Cyclic nucleotide-specific phosphodiesterases of Plasmodium falciparum: PfPDEα, a non-essential cGMP-specific PDE that is an integral membrane protein

Wentzinger, Laurent; Bopp, Selina; Tenor, Hermann; Klar, Jürgen; Brun, Reto; Beck, H. P.; Seebeck, Thomas

doi:10.1016/j.ijpara.2008.05.016

Cited by 43 publications

(65 citation statements)

References 48 publications

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“…The discrepancy in the asexual stage specificity of activity might be partly explained by the relative purity of parasite preparations between studies or the possibility that native PfPKG present in schizont lysates may already be fully activated and therefore not stimulated further by cGMP addition in kinase assays. Genes responsible for the synthesis (encoding guanylyl cyclase PfGC␣ [PF11_0395]) and hydrolysis (encoding phosphodiesterases PfPDE␣ [PFL0475w], a cGMP-PDE [30,32], and PfPDE␤ [MAL13P1.118], a PDE with potential for dual substrate specificity [30]) of cGMP also have peak mRNA expression in late schizonts (PlasmoDB). This further suggests a role for the cGMP signaling pathway at this stage of parasite development.…”

Section: Discussionmentioning

confidence: 99%

The Malaria Parasite Cyclic GMP-Dependent Protein Kinase Plays a Central Role in Blood-Stage Schizogony

Taylor

McRobert

Grainger³

et al. 2010

Eukaryot Cell

186

221

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A role for the Plasmodium falciparum cyclic GMP (cGMP)-dependent protein kinase (PfPKG) in gametogenesis in the malaria parasite was elucidated previously. In the present study we examined the role of PfPKG in the asexual blood-stage of the parasite life cycle, the stage that causes malaria pathology. A specific PKG inhibitor (compound 1, a trisubstituted pyrrole) prevented the progression of P. falciparum schizonts through to ring stages in erythrocyte invasion assays. Addition of compound 1 to ring-stage parasites allowed normal development up to 30 h postinvasion, and segmented schizonts were able to form. However, synchronized schizonts treated with compound 1 for >6 h became large and dysmorphic and were unable to rupture or liberate merozoites. To conclusively demonstrate that the effect of compound 1 on schizogony was due to its selective action on PfPKG, we utilized genetically manipulated P. falciparum parasites expressing a compound 1-insensitive PfPKG. The mutant parasites were able to complete schizogony in the presence of compound 1 but not in the presence of the broad-spectrum protein kinase inhibitor staurosporine. This shows that PfPKG is the primary target of compound 1 during schizogony and provides direct evidence of a role for PfPKG in this process. Discovery of essential roles for the P. falciparum PKG in both asexual and sexual development demonstrates that cGMP signaling is a key regulator of both of these crucial life cycle phases and defines this molecule as an exciting potential drug target for both therapeutic and transmission blocking action against malaria.

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Section: Discussionmentioning

confidence: 99%

The Malaria Parasite Cyclic GMP-Dependent Protein Kinase Plays a Central Role in Blood-Stage Schizogony

Taylor

McRobert

Grainger³

et al. 2010

Eukaryot Cell

186

221

View full text Add to dashboard Cite

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“…The synthesis of all the compounds derive from the key precursor 4 prepared by adaptation of literature methods (Scheme 1). Condensation of 4 with various carboxylic acids using PyBroP under microwave conditions yielded intermediate amides 5, which underwent base catalysed cyclisation to yield the desired pyrazolopyrimidinones (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). An N-methyl derivative 24 was prepared by direct methylation of 6 (see Supporting Information).…”

Section: Discovery Of 5-benzyl-3-isopropyl-1h-pyrazolo[43-d]pyrimidimentioning

confidence: 99%

Identification of Potent Phosphodiesterase Inhibitors that Demonstrate Cyclic Nucleotide-Dependent Functions in Apicomplexan Parasites

et al. 2015

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Apicomplexan parasites, including Plasmodium falciparum and Toxoplasma gondii, the causative agents of severe malaria and toxoplasmosis, respectively, undergo several critical developmental transitions during their lifecycle. Most important for human pathogenesis is the asexual cycle, in which parasites undergo rounds of host cell invasion, replication, and egress (exit), destroying host cell tissue in the process. Previous work has identified important roles for Protein Kinase G (PKG) and Protein Kinase A (PKA) in parasite egress and invasion, yet little is understood about the regulation of cyclic nucleotides, cGMP and cAMP, that activate these enzymes. To address this, we have focused upon the development of inhibitors of 3',5'-cyclic nucleotide phosphodiesterases (PDEs) to block the breakdown of cyclic nucleotides. This was done by repurposing human PDE inhibitors noting various similarities of the human and apicomplexan PDE binding sites. The most potent inhibitors blocked the in vitro proliferation of P. falciparum and T. gondii more potently than the benchmark compound zaprinast. 5-Benzyl-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (BIPPO) was found to be a potent inhibitor of recombinant P. falciparum PfPDEα and activated PKG-dependent egress of T. gondii and P. falciparum, likely by promoting the exocytosis of micronemes, an activity that was reversed by a specific Protein Kinase G inhibitor. BIPPO also promotes cAMP-dependent phosphorylation of a P. falciparum ligand critical for host cell invasion, suggesting that the compound inhibits single or multiple PDE isoforms that regulate both cGMP and cAMP levels. BIPPO is therefore a useful tool for the dissection of signal transduction pathways in apicomplexan parasites.

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“…An example of the latter strategy is to target phosphodiesterase (PDE) enzymes [8]. The PDEs are a superfamily of metal ion-dependent enzymes whose primary role is to terminate the cyclic nucleotide second Dedicated to the memory of Kate Burt.…”

Section: Introductionmentioning

confidence: 99%

Active site similarity between human and Plasmodium falciparum phosphodiesterases: considerations for antimalarial drug design

Howard

Thompson

Manallack

2011

J Comput Aided Mol Des

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The similarity between Plasmodium falciparum phosphodiesterase enzymes (PfPDEs) and their human counterparts have been examined and human PDE9A was found to be a suitable template for the construction of homology models for each of the four PfPDE isoforms. In contrast, the architecture of the active sites of each model was most similar to human PDE1. Molecular docking was able to model cyclic guanosine monophosphate (cGMP) substrate binding in each case but a docking mode supporting cyclic adenosine monophosphate (cAMP) binding could not be found. Anticipating the potential of PfPDE inhibitors as anti-malarial drugs, a range of reported PDE inhibitors including zaprinast and sildenafil were docked into the model of PfPDEα. The results were consistent with their reported biological activities, and the potential of PDE1/9 inhibitor analogues was also supported by docking.

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Cyclic nucleotide-specific phosphodiesterases of Plasmodium falciparum: PfPDEα, a non-essential cGMP-specific PDE that is an integral membrane protein

Cited by 43 publications

References 48 publications

The Malaria Parasite Cyclic GMP-Dependent Protein Kinase Plays a Central Role in Blood-Stage Schizogony

The Malaria Parasite Cyclic GMP-Dependent Protein Kinase Plays a Central Role in Blood-Stage Schizogony

Identification of Potent Phosphodiesterase Inhibitors that Demonstrate Cyclic Nucleotide-Dependent Functions in Apicomplexan Parasites

Active site similarity between human and Plasmodium falciparum phosphodiesterases: considerations for antimalarial drug design

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