Plasmodium falciparum phosphatidylinositol 4-kinase | Antimalarial targets | IUPHAR/MMV Guide to MALARIA PHARMACOLOGY

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Plasmodium falciparum phosphatidylinositol 4-kinase

Target id: 2972

Nomenclature: Plasmodium falciparum phosphatidylinositol 4-kinase

Abbreviated Name: PfPI4K

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

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Plasmodium falciparum 3D7 - 1559 PI4K phosphatidylinositol 4-kinase
Database Links
UniProtKB
Other Binding Ligands
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Ligand Sp. Action Value Parameter Reference
MMV048 Pf Binding 6.5 – 7.0 pKd 4
pKd 7.0 (Kd 1x10-7 M) [4]
pKd 6.5 (Kd 3x10-7 M) [4]
MMV024101 Pf3D7 - 6.2 pIC50 2
pIC50 6.2 (IC50 6x10-7 M) [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Whole Organism Assay Data Linked to This Target
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Ligand Sp. Assay description Type Action Value Parameter Reference
UCT943 Pb Parasite liver stage assay - - 9.0 pIC50 1
pIC50 9.0 (IC50 9.2x10-10 M) Luciferase bioluminescence assay to measure sporozoite invasion (prophylactic activity) [1]
Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
UCT943 PfHB3 Parasite growth inhibition assay - - 8.4 pIC50 1
pIC50 8.4 (IC50 3.7x10-9 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
UCT943 Pf7G8 Parasite growth inhibition assay - - 8.4 pIC50 1
pIC50 8.4 (IC50 4.1x10-9 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
UCT943 PfV1/S Parasite growth inhibition assay - - 8.4 pIC50 1
pIC50 8.4 (IC50 4.2x10-9 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
UCT943 PfK1 Parasite growth inhibition assay - - 8.3 pIC50 1
pIC50 8.3 (IC50 4.7x10-9 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
UCT943 PfD6 Parasite growth inhibition assay - - 8.3 pIC50 1
pIC50 8.3 (IC50 5.2x10-9 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
UCT943 PfNF54 Parasite growth inhibition assay - - 8.3 pIC50 1
pIC50 8.3 (IC50 5.4x10-9 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
UCT943 PfDd2 Parasite growth inhibition assay - - 8.2 pIC50 1
pIC50 8.2 (IC50 5.7x10-9 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
UCT943 Pc Parasite liver stage assay - - >8.0 pIC50 1
pIC50 >8.0 (IC50 <1x10-8 M) P. cynomolgi assay to assess inhibition of liver stage development (prophylactic activity) [1]
Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
MMV048 PfNF54 Parasite growth inhibition assay - - 7.6 pIC50 4
pIC50 7.6 (IC50 2.8x10-8 M) [3H]-hypoxanthine incorporation assay [4]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
compound 55 [PMID: 29889526] PfNF54 - - 7.2 pIC50 2
pIC50 7.2 (IC50 6.3x10-8 M) [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
UCT943 Pf Parasite dual gamete formation assay (DGFA) - - 7.1 pIC50 1
pIC50 7.1 (IC50 8x10-8 M) Reports on the functional viability of male and female mature stage V gametocytes [1]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
UCT943 Pf Parasite gametocyte viability assay - - 6.9 – 7.2 pIC50 1
pIC50 7.2 (IC50 6.6x10-8 M) Parasite late stage (IV-V) gametocyte assay using luciferase reporter line [1]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
pIC50 6.9 (IC50 1.34x10-7 M) Parasite early stage (I-III) gametocyte assay using luciferase reporter line [1]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
UCT943 Pf Standard membrane feeding assay (SMFA) - - 7.0 pIC50
pIC50 7.0 (IC50 9.6x10-8 M)
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
compound 55 [PMID: 29889526] PfK1 - - 7.0 pIC50 2
pIC50 7.0 (IC50 1.02x10-7 M) [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
MMV048 Pf Standard membrane feeding assay (SMFA) - - 6.9 pIC50 4
pIC50 6.9 (IC50 1.11x10-7 M) Indirect SMFA [4]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
MMV048 PfNF54 Parasite gametocyte viability assay - - 6.6 – 6.8 pIC50 4
pIC50 6.8 (IC50 1.4x10-7 M) Parasite late stage (IV-V) gametocyte assay using luciferase reporter line [4]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
pIC50 6.7 (IC50 2.14x10-7 M) Parasite early stage (I-III) gametocyte assay using luciferase reporter line [4]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
pIC50 6.6 (IC50 2.85x10-7 M) Parasite late stage (IV-V) gametocyte assay: parasitic lactate dehydrogenase (pLDH) assay [4]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
MMV024101 PfNF54 - - 6.3 pIC50 2
pIC50 6.3 (IC50 5.43x10-7 M) [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
MMV048 Pc Parasite liver stage assay - - 5.0 – 7.2 pIC50 4
pIC50 7.2 (IC50 6.1x10-8 M) P. cynomolgi assay to assess inhibition of liver stage development (prophylactic activity) [4]
Lifecycle stages: Plasmodium dormant liver stage (hypnozoite)
pIC50 7.2 (IC50 6.4x10-8 M) P. cynomolgi assay to assess inhibition of liver stage development (prophylactic activity) [4]
Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
pIC50 <5.0 (IC50 >1x10-5 M) P. cynomolgi assay to assess elimination of hypnozoites (potential as a radical cure) [4]
Lifecycle stages: Plasmodium dormant liver stage (hypnozoite)
Malaria Pharmacology Comments
The Plasmodium lipid kinase, phosphatidylinositol-4 kinase (PfPI4K), was first identified as the target of the imidazopyrazines, a novel class of experimental antimalarial compounds that have been shown to be active in multiple Plasmodium spp. and at each stage of malaria infection in the vertebrate host [3]. This study also reported that the imidazopyrazines act through inhibitory interaction with the ATP-binding pocket of the kinase and proposed that PfPI4K acts at the Golgi to regulate essential membrane trafficking events.

References

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1. Brunschwig C, Lawrence N, Taylor D, Abay E, Njoroge M, Basarab GS, Le Manach C, Paquet T, Cabrera DG, Nchinda AT et al.. (2018) UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria. Antimicrob. Agents Chemother., 62 (9). [PMID:29941635]

2. Kandepedu N, Gonzàlez Cabrera D, Eedubilli S, Taylor D, Brunschwig C, Gibhard L, Njoroge M, Lawrence N, Paquet T, Eyermann CJ et al.. (2018) Identification, Characterization, and Optimization of 2,8-Disubstituted-1,5-naphthyridines as Novel Plasmodium falciparum Phosphatidylinositol-4-kinase Inhibitors with in Vivo Efficacy in a Humanized Mouse Model of Malaria. J. Med. Chem., 61 (13): 5692-5703. [PMID:29889526]

3. McNamara CW, Lee MC, Lim CS, Lim SH, Roland J, Simon O, Yeung BK, Chatterjee AK, McCormack SL, Manary MJ et al.. (2013) Targeting Plasmodium PI(4)K to eliminate malaria. Nature, 504 (7479): 248-253. [PMID:24284631]

4. Paquet T, Le Manach C, Cabrera DG, Younis Y, Henrich PP, Abraham TS, Lee MCS, Basak R, Ghidelli-Disse S, Lafuente-Monasterio MJ et al.. (2017) Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase. Sci Transl Med, 9 (387). [PMID:28446690]

How to cite this page

Antimalarial targets: Plasmodium falciparum phosphatidylinositol 4-kinase. Last modified on 08/04/2019. Accessed on 18/08/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2972.