or natural product PfNF54 Parasite late stage (III–V) gametocyte assay - - - - 7
Giemsa-stained blood film counts: dose-dependent, inhibition of stage V gametocyte development [7]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
cipargamin Small molecule or natural product PfNF54 Standard membrane feeding assay (SMFA) - - - - 7
Oocyst count: significantly reduced count observed with the addition of cipargamin when compared to control feeds [7]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Malaria Pharmacology Comments
Mutations in PfATP4 have been shown to confer resistance by the Plasmodium parasite to the activity of a chemically diverse range of antimalarial drug candidates, including the spiroindolones, the dihydroisoquinolones and the aminopyrazoles [2-4]. Exposure of the parasite to these drug classes disrupts Na+ regulation [3,5], with the maintenance of a low cytosolic Na+ concentration essential for parasite survival during the intraerythrocytic stages of development. The exact interaction and mechanism by which these compounds lead to parasite death have not been fully elucidated, but host-mediated clearance of infected erythrocytes may be responsible for the rapid action of PfATP4 inhibitors [3].

References

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1. Diaz-Hernandez B., Fernandez Velando E.P., Wilson D.M. (2016) Thiotriazole compound and its use in parasitic protozoal infections. Patent number: WO2016102431A1. Assignee: GlaxoSmithKline. Priority date: 22/12/2014. Publication date: 30/06/2016.

2. Flannery EL, McNamara CW, Kim SW, Kato TS, Li F, Teng CH, Gagaring K, Manary MJ, Barboa R, Meister S et al.. (2015) Mutations in the P-type cation-transporter ATPase 4, PfATP4, mediate resistance to both aminopyrazole and spiroindolone antimalarials. ACS Chem Biol, 10 (2): 413-20. [PMID:25322084]

3. Jiménez-Díaz MB, Ebert D, Salinas Y, Pradhan A, Lehane AM, Myrand-Lapierre ME, O'Loughlin KG, Shackleford DM, Justino de Almeida M, Carrillo AK et al.. (2014) (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium. Proc Natl Acad Sci USA, 111 (50): E5455-62. [PMID:25453091]

4. Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J et al.. (2010) Spiroindolones, a potent compound class for the treatment of malaria. Science, 329 (5996): 1175-80. [PMID:20813948]

5. Spillman NJ, Allen RJ, McNamara CW, Yeung BK, Winzeler EA, Diagana TT, Kirk K. (2013) Na(+) regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials. Cell Host Microbe, 13 (2): 227-37. [PMID:23414762]

6. Vaidya AB, Morrisey JM, Zhang Z, Das S, Daly TM, Otto TD, Spillman NJ, Wyvratt M, Siegl P, Marfurt J et al.. (2014) Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum. Nat Commun, 5: 5521. [PMID:25422853]

7. van Pelt-Koops JC, Pett HE, Graumans W, van der Vegte-Bolmer M, van Gemert GJ, Rottmann M, Yeung BK, Diagana TT, Sauerwein RW. (2012) The spiroindolone drug candidate NITD609 potently inhibits gametocytogenesis and blocks Plasmodium falciparum transmission to anopheles mosquito vector. Antimicrob Agents Chemother, 56 (7): 3544-8. [PMID:22508309]

How to cite this page

Transporters (Plasmodium spp.): Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase. Last modified on 18/02/2021. Accessed on 31/07/2021. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2971.