Plasmodium falciparum cGMP-dependent protein kinase | Antimalarial targets | IUPHAR/MMV Guide to MALARIA PHARMACOLOGY

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Plasmodium falciparum cGMP-dependent protein kinase

Target id: 3013

Nomenclature: Plasmodium falciparum cGMP-dependent protein kinase

Abbreviated Name: PfPKG

Family: Antimalarial targets

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Plasmodium falciparum 3D7 - 853 PKG cGMP-dependent protein kinase
Database Links
PlasmoDB
UniProtKB
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of PF3D7_1436600
PDB Id:  5DYK
Resolution:  2.45Å
Species:  Plasmodium falciparum
References: 
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
ML10 Pf3D7 Inhibition 9.8 pIC50 2
pIC50 9.8 (IC50 1.6x10-10 M) [2]
Description: microfluidic mobility shift assay
MMV030084 Pf Inhibition 9.4 pIC50 3
pIC50 9.4 (IC50 4x10-10 M) [3]
Description: Kinase inhibition assay using recombinant PfPKG
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
ML10 Pf3D7 Parasite growth inhibition assay - - 8.7 pEC50 2
pEC50 8.7 (EC50 2.1x10-9 M) [3H]-hypoxanthine incorporation [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
MMV030084 Pf3D7 Parasite growth inhibition assay - - 7.0 pIC50 3
pIC50 7.0 (IC50 1.09x10-7 M) 72 hour growth inhibition assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
MMV030084 PfDd2 Parasite growth inhibition assay - - 6.9 pIC50 3
pIC50 6.9 (IC50 1.2x10-7 M) 72 hour growth inhibition assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
MMV030084 PfNF54 Parasite exflagellation assay - - 6.8 pIC50 3
pIC50 6.8 (IC50 1.41x10-7 M) Dual Gamete Formation Assay (DGFA): male gamete exflagellation was inhibited in the presence of MMV030084, but not when the compound was washed out prior to gamete formation. Activity against female gametes was not clearly identified [3]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
MMV030084 Pb Parasite liver stage assay - - 6.7 pIC50 3
pIC50 6.7 (IC50 1.99x10-7 M) Luciferase bioluminescence assay to measure sporozoite invasion into HepG2 liver cells (prophylactic activity) [3]
Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
Malaria Pharmacology Comments
The Plasmodium cGMP-dependent protein kinase (PfPKG) is an attractive target for next-generation antimalarials as it has been implicated in multiple cellular activities at various stages of the parasite lifecycle [1]. A medicinal chemistry programme has identified an imidazopyridine series that demonstrates promising activity and may warrant further development [2].

References

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1. Alam MM, Solyakov L, Bottrill AR, Flueck C, Siddiqui FA, Singh S, Mistry S, Viskaduraki M, Lee K, Hopp CS et al.. (2015) Phosphoproteomics reveals malaria parasite Protein Kinase G as a signalling hub regulating egress and invasion. Nat Commun, 6: 7285. [PMID:26149123]

2. Baker DA, Stewart LB, Large JM, Bowyer PW, Ansell KH, Jiménez-Díaz MB, El Bakkouri M, Birchall K, Dechering KJ, Bouloc NS et al.. (2017) A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission. Nat Commun, 8 (1): 430. [PMID:28874661]

3. Vanaerschot M, Murithi JM, Pasaje CFA, Ghidelli-Disse S, Dwomoh L, Bird M, Spottiswoode N, Mittal N, Arendse LB, Owen ES et al.. (2020) Inhibition of Resistance-Refractory P. falciparum Kinase PKG Delivers Prophylactic, Blood Stage, and Transmission-Blocking Antiplasmodial Activity. Cell Chem Biol, 27 (7): 806-816.e8. [PMID:32359426]

How to cite this page

Antimalarial targets: Plasmodium falciparum cGMP-dependent protein kinase. Last modified on 23/08/2020. Accessed on 25/09/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=3013.