The H89 cAMP-dependent protein kinase inhibitor blocks Plasmodium falciparum development in infected erythrocytes

C Syin; D Parzy; F Traincard; I Boccaccio; M B Joshi; D T Lin; X M Yang; K Assemat; C Doerig; G Langsley

doi:10.1046/j.1432-1327.2001.02403.x

The H89 cAMP-dependent protein kinase inhibitor blocks Plasmodium falciparum development in infected erythrocytes

Eur J Biochem. 2001 Sep;268(18):4842-9. doi: 10.1046/j.1432-1327.2001.02403.x.

Authors

C Syin¹, D Parzy, F Traincard, I Boccaccio, M B Joshi, D T Lin, X M Yang, K Assemat, C Doerig, G Langsley

Affiliation

¹ Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD, USA.

PMID: 11559352
DOI: 10.1046/j.1432-1327.2001.02403.x

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Amino Acid Sequence
Animals
Antimalarials / pharmacology
Blotting, Western
Catalytic Domain
Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors*
Cyclic AMP-Dependent Protein Kinases / genetics
Cyclic AMP-Dependent Protein Kinases / metabolism
Drug Design
Enzyme Inhibitors / pharmacology*
Erythrocytes / drug effects
Erythrocytes / parasitology*
Gene Expression Regulation, Developmental
Humans
Inhibitory Concentration 50
Isoquinolines / pharmacology*
Models, Molecular
Molecular Sequence Data
Plasmodium falciparum / drug effects*
Plasmodium falciparum / enzymology
Plasmodium falciparum / genetics
Plasmodium falciparum / growth & development*
Protein Conformation
Protein Subunits
RNA, Messenger / genetics
RNA, Messenger / metabolism
Sequence Alignment
Sulfonamides*

Substances

Antimalarials
Enzyme Inhibitors
Isoquinolines
Protein Subunits
RNA, Messenger
Sulfonamides
Cyclic AMP-Dependent Protein Kinases
N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide