Plasmodium falciparum ATPase4 | Antimalarial targets | IUPHAR/MMV Guide to MALARIA PHARMACOLOGY

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Plasmodium falciparum ATPase4

Target id: 2971

Nomenclature: Plasmodium falciparum ATPase4

Abbreviated Name: PfATP4

Family: Antimalarial targets

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Contents:

Gene and Protein Information
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
P-type ATPase4
Database Links
PlasmoDB PF3D7_1211900 (Pf3D7)
UniProtKB A0A143ZZK9 (Pf3D7)
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 PfTM90C2B

Plasmodium falciparum TM90C2B

P. falciparum TM90C2B (PfTM90C2B) is a clinical isolate, first described during a Phase 2 clinical trial to determine atovaquone efficacy in Thailand (PMID:8651372). A point mutation (Y268S) at the Qo site of cytochrome b results in a 3,000-fold loss of atovaquone sensitivity. It is used as a screening tool for the development of new cytochrome b inhibitors.
✖
 Parasite growth inhibition assay - - 7.9 pEC50 5
⤷ pEC50 7.9 (EC50 1.3x10-8 M) [3H]-hypoxanthine incorporation [5]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
PA21A092 PfTM90C2A

Plasmodium falciparum TM90C2A

P. falciparum TM90C2A (PfTM90C2A) is a clinical isolate, first described during a Phase 2 clinical trial to determine atovaquone efficacy in Thailand (PMID:8651372). PfTM90C2A is sensitive to atovaquone.
✖
 Parasite growth inhibition assay - - 7.8 pEC50 5
⤷ pEC50 7.8 (EC50 1.4x10-8 M) [3H]-hypoxanthine incorporation [5]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
PA21A092 Pf3D7

Plasmodium falciparum 3D7

P. falciparum strain 3D7 (Pf3D7) was derived from isolate NF54 by limiting dilution. The complete genome of Pf3D7 has been sequenced (GenBank: LN999946.1).
Pf3D7 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine.
✖
 Parasite growth inhibition assay - - 7.7 pEC50 5
⤷ pEC50 7.7 (EC50 1.8x10-8 M) [3H]-hypoxanthine incorporation [5]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
PA21A092 PfFCR3

Plasmodium falciparum FCR3

P. falciparum strain FCR3 (PfFCR3) was originally isolated from a patient in The Gambia, West Africa in 1976.
PfFCR3 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4). Differences in sensitivity of PfFCR3 clones to chloroquine have been reported, with the original isolate that was chloroquine sensitive rapidly acquiring resistance in culture (PMID: 7031656, PMID: 51801).
✖
 Parasite growth inhibition assay - - 7.7 pEC50 5
⤷ pEC50 7.7 (EC50 1.9x10-8 M) [3H]-hypoxanthine incorporation [5]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
(+)-SJ733 PfDd2

Plasmodium falciparum Dd2

P. falciparum strain Dd2 (PfDd2) is a clone derived from PfW2, following continuous culture in mefloquine. PfW2 was cloned from the Indochina III/CDC isolate, originally derived from a Laotian patient who failed chloroquine therapy.
PfDd2 can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine, pyrimethamine and mefloquine.
✖
 Parasite growth inhibition assay - - 7.7 pEC50 2
⤷ pEC50 7.7 (EC50 2x10-8 M) SYBR Green I assay [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
PA21A092 PfDd2

Plasmodium falciparum Dd2

P. falciparum strain Dd2 (PfDd2) is a clone derived from PfW2, following continuous culture in mefloquine. PfW2 was cloned from the Indochina III/CDC isolate, originally derived from a Laotian patient who failed chloroquine therapy.
PfDd2 can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine, pyrimethamine and mefloquine.
✖
 Parasite growth inhibition assay - - 7.7 pEC50 5
⤷ pEC50 7.7 (EC50 2.2x10-8 M) [3H]-hypoxanthine incorporation [5]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
(+)-SJ733 Pf3D7

Plasmodium falciparum 3D7

P. falciparum strain 3D7 (Pf3D7) was derived from isolate NF54 by limiting dilution. The complete genome of Pf3D7 has been sequenced (GenBank: LN999946.1).
Pf3D7 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine.
✖
 Parasite growth inhibition assay - - 7.5 pEC50 2
⤷ pEC50 7.5 (EC50 3x10-8 M) SYBR Green I assay [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
PA21A092 PfHB3

Plasmodium falciparum HB3

P. falciparum strain HB3 (PfHB3) was cloned from the Honduras I/CDC strain, originally isolated from a patient in Choluteca, Honduras, during an outbreak of urban malaria in January 1980.
PfHB3 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be chloroquine sensitive.
✖
 Parasite growth inhibition assay - - 7.5 pEC50 5
⤷ pEC50 7.5 (EC50 3.2x10-8 M) [3H]-hypoxanthine incorporation [5]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
PA21A092 PfV1/S

Plasmodium falciparum V1/S

P. falciparum strain V1/S (PfV1/S) is an in vitro culture-adapted clone of V1, that originated in Vietnam.
PfV1/S can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine and quinine.
✖
 Parasite growth inhibition assay - - 7.4 pEC50 5
⤷ pEC50 7.4 (EC50 3.8x10-8 M) [3H]-hypoxanthine incorporation [5]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
(+)-SJ733 PfK1

Plasmodium falciparum K1

P. falciparum strain K1 (PfK1) was isolated in Kanchanaburi, Thailand in 1979.
PfK1 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be a multidrug-resistant strain.
✖
 Parasite growth inhibition assay - - 7.4 pEC50 2
⤷ pEC50 7.4 (EC50 4x10-8 M) SYBR Green I assay [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
PA21A092 PfNF54

Plasmodium falciparum NF54

P. falciparum strain NF54 (PfNF54) was derived from a patient who had never left the Netherlands.
PfNF54 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine.
✖
 Parasite dual gamete formation assay (DGFA) - - 7.1 – 7.4 pEC50 5
⤷ pEC50 7.4 (EC50 3.9x10-8 M) inhibition of gamete formation from mature Stage V male gametocytes [5]
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 [5]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
(+)-SJ733 PfV1/S

Plasmodium falciparum V1/S

P. falciparum strain V1/S (PfV1/S) is an in vitro culture-adapted clone of V1, that originated in Vietnam.
PfV1/S can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine and quinine.
✖
 Parasite growth inhibition assay - - 7.2 pEC50 2
⤷ pEC50 7.2 (EC50 6x10-8 M) SYBR Green I assay [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin PfNF54

Plasmodium falciparum NF54

P. falciparum strain NF54 (PfNF54) was derived from a patient who had never left the Netherlands.
PfNF54 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine.
✖
 Parasite growth inhibition assay - - 9.3 pIC50 3
⤷ pIC50 9.3 (IC50 5x10-10 M) [3H]-hypoxanthine incorporation assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin PfTM90C2A

Plasmodium falciparum TM90C2A

P. falciparum TM90C2A (PfTM90C2A) is a clinical isolate, first described during a Phase 2 clinical trial to determine atovaquone efficacy in Thailand (PMID:8651372). PfTM90C2A is sensitive to atovaquone.
✖
 Parasite growth inhibition assay - - 9.3 pIC50 3
⤷ pIC50 9.3 (IC50 5x10-10 M) [3H]-hypoxanthine incorporation assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin PfK1

Plasmodium falciparum K1

P. falciparum strain K1 (PfK1) was isolated in Kanchanaburi, Thailand in 1979.
PfK1 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be a multidrug-resistant strain.
✖
 Parasite growth inhibition assay - - 9.2 pIC50 3
⤷ pIC50 9.2 (IC50 6x10-10 M) [3H]-hypoxanthine incorporation assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin Pf3D7

Plasmodium falciparum 3D7

P. falciparum strain 3D7 (Pf3D7) was derived from isolate NF54 by limiting dilution. The complete genome of Pf3D7 has been sequenced (GenBank: LN999946.1).
Pf3D7 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine.
✖
 Parasite growth inhibition assay - - 9.1 pIC50 3
⤷ pIC50 9.1 (IC50 7x10-10 M) [3H]-hypoxanthine incorporation assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin PfW2

Plasmodium falciparum W2

P. falciparum strain W2 (PfW2) was cloned from the Indochina III/CDC isolate, originally derived from a Laotian patient who failed chloroquine therapy.
PfW2 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine and susceptible to mefloquine.
✖
 Parasite growth inhibition assay - - 9.1 pIC50 3
⤷ pIC50 9.1 (IC50 9x10-10 M) [3H]-hypoxanthine incorporation assay [3]
cipargamin PfTM91C235

Plasmodium falciparum TM91C235

P. falciparum TM91C235 (PfTM91C235) is a clinical isolate from a patient in Thailand who failed mefloquine treatment twice. It can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine, sulfadoxime, pyrimethamine and quinine.
✖
 Parasite growth inhibition assay - - 9.1 pIC50 3
⤷ pIC50 9.1 (IC50 9x10-10 M) [3H]-hypoxanthine incorporation assay [3]
cipargamin PfD6

Plasmodium falciparum D6

P. falciparum strain D6 (PfD6) was collected in Sierra Leone.
PfD6 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is generally considered drug sensitive with minor mefloquine resistance.
✖
 Parasite growth inhibition assay - - 9.0 pIC50 3
⤷ pIC50 9.0 (IC50 1x10-9 M) [3H]-hypoxanthine incorporation assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin Pf7G8

Plasmodium falciparum 7G8

P. falciparum strain 7G8 (Pf7G8) was subcloned from the IMTM22 strain by limiting dilution. The original IMTM22 strain was isolated from a 12 year old male near Manaus, Brazil in 1980.
Pf7G8 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4). This strain is a gametocyte producer and is reported to be chloroquine-sensitive and pyrimethamine-resistant.
✖
 Parasite growth inhibition assay - - 8.9 pIC50 3
⤷ pIC50 8.9 (IC50 1.2x10-9 M) [3H]-hypoxanthine incorporation assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin PfV1/S

Plasmodium falciparum V1/S

P. falciparum strain V1/S (PfV1/S) is an in vitro culture-adapted clone of V1, that originated in Vietnam.
PfV1/S can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine and quinine.
✖
 Parasite growth inhibition assay - - 8.9 pIC50 3
⤷ pIC50 8.9 (IC50 1.4x10-9 M) [3H]-hypoxanthine incorporation assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin PfNF54

Plasmodium falciparum NF54

P. falciparum strain NF54 (PfNF54) was derived from a patient who had never left the Netherlands.
PfNF54 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine.
✖
 Parasite early stage (I–II) gametocyte assay - - - - 6
⤷ Giemsa-stained blood film counts: dose-dependent, significant inhibition of stage II gametocyte development [6]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
cipargamin PfNF54

Plasmodium falciparum NF54

P. falciparum strain NF54 (PfNF54) was derived from a patient who had never left the Netherlands.
PfNF54 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine.
✖
 Parasite late stage (III–V) gametocyte assay - - - - 6
⤷ Giemsa-stained blood film counts: dose-dependent, inhibition of stage V gametocyte development [6]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
cipargamin PfNF54

Plasmodium falciparum NF54

P. falciparum strain NF54 (PfNF54) was derived from a patient who had never left the Netherlands.
PfNF54 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine.
✖
 Standard membrane feeding assay (SMFA) - - - - 6
⤷ Oocyst count: significantly reduced count observed with the addition of cipargamin when compared to control feeds [6]
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 [1-3]. Exposure of the parasite to these drug classes disrupts Na+ regulation [2,4], 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 [2].

References

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1. 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]

2. 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. U.S.A., 111 (50): E5455-62. [PMID:25453091]

3. 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]

4. 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]

5. 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]

6. 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

Antimalarial targets: Plasmodium falciparum ATPase4. Last modified on 30/03/2020. Accessed on 13/07/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2971.