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Plasmodium falciparum cGMP-dependent protein kinase

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Target id: 3013

Nomenclature: Plasmodium falciparum cGMP-dependent protein kinase

Abbreviated Name: PfPKG

Family: Kinases (Plasmodium spp.)

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Plasmodium falciparum 3D7 - 853 PKG cGMP-dependent protein kinase
Previous and Unofficial Names Click here for help
PKG | Pf3D7_14_v3:1,490,321..1,494,453(-) | PF14_0346
Database Links Click here for help
Alphafold
PlasmoDB
UniProtKB
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of PF3D7_1436600
PDB Id:  5DYK
Resolution:  2.45Å
Species:  Plasmodium falciparum
References:  3
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
ML10 Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Pf3D7 Inhibition 9.8 pIC50 2
pIC50 9.8 (IC50 1.6x10-10 M) [2]
Description: microfluidic mobility shift assay
MMV030084 Small molecule or natural product Guide to Malaria Pharmacology Ligand Pf Inhibition 9.4 pIC50 4
pIC50 9.4 (IC50 4x10-10 M) [4]
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 Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand 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 Small molecule or natural product Guide to Malaria Pharmacology Ligand Pf3D7 Parasite growth inhibition assay - - 7.0 pIC50 4
pIC50 7.0 (IC50 1.09x10-7 M) 72 hour growth inhibition assay [4]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
MMV030084 Small molecule or natural product Guide to Malaria Pharmacology Ligand PfDd2 Parasite growth inhibition assay - - 6.9 pIC50 4
pIC50 6.9 (IC50 1.2x10-7 M) 72 hour growth inhibition assay [4]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
MMV030084 Small molecule or natural product Guide to Malaria Pharmacology Ligand PfNF54 Parasite exflagellation assay - - 6.8 pIC50 4
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 [4]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
MMV030084 Small molecule or natural product Guide to Malaria Pharmacology Ligand Pb Parasite liver stage assay - - 6.7 pIC50 4
pIC50 6.7 (IC50 1.99x10-7 M) Luciferase bioluminescence assay to measure sporozoite invasion into HepG2 liver cells (prophylactic activity) [4]
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. El Bakkouri M, Kouidmi I, Wernimont AK, Amani M, Hutchinson A, Loppnau P, Kim JJ, Flueck C, Walker JR, Seitova A et al.. (2019) Structures of the cGMP-dependent protein kinase in malaria parasites reveal a unique structural relay mechanism for activation. Proc Natl Acad Sci U S A, 116 (28): 14164-14173. [PMID:31239348]

4. 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

Kinases (Plasmodium spp.): Plasmodium falciparum cGMP-dependent protein kinase. Last modified on 11/10/2021. Accessed on 11/11/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=3013.