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The H89 cAMP-dependent protein kinase inhibitor blocks Plasmodium falciparum development in infected erythrocytes
1Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD, USA.
Abstract:
In Plasmodium falciparum, the causative agent of human malaria, the catalytic subunit gene of cAMP-dependent protein kinase (Pfpka-c) exists as a single copy. Interestingly, its expression appears developmentally regulated, being at higher levels in the pathogenic asexual stages than in the sexual forms of parasite that are responsible for transmission to the mosquito vector. Within asexual parasites, PfPKA activity can be readily detected in schizonts. Similar to endogenous PKA activity of noninfected red blood cells, the parasite enzyme can be stimulated by cAMP and inhibited by protein kinase inhibitor.Importantly, ex vivo treatment of infected erythrocytes with the classical PKA-C inhibitor H89 leads to a block in parasite growth. This suggests that the PKA activities of infected red blood cells are essential for parasite multiplication. Finally, structural considerations suggest that drugs targeting the parasite, rather than the erythrocyte enzyme, might be developed that could help in the fight against malaria.
Insights
The catalytic subunit of cAMP-dependent protein kinase (PKA) in Plasmodium falciparum is crucial for parasite multiplication. Inhibiting this PKA enzyme blocks malaria parasite growth, suggesting it as a potential drug target.
Area of Science:
- Malariology
- Parasitology
- Molecular Biology
Background:
- Plasmodium falciparum causes human malaria.
- cAMP-dependent protein kinase (PKA) is essential in eukaryotes.
- PKA's role in P. falciparum malaria parasites is not fully understood.
Purpose of the Study:
- To investigate the role of PKA in P. falciparum asexual stages.
- To determine if PKA is a potential drug target for malaria.
Main Methods:
- Studied the gene expression of Pfpka-c.
- Assayed PKA activity in infected red blood cells.
- Treated ex vivo infected erythrocytes with PKA-C inhibitor H89.
Main Results:
- Pfpka-c gene expression is higher in pathogenic asexual stages than sexual stages.
- PKA activity is detectable in schizonts and stimulated by cAMP.
- Inhibition of PKA with H89 blocked parasite growth.
Conclusions:
- PKA activity is essential for P. falciparum multiplication.
- Targeting parasite PKA, not host PKA, may yield effective malaria drugs.
