Phosphodiesterase delta governs the mechanical properties of erythrocytes infected with Plasmodium falciparum gametocytes

N’Dri, Marie-Esther; Tavella, Tatyana Almeida; Royer, Ludivine; Dupuy, Florian; Bedault, Laurianne; Verdier, Frédérique; Lavazec, Catherine

doi:10.1016/j.micinf.2023.105102

Cited by 2 publications

(1 citation statement)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PKA activity was shown to contribute to the stiffness of immature gametocyte-infected erythrocytes (GIE). Rising expression of PfPDEδ in mature gametocyte stages is correlated with a drop in cAMP levels and an increase in infected erythrocyte deformability ( 29 , 40 ), raising the possibility that PfPDEδ displays some cAMP hydrolytic activity, which was further suggested by the characterization of the enzymatic activity of the recombinant catalytic domain of PfPDEδ ( 41 ) ( Fig. 2A ).…”

Section: Cyclic Nucleotide Signaling In Plasmodiummentioning

confidence: 95%

Apicomplexan phosphodiesterases in cyclic nucleotide turnover: conservation, function, and therapeutic potential

Moss,

Brusini,

Kuehnel

et al. 2024

mBio

View full text Add to dashboard Cite

Apicomplexa encompasses a large number of intracellular parasites infecting a wide range of animals. Cyclic nucleotide signaling is crucial for a variety of apicomplexan life stages and cellular processes. The cyclases and kinases that synthesize and respond to cyclic nucleotides (i.e., 3′,5′-cyclic guanosine monophosphate and 3′,5′-cyclic adenosine monophosphate) are highly conserved and essential throughout the parasite phylum. Growing evidence indicates that phosphodiesterases (PDEs) are also critical for regulating cyclic nucleotide signaling via cyclic nucleotide hydrolysis. Here, we discuss recent advances in apicomplexan PDE biology and opportunities for therapeutic interventions, with special emphasis on the major human apicomplexan parasite genera Plasmodium , Toxoplasma , Cryptosporidium , and Babesia . In particular, we show a highly flexible repertoire of apicomplexan PDEs associated with a wide range of cellular requirements across parasites and lifecycle stages. Despite this phylogenetic diversity, cellular requirements of apicomplexan PDEs for motility, host cell egress, or invasion are conserved. However, the molecular wiring of associated PDEs is extremely malleable suggesting that PDE diversity and redundancy are key for the optimization of cyclic nucleotide turnover to respond to the various environments encountered by each parasite and life stage. Understanding how apicomplexan PDEs are regulated and integrating multiple signaling systems into a unified response represent an untapped avenue for future exploration.

show abstract

Section: Cyclic Nucleotide Signaling In Plasmodiummentioning

confidence: 95%

Apicomplexan phosphodiesterases in cyclic nucleotide turnover: conservation, function, and therapeutic potential

Moss,

Brusini,

Kuehnel

et al. 2024

mBio

View full text Add to dashboard Cite

show abstract

Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission

Gomez-Gonzalez,

Gupta,

Drought

et al. 2024

Sci. Adv.

View full text Add to dashboard Cite

Cyclic nucleotide–dependent phosphodiesterases (PDEs) play essential roles in regulating the malaria parasite life cycle, suggesting that they may be promising antimalarial drug targets. PDE inhibitors are used safely to treat a range of noninfectious human disorders. Here, we report three subseries of fast-acting and potent Plasmodium falciparum PDEβ inhibitors that block asexual blood-stage parasite development and that are also active against human clinical isolates. Two of the inhibitor subseries also have potent transmission-blocking activity by targeting PDEs expressed during sexual parasite development. In vitro drug selection experiments generated parasites with moderately reduced susceptibility to the inhibitors. Whole-genome sequencing of these parasites detected no mutations in PDEβ but rather mutations in downstream effectors: either the catalytic or regulatory subunits of cyclic adenosine monophosphate–dependent protein kinase (PKA) or in the 3-phosphoinositide-dependent protein kinase that is required for PKA activation. Several properties of these P. falciparum PDE inhibitor series make them attractive for further progression through the antimalarial drug discovery pipeline.

show abstract

Phosphodiesterase delta governs the mechanical properties of erythrocytes infected with Plasmodium falciparum gametocytes

Cited by 2 publications

References 43 publications

Apicomplexan phosphodiesterases in cyclic nucleotide turnover: conservation, function, and therapeutic potential

Apicomplexan phosphodiesterases in cyclic nucleotide turnover: conservation, function, and therapeutic potential

Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission

Contact Info

Product

Resources

About